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Transcranial low level laser (light) therapy for traumatic brain injury
Abstract
We review the use of transcranial low-level laser (light) therapy (LLLT) as a possible treatment for traumatic-brain injury (TBI). The basic mechanisms of LLLT at the cellular and molecular level and its effects on the brain are outlined. Many interacting processes may contribute to the beneficial effects in TBI including neuroprotection, reduction of inflammation and stimulation of neurogenesis. Animal studies and clinical trials of transcranial-LLLT for ischemic stroke are summarized. Several laboratories have shown that LLLT is effective in increasing neurological performance and memory and learning in mouse models of TBI. There have been case report papers that show beneficial effects of transcranial-LLLT in a total of three patients with chronic TBI. Our laboratory has conducted three studies on LLLT and TBI in mice. One looked at pulsed-vs-continuous wave laser-irradiation and found 10 Hz to be superior. The second looked at four different laser-wavelengths (660, 730, 810, and 980 nm); only 660 and 810 nm were effective. The last looked at different treatment repetition regimens (1, 3 and 14-daily laser-treatments). (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim).
... LLLT is a technique of NIBS that the irradiation of specific infrared wavelengths is able to penetrate deeply into the brain [22]. These effects produce many biological responses, such as affecting the forming of adenosine triphosphate (ATP), increasing deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), releasing nitric oxide (NO), cytochrome c oxidase (CCO), regulating reactive oxygen species (ROS), and modifying intracellular organelle membrane activity particularly in mitochondria, calcium flux, and stress proteins [23][24][25]. LLLT produces a shift toward higher oxidation in the overall cell redox potential [26] and briefly increases the level of ROS [27]. This change in the redox state of the mitochondria regulates several transcription factors [28]. ...
... Beck Depression Inventory (BDI-II), used to assess depressive symptoms, classified as minimal (0-11 scores), mild (12)(13)(14)(15)(16)(17)(18)(19), moderate (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), and severe Sequence Numbers and Letters (Wechsler subscale -WAIS-III), used to evaluate working memory, random numbers, and letters is presented orally to the patient and must be mentally organized and immediately reported to the examiner with the following rule: first the crescent numbers then the letters (in alphabetical order). In test difficulty increases the patients correctly perform the task [49]; Digit Span (DS) Forward and Backwards (WAIS-III), the DS assesses working memory. ...
... LLLT can modulate many biological effects penetrating the scalp into the brain [25], playing a role improving the outcome of the patients in two different ways, depending on the stage of the trauma. In the acute phase after TBI, the initial neuronal injury occurs instantly and oftentimes causes irreversible damage to the central nervous system, due to impairment of neuronal cell functions, including mitochondria, and glia cells [18,58]. ...
Background
Photobiomodulation describes the use of red or near-infrared light to stimulate or regenerate tissue. It was discovered that near-infrared wavelengths (800–900 nm) and red (600 nm) light-emitting diodes (LED) are able to penetrate through the scalp and skull and have the potential to improve the subnormal cellular activity of compromised brain tissue. Different experimental and clinical studies were performed to test LED therapy for traumatic brain injury (TBI) with promising results. One of the proposals of this present study is to develop different approaches to maximize the positive effects of this therapy and improve the quality of life of TBI patients.
Methods/design
This is a double-blinded, randomized, controlled trial of patients with diffuse axonal injury (DAI) due to a severe TBI in an acute stage (less than 8 h). Thirty two patients will be randomized to active coil helmet and inactive coil (sham) groups in a 1:1 ratio. The protocol includes 18 sessions of transcranial LED stimulation (627 nm, 70 mW/cm², 10 J/cm²) at four points of the frontal and parietal regions for 30 s each, totaling 120 s, three times per week for 6 weeks, lasting 30 min. Patients will be evaluated with the Glasgow Outcome Scale Extended (GOSE) before stimulation and 1, 3, and 6 months after the first stimulation. The study hypotheses are as follows: (1) transcranial LED therapy (TCLT) will improve the cognitive function of DAI patients and (2) TCLT will promote beneficial hemodynamic changes in cerebral circulation.
Discussion
This study evaluates early and delayed effects of TCLT on the cognitive rehabilitation for DAI following severe acute TBI. There is a paucity of studies regarding the use of this therapy for cognitive improvement in TBI. There are some experimental studies and case series presenting interesting results for TBI cognitive improvement but no clinical trials.
Trial registration
ClinicalTrials.gov, NCT03281759. Registered on 13 September 2017.
... LLLT is a technique of NIBS that the irradiation of specific infrared wavelengths is able to penetrate deeply into the brain [22]. These effects produce many biological responses, such as affecting the forming of adenosine triphosphate (ATP), increasing deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), releasing nitric oxide (NO), cytochrome c oxidase (CCO), regulating reactive oxygen species (ROS), and modifying intracellular organelle membrane activity particularly in mitochondria, calcium flux, and stress proteins [23][24][25]. LLLT produces a shift toward higher oxidation in the overall cell redox potential [26] and briefly increases the level of ROS [27]. This change in the redox state of the mitochondria regulates several transcription factors [28]. ...
... Beck Depression Inventory (BDI-II), used to assess depressive symptoms, classified as minimal (0-11 scores), mild (12)(13)(14)(15)(16)(17)(18)(19), moderate (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), and severe Sequence Numbers and Letters (Wechsler subscale -WAIS-III), used to evaluate working memory, random numbers, and letters is presented orally to the patient and must be mentally organized and immediately reported to the examiner with the following rule: first the crescent numbers then the letters (in alphabetical order). In test difficulty increases the patients correctly perform the task [49]; Digit Span (DS) Forward and Backwards (WAIS-III), the DS assesses working memory. ...
... LLLT can modulate many biological effects penetrating the scalp into the brain [25], playing a role improving the outcome of the patients in two different ways, depending on the stage of the trauma. In the acute phase after TBI, the initial neuronal injury occurs instantly and oftentimes causes irreversible damage to the central nervous system, due to impairment of neuronal cell functions, including mitochondria, and glia cells [18,58]. ...
Background:
Photobiomodulation using low-level laser therapy (LLLT) has been tested as a new technique to optimize recovery of patients with traumatic brain injury (TBI). The aim of this study is to evaluate inhibitory attentional control after 18 sessions of active LLLT and compare with the placebo group (sham LLLT). Our exploratory analysis will evaluate the efficacy of the active LLLT on verbal and visuospatial episodic memory, executive functions (working memory, verbal and visuospatial fluency, attentional processes), and anxiety and depressive symptoms compared to the sham group.
Methods/design:
A randomized double-blinded trial will be made in 36 patients with moderate and severe TBI. The active LLLT will use an optical device composed of LEDs emitting 632 nm of radiation at the site with full potency of 830 mW. The cranial region with an area of 400 cm2 will be irradiated for 30 min, giving a total dose per session of 3.74 J/cm2. The sham LLLT group contains only an LED device with power < 1 mW, only serving to simulate the irradiation. Each patient will be irradiated three times per week for six weeks, totaling 18 sessions. Neuropsychological assessments will be held one week before the beginning of the sessions, after one week, and three months after the end of LLLT sessions. Memory domain, attention, executive functioning, and visual construction will be evaluated, in addition to symptoms of depression, anxiety, and social demographics.
Discussion:
LLLT has been demonstrated as a safe and effective technique in significantly improving the memory, attention, and mood performance in healthy and neurologic patients. We expect that our trial can complement previous finds, as an effective low-cost therapy to improve cognitive sequel after TBI.
Trial registration:
ClinicalTrials.gov, NCT02393079 . Registered on 20 February 2015.
... The enhancement of ATP can increase oxygen consumption and improve cerebellar metabolism [18]. This mechanism facilitates formation of new synaptic connections between neurons [18,24]. ...
... the coherence was calculated for each segment between all pairs of electrodes (totally 171 pairs) in different frequencies. Then the values between each pair were averaged over all segments and all frequencies in the specific EEG bands, i.e. delta (1-3.5 Hz), theta (4-7.5 Hz), alpha (8-12.5 Hz), beta1 (13-15.5 Hz), beta2 (16-18.5 Hz), beta3 (18.5-22.5 Hz), beta4 (23)(24)(25)(26)(27)(28)(29)(30). The coherence was calculated based on: ...
Objective. Transcranial photobiomodulation (tPBM) is a recently proposed non-invasive brain stimulation approach with various effects on the nervous system from the cells to the whole brain networks. Specially in the neural network level, tPBM can alter the topology and synchronizability of functional brain networks. However, the functional properties of the neural networks after tPBM are still poorly clarified.Approach. Here, we employed electroencephalography and different methods (conventional and spectral) in the graph theory analysis to track the significant effects of tPBM on the resting state brain networks. The non-parametric statistical analysis showed that just one short-term tPBM session over right medial frontal pole can significantly change both topological (i.e. clustering coefficient, global efficiency, local efficiency, eigenvector centrality) and dynamical (i.e. energy, largest eigenvalue, and entropy) features of resting state brain networks.Main results. The topological results revealed that tPBM can reduce local processing, centrality, and laterality. Furthermore, the increased centrality of central electrode was observed.Significance. These results suggested that tPBM can alter topology of resting state brain network to facilitate the neural information processing. On the other hand, the dynamical results showed that tPBM reduced stability of synchronizability and increased complexity in the resting state brain networks. These effects can be considered in association with the increased complexity of connectivity patterns among brain regions and the enhanced information propagation in the resting state brain networks. Overall, both topological and dynamical features of brain networks suggest that although tPBM decreases local processing (especially in the right hemisphere) and disrupts synchronizability of network, but it can increase the level of information transferring and processing in the brain network.
... Antioxidants 2020, 9, 248 2 of 15 nervous system disorders by affecting synaptic plasticity, elevating neurotrophic factors, offering neuroprotection, fostering maintenance of the blood-brain barrier, and inducing cell proliferation, antioxidant activity, anti-inflammatory and anti-apoptosis effects [15,16]. Low-intensity laser therapy has been used in neurorehabilitation and in cases of cognitive dysfunction and traumatic brain injury [17,18]. Moreover, laser acupuncture (LA), the combination of low-intensity laser therapy and acupuncture, has also been widely used for several disorders [19]. ...
... Electroacupuncture (EA), a combination of modern electric stimulation and acupuncture, have been reported to be effective for treating numerous acupuncture, have been reported to be effective for treating numerous nervous system disorders by affecting synaptic plasticity, elevating neurotrophic factors, offering neuroprotection, fostering maintenance of the blood-brain barrier, and inducing cell proliferation, antioxidant activity, antiinflammatory and anti-apoptosis effects [15,16]. Low-intensity laser therapy has been used in neurorehabilitation and in cases of cognitive dysfunction and traumatic brain injury [17,18]. Moreover, laser acupuncture (LA), the combination of low-intensity laser therapy and acupuncture, has also been widely used for several disorders [19]. ...
In this article, we review how acupuncture regulates oxidative stress to prevent ischemia–reperfusion injury. We electronically searched databases, including PubMed, Clinical Key and the Cochrane Library, from their inception to November 2019 by using the following medical subject headings and keywords: acupuncture, ischemia-reperfusion injury, oxidative stress, reactive oxygen species, and antioxidants. We concluded that acupuncture is effective in treating oxidation after ischemia-reperfusion injury. In addition to increasing the activity of antioxidant enzymes and downregulating the generation of reactive oxygen species (ROS), acupuncture also repairs the DNA, lipids, and proteins attacked by ROS and mediates downstream of the ROS pathway to apoptosis.
... Laser technologies are successfully used in a wide variety of medical fields such as surgery [1][2][3][4][5], therapy [5,6], cosmetology [7][8][9][10] and for effective treatment of medical instruments [11]. The use of lasers in medicine is based on the management of biological, physical and chemical processes during laser irradiation of biological tissue [12]. ...
... The carbonization (charring) leads to an increase in effective absorption of hard biological tissue [12]. Therefore, the obtained discrepancy can be eliminated, if we allow for a change in optical characteristics of bone tissue (α and A) at the repetition rate of 15 kHz due to its carbonization in Eq. (6). It should be noted that in different papers the carbonization temperatures have significantly different values from more than 100 to 300 °C [12,18,[44][45][46][47].This is due to the effect of the exposure time on the result of laser treatment and the specificity of particular biological tissue. ...
An analytical model is presented that qualitatively describes the cooling of a biological tissue after irradiation with short and ultrashort laser pulses. The assumption that the distribution of temperature at the initial moment of surface cooling repeats the distribution of the absorbed laser energy allowed us to use the thermal conductivity approximation in both cases. The experimental results of irradiation of dry bone with nanosecond and femtosecond laser pulses are compared with the calculated data. The necessity of taking into account the change in the optical parameters of hard tissue in the field of laser irradiation during its treatment by nanosecond and femtosecond laser pulses and the key role of residual heating in its carbonization around the exposure region is shown. The application of the model to a particular biological tissue can significantly simplify the search for optimal parameters of lasers for surgical procedures.
... NF-jB also stimulates expression of genes related to cellular proliferation and migration, and also modulates production of cytokines and growth factors. 13 In small-animal studies, vascular endothelial growth factor (VEGF; a well-known factor for stimulating angiogenesis) has also been reported to enhance neurogenesis (the formation of new neurons or brain cells) in damaged brain. Neurogenesis directly improves the self-repair capacity of the brain. ...
... The anti-inflammatory, antiedema, and proangiogenic properties of PBMT taken together suggest that this form of therapy could also be effective in treating acute stroke. 13,16 Neurogenesis is the term for differentiation of progenitor cells into newly formed neurons, and within the brain this occurs initially in the hippocampus or subventricular zone, and then, the cells migrate to the location in the brain where they are needed. Synaptogenesis is the formation of new synapses, or connections between existing neurons, and is among the most important mechanisms the brain uses to recover from acute TBI or stroke. ...
Objective: We review the general topic of traumatic brain injury (TBI) and our research utilizing transcranial photobiomodulation (tPBM) to improve cognition in chronic TBI using red/near-infrared (NIR) light-emitting diodes (LEDs) to deliver light to the head. tPBM improves mitochondrial function increasing oxygen consumption, production of adenosine triphosphate (ATP), and improving cellular energy stores. Nitric oxide is released from the cells increasing regional blood flow in the brain. Review of published studies: In our previously published study, 11 chronic TBI patients with closed-head TBI caused by different accidents (motor vehicle accident, sports-related, improvised explosive device blast injury) and exhibiting long-lasting cognitive dysfunction received 18 outpatient treatments (Monday, Wednesday, Friday for 6 weeks) starting at 10 months to 8 years post-TBI. LED therapy is nonthermal, painless, and noninvasive. An LED-based device classified as nonsignificant risk (FDA cleared) was used. Each LED cluster head (5.35 cm diameter, 500mW, 22.2 mW/cm2) was applied for 9 min 45 sec (13 J/cm2) using 11 locations on the scalp: midline from front-to-back hairline and bilaterally on frontal, parietal, and temporal areas. Testing was performed before and after transcranial LED (tLED; at 1 week, 1 month, and at 2 months after the 18th treatment) and showed significant improvements in executive function and verbal memory. There were also fewer post-traumatic stress disorder (PTSD) symptoms reported. Ongoing studies: Ongoing, current studies involve TBI patients who have been treated with tLED using either 26 J/cm2 per LED location on the head or treated with intranasal only (iLED) using red (633 nm) and NIR (810 nm) diodes placed into the nostrils. The NIR iLED is hypothesized to deliver photons to the hippocampus, and the red 633 nm iLED is believed to increase melatonin. Results have been similar to the previously published tLED study. Actigraphy sleep data showed increased time asleep (on average one additional hour per night) after the 18th tLED or iLED treatment. LED treatments may be performed in the home. Sham-controlled studies with veterans who have cognitive dysfunction from Gulf War Illness, blast TBI, and TBI/PTSD are currently ongoing.
... In fact, different preclinical studies suggest the applicability of PBM-induced biological effects to wound healing, 22 muscle regeneration, [23][24][25] and neuropathic pain, 26,27 among others. PBM has also been used to treat acute stroke, traumatic brain injury, 28 and several neurological and affective disorders, including MDD. 29 In psychiatry, most studies have investigated the potential of PBM (especially t-PBM) in the range of NIR (750-1400 nm) or red (620-750 nm) spectra. 18 t-PBM encompasses a variety of procedures involving the placement of one or multiple light sources on specific areas of the head. ...
Incompletely treated major depressive disorder (MDD) poses an enormous global health burden. Conventional treatment for MDD consists of pharmacotherapy and psychotherapy, though a significant number of patients do not achieve remission with such treatments. Transcranial photobiomodulation (t-PBM) is a promising novel therapy that uses extracranial light, especially in the near-infrared (NIR) and red spectra, for biological and therapeutic effects. The aims of this Review are to evaluate the current clinical and preclinical literature on t-PBM in MDD and to discuss candidate mechanisms for effects of t-PBM in MDD, with specific attention to biophotons and oxidative stress. A search on PubMed and ClinicalTrials.gov identified clinical and preclinical studies using t-PBM for the treatment of MDD as a primary focus. After a systematic screening, only 19 studies containing original data were included in this review (9 clinical and 10 preclinical trials). Study results demonstrate consensus that t-PBM is a safe and potentially effective treatment; however, varying treatment parameters among studies complicate definitive conclusions about efficacy. Among other mechanisms of action, t-PBM stimulates the complex IV of the mitochondrial respiratory chain and induces an increase in cellular energy metabolism. We suggest that future trials include biological measures to better understand the mechanisms of action of t-PBM and to optimize treatment efficiency. Of particular interest going forward will be studying potential effects of t-PBM-an external light source on the NIR spectra-on neural circuitry implicated in depression.
... In addition, the same effect is observed in the neurogenic band of bCONCCO. This desynchronization is supported by the locally-driven nature of photo-oxidation of CCO in mitochondria[176][177][178], especially in axon terminals of the cortical neurons where the release of neurotransmitters modulates the oscillation in the neurogenic band. Another indication of the location-related effect of tPBM is the myogenic band of bCONCCO where the right and left 800-nm lasers resulted in opposite modulation of bilateral metabolic connectivity. ...
Transcranial photobiomodulation (tPBM) targets the human brain with near-infrared (NIR) light and is shown to affect human cognitive performance and neural electrophysiological activity as well as concentration changes of oxidized cytochrome-c-oxidase ([CCO]) and hemoglobin oxygenation ([HbO]) in human brain.
Brain topographical connectivity, which shows the communication between regions of the brain, and its alteration can be assessed to quantify the effects of external stimuli, diseases, and cognitive decline, in resting-state or task-based measurements. Furthermore, understanding the interactions between different physiological representations of neural activity, namely electrophysiological, hemodynamic, and metabolic signals in the human brain, has been an important topic among researchers in recent decades. In my doctoral study, neurophysiological networks were constructed using frequency-domain analyses on oscillations of electroencephalogram (EEG), [CCO], and [HbO] time series that were acquired by a portable EEG and 2-channel broadband near-infrared spectroscopy (2-bbNIRS).
Specifically, my dissertation included three aims. The first one was to examine how tPBM altered the topographical connectivity in the electrophysiological oscillations of the resting human brain. As the first step, I defined and found key regions and clusters in the EEG sensor space that were affected the most by tPBM during and after the stimulation using both cluster-based power analysis and graph-based connectivity analysis. The results showed that the right prefrontal 1064-nm tPBM modulates several global and regional electrophysiological networks by shifting the information path towards frontal regions, especially in the beta band. For the second aim, I performed 2-bbNIRS measurements from 26 healthy humans and developed a methodology that enabled quantification of the infra-slow oscillation (ISO) power and connectivity between bilateral frontal regions of the human brain in resting state and in response to frontal tPBM stimulation at different sites and laser wavelengths. As the result, several stable and consistent features were extracted in the resting state of 26 young healthy adults. Moreover, these features were used to reveal some effects of tPBM on prefrontal metabolism and hemodynamics, while illustrating the similarities and differences between different stimulation conditions. Finally, the third aim was to investigate the resting-state prefrontal physiological network and the corresponding modulation in response to left frontal 800-nm tPBM by determining the effective connectivity/coupling between each pair of the electrophysiological, hemodynamic, and metabolic ISO of the human brain. Complementary to the previous studies, my study showed that prefrontal tPBM not only modulates the information path between two locations of the prefrontal cortex, it can also induce unilateral alterations in interactions between neural activity, hemodynamics, and metabolism. Overall, my dissertation shed light on the mechanism of action of prefrontal tPBM.
... The basic mechanism of tPBM was believed as the photo-oxidation of CCO in mitochondria [68][69][70]. As seen in our results (Figure 3b), right-forehead tPBM enabled Δ[ox-CCO] spectral magnitude, ΔIA, in both ipsilateral and contralateral enhancement in all three ISO bands. ...
Billions of neurons in the human brain form neural networks with oscillation rhythms. Infra-slow oscillation (ISO) presents three main physiological sources: endogenic, neurogenic, and myogenic vasomotions. Having an in vivo methodology for the absolute quantification of ISO from the human brain can facilitate the detection of brain abnormalities in cerebral hemodynamic and metabolic activities. In this study, we introduced a novel measurement-plus-analysis framework for the non-invasive quantification of prefrontal ISO by (1) taking dual-channel broadband near infra-red spectroscopy (bbNIRS) measurements from 12 healthy humans during a 6-min rest and 4-min post transcranial photobiomodulation (tPBM) and (2) performing wavelet transform coherence (WTC) analysis on the measured time series data. The WTC indexes (IC, between 0 and 1) enabled the assessment of ipsilateral hemodynamic-metabolic coherence and bilateral functional connectiv-ity in each ISO band of the human prefrontal cortex. At rest, bilateral hemodynamic connectivity was consistent across the three ISO bands (IC ≅ 0.66), while bilateral metabolic connectivity was relatively weaker. For post-tPBM/sham comparison, our analyses revealed three key findings: 8-min, right-forehead, 1064-nm tPBM (1) enhanced the amplitude of metabolic oscillation bilaterally, (2) promoted the bilateral metabolic connectivity of neurogenic rhythm, and (3) made the main effect on endothelial cells, causing alteration of hemodynamic-metabolic coherence on each side of the prefrontal cortex.
... Photons in the red/NIR wavelengths promote increased adenosine tri-phosphate (ATP), which is important for basic cellular metabolism and respiration. Repeated LED applications of red/NIR light can improve cellular activity of damaged brain tissue, decrease inflammation and promote synaptic plasticity, which can improve outcome in TBI (Huang, et al., 2012). Therapeutic effects of red/NIR LED application have been shown in individuals with insomnia, as evidenced by increase in serum melatonin and improved sleep (measured by polysomnography) (Xu, et al., 2001;Xu, et al., 2002), and in a healthy population, as evidenced by a correlation between increased post-treatment levels of serum melatonin (levels nearly doubled compared to no significant change in placebo group) and enhanced subjective sleep quality (Zhao, et al., 2012). ...
Sleep disturbance is one of the primary symptoms of traumatic brain injury (TBI) and is also a mediating factor that can affect other TBI treatment outcomes. While the etiology of sleep problems in TBI remains under investigation, recent research points to neurobiological factors, such as a dysfunction of neural circuits involved in sleep-wake regulation. Sleep problems may impact functional status and quality of life across multiple domains, including cognitive, psychological, and physiological functioning. Research suggests that sleep problems may also adversely affect recovery, treatment outcome, and functional status following TBI. Taken together, recent research findings suggest that early treatment of sleep disturbance may improve a spectrum of outcomes following TBI onset and potentially prevent the development of or improve the outcome of existing TBI-associated neuropsychiatric disorders. Despite the apparent clinical need, there is limited evidence for treatment or rehabilitation protocols specifically aimed at alleviating sleep disturbance following TBI.
This paper provides a brief review of emerging evidence for the efficacy of non-pharmacologic interventions, including novel non-invasive neuromodulation interventions, such as photobiomodulation and transcranial magnetic stimulation (TMS), in treatment of sleep disorders following TBI.
Conclusion: Recently developed non-invasive neuromodulation therapeutic modalities offer the potential to reduce sleep disturbance, promote neural recovery, and to treat associated neuropsychiatric symptoms in patients with TBI. More research is needed to investigate specific effect of rTMS and LED on sleep and neuropsychiatric symptoms in this population.
... Red-Light Transcranial Led Therapy (RL-TLTC) involves power-efficient, low heat-producing light sources that have the potential to deliver high-intensity RL of 600-690 wavelengths, that can be pulsed or continuous [30]. In this therapy, the light goes through the layers of the skin and skull, to stimulate the brain and specific cerebral regions, causing biological responses that result in benefits for the individual [7,8,31]. In particular, RL-LED mediated a vibrational absorption process, which produces a photochemical effect that leads to the absorption of photons by specific molecules in the cell [5]. ...
The hippocampus is an integral portion of the limbic system and executes a critical role in spatial and recognition learning, memory encoding, and memory consolidation. Hippocampal aging showed neurobiological alterations, including increased oxidative stress, altered intracellular signaling pathways, synaptic impairment, and organelle deterioration such as mitochondrial dysfunction. These alterations lead to hippocampal cognitive decline during aging. Therefore, the search for new non-invasive therapies focused on preserving or attenuating age-related hippocampal memory impairment could have of great impact on aging, considering the increasing life expectancy in the world. Red light Transcranial LED therapy (RL-TCLT) is a promising but little explored strategy, which involves red light LED irradiation without surgical procedures, safe and at a low cost. Nevertheless, the precise mechanism involved and its real impact on age-related cognitive impairment is unclear, due to differences in protocol, wavelength applied, and time. Therefore, in this chapter, we will discuss the evidence about RL-TCLT and its effects on the hippocampal structure and function, and how this therapy could be used as a promising treatment for memory loss during aging and in age-related diseases such as Alzheimer’s Disease (AD). Finally, we will mention our advances in Red 630-light-Transcranial LED therapy on the hippocampus in aging and AD.
... 3LT is a technique of noninvasive stimulation of which the irradiation of specific infrared wavelengths can penetrate the body [119]. These effects produce various biological responses, such as enhancing the formation of adenosine triphosphate (ATP), deoxyribonucleic acid (DNA), and ribonucleic acid (RNA); releasing nitric oxide (NO) and cytochrome c oxidase (CCO); regulating reactive oxygen species (ROS); and altering intracellular organelle membrane activity, mainly in mitochondria, calcium flux, and stress proteins [66, [120][121][122][123][124]. 3LT produces a shift toward higher oxidation in the overall cell redox potential [125] and briefly increases the level of ROS [111,126]. ...
Autism spectrum disorder (ASD) is the joint name for neurodevelopmental impairments characterized by abnormal social interaction, communication difficulties, limited range of activities and areas of interest, and typical motor impairments. There is a remarkable increase in the prevalence of ASD over the past 30 years. Studies indicate that genetic, neurological, and environmental factors are involved in the emergence of ASD, and recent works describe the neuromolecular mechanism implicated in the basis of ASD. 3LT has now developed into a therapeutic procedure that is used for three main goals: to reduce inflammation, edema, and chronic orthopedic disorders; to promote healing of wounds, deeper tissues, and nerves; and to treat neurological injuries and pain. 3LT may treat neurological injuries by lowering levels of inflammation proteins and by stimulation of mitochondria to increase the production of adenosine triphosphate and neural growth factors. This review aims to discuss the current evidence for the effects and mechanisms of 3LT at the cellular level and the effects of 3LT-induced changes in brain development and function. Early and effective intervention, through the developmental time window of high ASD susceptibility, using tools that are directed to the mechanism of pathology, may minimize neurological and functional deficits.
... Studies have suggested that the anti-inflammatory, anti-edema, and pro-angiogenic property of LLLT can act transcranially, as an effective treatment modality for stroke (Huang et al. 2012). It is suggested that the mechanism of action of LLLT on neurons in culture is through the stimulation of cytochrome c oxidase, a process called photobiomodulation. ...
... 51,52 They are also useful for neurological and neurodegenerative disorders such as traumatic brain injury, stroke, and damage to the spinal cord. 44,[53][54][55][56] In previous studies, lasers were divided into high and low power. High-power lasers have immediate effects and are most commonly used in surgical operations. ...
Introduction: Damage to the spinal cord is a central nervous system disorder that results in direct damage to neural cells (axons, cell bodies) and glia, followed by autonomic, motor and sensory impairments. Inflammatory response after this injury can contribute to secondary tissue damage that leads to further behavioral and functional disorders. Inflammation is a complex process, which occurs after an injury. If this progressive process is not well controlled can lead to additional damage to the spinal cord which is preventing neural improvement and regeneration and, which ultimately will not provide good clinical consequences. Inflammation in the injured spinal cord is a physiological response that causes the death of glial and neuronal cells. The reduction of the initial inflammatory process after damage to the spinal cord is one of the important therapeutic strategies. It has been proposed that low-level laser (LLL) therapy, as a noninvasive manner, can modulate inflammatory processes, which leads to a significant improvement in neurological symptoms after spinal cord injury (SCI). Methods: A comprehensive review was performed on SCI, the etiologies, and treatment methods using the keywords spinal cord injury, low-level laser, and inflammation in valid medical databases such as Google Scholar, PubMed, and Elsevier (76 articles). Among the collected papers, articles that were most relevant to the purposes of the study were selected and studied. Results: LLL therapy was able to reduce inflammation and also attenuate neuronal damage after spinal cord damage. Conclusion: The present study illustrates that LLL therapy has positive effects on improving functional recovery and regulating the inflammatory function in the SCI.
... This photo-oxidation process of CCO accelerates the utilization of oxygen within mitochondria and the production of intracellular ATP [3,12]. Accordingly, cells and neurons that have a high concentration of mitochondria will be facilitated to be more active in their mitochondrial oxygen metabolism and thus their functional activities, leading to enhancement of synaptic connections [13][14][15]. ...
Background and objectives:
In our previous proof-of-principle study, transcranial photobiomodulation (tPBM) with 1,064-nm laser was reported to significantly increase concentration changes of oxygenated hemoglobin (∆[HbO]) and oxidized-state cytochrome c oxidase (∆[oxi-CCO]) in the human brain. This paper further investigated (i) its validity in two different subsets of young human subjects at two study sites over a period of 3 years and (ii) age-related effects of tPBM by comparing sham-controlled increases of ∆[HbO] and ∆[oxi-CCO] between young and older adults.
Study design/materials and methods:
We measured sham-controlled ∆[HbO] and ∆[oxi-CCO] using broadband near-infrared spectroscopy (bb-NIRS) in 15 young (26.7 ± 2.7 years of age) and 5 older (68.2 ± 4.8 years of age) healthy normal subjects before, during, and after right-forehead tPBM/sham stimulation with 1,064-nm laser. Student t tests were used to test statistical differences in tPBM-induced ∆[HbO] and ∆[oxi-CCO] (i) between the 15 young subjects and those of 11 reported previously and (ii) between the two age groups measured in this study.
Results:
Statistical analysis showed that no significant difference existed in ∆[HbO] and ∆[oxi-CCO] during and post tPBM between the two subsets of young subjects at two study sites over a period of 3 years. Furthermore, the two age groups showed statistically identical net increases in sham-controlled ∆[HbO] and ∆[oxi-CCO].
Conclusions:
This study provided strong evidence to validate/confirm our previous findings that tPBM with 1,064-nm laser enables to increase cerebral ∆[HbO] and ∆[oxi-CCO] in the human brain, as measured by bb-NIRS. Overall, it demonstrated the robust reproducibility of tPBM being able to improve cerebral hemodynamics and metabolism of the human brain in vivo in both young and older adults. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.
... A terapia a laser de baixa intensidade (TLBI) tem sido utilizada para o tratamento de várias doenças neurológicas como acidente vascular encefálico, doenças neurodegenerativas, lesão cerebral e também nas lesões do sistema nervoso periférico [8][9][10][11][12] . A TLBI consiste em uma abordagem promissora também no tratamento da LM 7,13 , porém uma pesquisa abrangente da literatura científica mostrou escassez de estudos sobre o assunto, portanto ainda existem questões a serem elucidadas. ...
Objetivo. Realizar uma revisão sobre os efeitos da terapia a laser de baixa intensidade (TLBI) na regeneração do tecido nervoso após lesão medular (LM). Método. Buscou-se artigos nos bancos de dados Medline, Scielo e Lilacs, entre 2002 e 2014. Utilizou-se as palavras-chaves: terapia a laser de baixa intensidade, medula espinal, ferimentos e lesões. Resultados. Foram identificados sete estudos relacionados ao tema, a maioria usou modelo animal (86%) e apenas um (14%) humano. Em relação aos parâmetros de irradiação, o comprimento de onda variou de 780-904nm, a dose de 1,59-20 J/cm², o tempo de aplicação de 2-30 minutos, o período de irradiação de 5-21 dias consecutivos e no estudo com humanos, foram de 40-57 sessões (não consecutivas). As formas de irradiação foram direta ou transcutânea. Dois estudos utilizaram transplante de células associado à TLBI. As causas da LM foram secção completa, hemissecção e contusão. Todos os estudos mostraram resultados positivos da TLBI. Conclusão. A TLBI parece exercer efeitos positivos sobre a LM a partir da diminuição do processo inflamatório, diminuição de citocinas e quimiocinas, melhora da distribuição de fibrocartilagem/elastina, maior número e brotamento axonal, e consequentemente menor cavitação no local da lesão, melhor potencial evocado somatossensorial e melhor recuperação funcional.
... (3,(12)(13)(14)(15)(16)(17) Several vagal nerve electric stimulators have been developed over the years, but the most recent treatments have used subcutaneous chronic implanted devices in different places to stimulate the vagus nerve. (18)(19)(20), but studies using LLLT for VNS are scarce. (10) The superior portions of the vagus nerves are attached by multiple rootlets to the medulla. ...
In this paper we develop a pilot study to study the use of LLLT for VNS in normal subjects, and to assess its effects by QEEG. Twenty normal subjects from 22 to 46 years, paired in age and gender were studied recording QEEG in three experimental condition: Basal record (10 minutes), Laser stimulus (10 minutes), and Post-Laser stimulus records (10 minutes), with VIOLET (10 subjects), and RED/VIOLET (10 subjects) lasers. VIOLET laser provoked a decrement of Absolute Alpha Power values during the vagal stimulation experimental condition in all 10 cases. In 3 cases occurred a partial recovery of Absolute Alpha Power values, throughout the post-vagal stimulation phase. RED/VIOLET laser provoked an increment of the Absolute Alpha Power values during the vagal stimulation experimental condition in 9 cases. In the case in whom occurred a decrement of the Absolute Alpha Power values during the vagal stimulation, it called the attention that an increment in the Absolute Gamma Power values were found. We can conclude that the results using LLLT with the VIOLET laser might be effective in the treatment of epilepsy, because a reduction of brain activity can induce a decrement of paroxysmal activity. The results using the RED/VIOLET LLLT for VNS might be useful in conditions in which it is necessary to induce an increment of brain activity in many conditions, like in depression, neurorehabilitation, in coma, in disorders of consciousness, in dementia, and in some patients complaining autism. Of course, this is a pilot study. It is necessary to explore in future studies the whole EEG spectrum and other variables like Relative Powers in the different EEG bands. Moreover, it is necessary to run protocols on different diseases.
... ( Leisman et al. 2018) Several authors have suggested that applying near-infrared light to the head of animals that have suffered TBI produces improvement in neurological functioning, lessens the size of the brain lesion, reduces neuroinflammation, and stimulates the formation of new neurons. ( Xuan et al. 2014;Huang et al. 2012) Other authors have emphasized that photobiomodulation using LLLT has been demonstrated to be as safe and effective technique in significantly improving the memory, attention, and mood performance in for patients with chronic traumatic brain injury .( Poiani et al. 2018;Hamblin 2018;Naeser et al. 2016;Morries, Cassano, and Henderson 2015;Henderson and Morries 2015) LLLT can achieve a therapeutic effect by employing nonionizing light, including lasers, light-emitting diodes or broadband light in the visible red (600-700 nm) and nearinfrared (780-1100 nm) spectra. ...
We recently examined the efficacy of low level laser therapy (LLLT) to treat autistic children and adolescents. Twenty-one of the 40 participants received 5-minute active (test) procedure administrations across a four-week period, while the remaining 19 participants received fake (placebo) procedure administrations. The adjusted mean difference in the baseline to study endpoint change in the ABC Irritability Subscale score between test and placebo participants was 15.17 in favor of the test procedure group. In this paper, we present the results of the 6 months follow up assessment, and we demonstrated that improvement in symptoms continued after 6 months following completion of the LLLT procedure for autistics initially randomized to the active (test) group, with no change at all for placebo subjects. We suggest that LLLT progressively rearranges those neuronal networks related to the complex symptoms in autistics.
... I/R, ischemia-reperfusion; LED, light-emitting diodes; LSG, left stellate ganglion; NGF, nerve growth factor; PVN, paraventricular nucleus; VA, ventricular arrhythmia participate in various cellular responses because photons can be absorbed by the enzyme cytochrome c oxidase in the mitochondria [36]. It contributes to the elevation of ATP and reactive oxygen species, modulation of transcription factor, and activation or inhibition of downstream signaling pathway [37,38]. For example, LED therapy might inhibit the neuroinflammatory response by suppressing TLR-2 levels, MAPK signaling, and NF-κB activation [35]. ...
Background:
Sympathetic overactivation and inflammation are two major mediators to post-myocardial ischemia-reperfusion (I/R)-induced ventricular arrhythmia (VA). The vicious cycle between microglia and sympathetic activation plays an important role in sympathetic hyperactivity related to cardiovascular diseases. Recently, studies have shown that microglial activation might be attenuated by light-emitting diode (LED) therapy. Therefore, we hypothesized that LED therapy might protect against myocardial I/R-induced VAs by attenuating microglial and sympathetic activation.
Methods:
Thirty-six male anesthetized rats were randomized into four groups: control group (n = 6), LED group (n = 6), I/R group (n = 12), and LED+I/R group (n = 12). I/R was generated by left anterior descending artery occlusion for 30 min followed by 3 h reperfusion. ECG and left stellate ganglion (LSG) neural activity were recorded continuously. After 3 h reperfusion, a programmed stimulation protocol was conducted to test the inducibility of VA. Furthermore, we extracted the brain tissue to examine the microglial activation, and the peri-ischemic myocardium to examine the expression of NGF and inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α).
Results:
As compared to the I/R group, LED illumination significantly inhibited the LSG neural activity (P < 0.01) and reduced the inducibility of VAs (arrhythmia score 4.417 ± 0.358 vs. 3 ± 0.3257, P < 0.01) in the LED+I/R group. Furthermore, LED significantly attenuated microglial activation and downregulated the expression of inflammatory cytokines and NGF in the peri-infarct myocardium.
Conclusions:
LED therapy may protect against myocardial I/R-induced VAs by central and peripheral neuro-immune regulation.
... Of note, the NEST trials demonstrated that NIR light (810 nm) delivered transcranially with a class 4 laser was safe, with no significant differences in rates of adverse events when compared to sham (simulated) exposure. Other preclinical studies and clinical trials have suggested that transcranial PBM is safe and effective in reducing brain lesion volume, reducing inflammation, stimulating neurogenesis, and enhancing learning, memory, and executive functioning in acute [34][35][36][37][38][39] and chronic [40][41][42] traumatic brain injury (TBI) and has beneficial effects on neurodegenerative diseases (Alzheimer's and Parkinson's) [43,44]. Studies on MDD will be discussed below. ...
Photobiomodulation (PBM) is a novel device-based treatment for major depressive disorder (MDD). PBM delivers near-infrared (NIR) or red light transcranially or systemically, aiming to modulate mitochondrial bioenergetics metabolism via the delivery of energy to the cytochrome c oxidase (CCO) enzyme. This primary action on mitochondria can lead to secondary effects on other pathways relevant for MDD such as oxidative stress, inflammation, and neurogenesis. Evidence supports that a fraction of the light delivered transcranially can reach the brain and modulate cortical activity and that light delivered in the periphery can exert systemic effects that include the brain. Preclinical studies indicate that PBM can treat depression-like behaviors in animal models of depression and also give some guidance on the optimal stimulation parameters. According to these studies, repeated sessions are more effective than a single session, and pulsed wave is more effective than continuous wave. Clinical studies also support the antidepressant effect of PBM and reinforce the need of repeated sessions. Clinical evidence also indicates that PBM can induce mild adverse effects, but the incidence of serious adverse effects is not different from that observed in sham (i.e., placebo) treatment. At this moment, PBM is an over-the-counter treatment for MDD and can be considered an alternative for patients who do not respond, tolerate, or accept antidepressant medication, evidence-based psychotherapies, or other FDA-approved device-based treatments.
... There is presently no accepted treatment for TBI, although some investigational approaches are being tested in both the acute (neuroprotection) and chronic (neurorehabilitation) settings (Loane & Faden, 2010). One of these novel approaches is PBM/LLLT (Hamblin, 2016a;Hamblin, 2016b;Huang et al., 2012;Thunshelle & Hamblin, 2016). ...
There is a notable lack of therapeutic alternatives for what is fast becoming a global epidemic of traumatic brain injury (TBI). Photobiomodulation (PBM) employs red or near-infrared (NIR) light (600–1100nm) to stimulate healing, protect tissue from dying, increase mitochondrial function, improve blood flow, and tissue oxygenation. PBM can also act to reduce swelling, increase antioxidants, decrease inflammation, protect against apoptosis, and modulate microglial activation state. All these mechanisms of action strongly suggest that PBM delivered to the head should be beneficial in cases of both acute and chronic TBI. Most reports have used NIR light either from lasers or from light-emitting diodes (LEDs). Many studies in small animal models of acute TBI have found positive effects on neurological function, learning and memory, and reduced inflammation and cell death in the brain. There is evidence that PBM can help the brain repair itself by stimulating neurogenesis, upregulating BDNF synthesis, and encouraging synaptogenesis. In healthy human volunteers (including students and healthy elderly women), PBM has been shown to increase regional cerebral blood flow, tissue oxygenation, and improve memory, mood, and cognitive function. Clinical studies have been conducted in patients suffering from the chronic effects of TBI. There have been reports showing improvement in executive function, working memory, and sleep. Functional magnetic resonance imaging has shown modulation of activation in intrinsic brain networks likely to be damaged in TBI (default mode network and salience network).
... In recent years the use of PBM as a treatment for traumatic brain injury [81,82], and other brain disorders including stroke, neurodegenerative diseases and even psychiatric disorders has increased markedly [83]. It is thought that the actions of NIR light shone on the head and penetrating into the brain are multi-factorial, but one clear effect is the anti-inflammatory action of transcranial PBM. ...
Photobiomodulation (PBM) also known as low-level level laser therapy is the use of red and near-infrared light to stimulate healing, relieve pain, and reduce inflammation. The primary chromophores have been identified as cytochrome c oxidase in mitochondria, and calcium ion channels (possibly mediated by light absorption by opsins). Secondary effects of photon absorption include increases in ATP, a brief burst of reactive oxygen species, an increase in nitric oxide, and modulation of calcium levels. Tertiary effects include activation of a wide range of transcription factors leading to improved cell survival, increased proliferation and migration, and new protein synthesis. There is a pronounced biphasic dose response whereby low levels of light have stimulating effects, while high levels of light have inhibitory effects. It has been found that PBM can produce ROS in normal cells, but when used in oxidatively stressed cells or in animal models of disease, ROS levels are lowered. PBM is able to up-regulate anti-oxidant defenses and reduce oxidative stress. It was shown that PBM can activate NF-kB in normal quiescent cells, however in activated inflammatory cells, inflammatory markers were decreased. One of the most reproducible effects of PBM is an overall reduction in inflammation, which is particularly important for disorders of the joints, traumatic injuries, lung disorders, and in the brain. PBM has been shown to reduce markers of M1 phenotype in activated macrophages. Many reports have shown reductions in reactive nitrogen species and prostaglandins in various animal models. PBM can reduce inflammation in the brain, abdominal fat, wounds, lungs, spinal cord.
... Studies have suggested that the anti-inflammatory, anti-edema, and pro-angiogenic property of LLLT can act transcranially, as an effective treatment modality for stroke (Huang et al. 2012). It is suggested that the mechanism of action of LLLT on neurons in culture is through the stimulation of cytochrome c oxidase, a process called photobiomodulation. ...
Tissue engineering techniques, to replace wounded or missing tissue, are advancing rapidly to ensure the speedy recovery of patients. However, this field faces limitations of cells and biomaterials which prevents the acceleration of regeneration. Low level light therapy, a physical therapy, shows potential in enhancing and supporting the existing medicinal treatments. Visible light in the red and near-infrared range has shown to have positive stimulatory effects on various types of cells involved in wound healing and tissue regeneration. As angiogenesis is an essential part of this process, light therapy was investigated in multiple studies to see its beneficial effect on vessel formation. In vitro, in vivo, and in a clinical setup, LLLT therapy proved that it is capable of stimulating not only endothelial cells but other cells such as fibroblasts, smooth muscle cells, and lymphocytes which are involved in the vessel formation process. It triggers the activation of cytochrome c oxidase, which leads to the production of NO, ROS, and ATP in the mitochondria. These molecules appear to act as secondary messengers initiating ERK/Sp1 and PI3K signaling pathway, which in turn leads to proliferation, migration, and the synthesis of proangiogenic factors. This data indicates that LLLT could be a promising adjuvant treatment in the future.
... Low-level laser therapy (LLLT), also known as phototherapy or photobiomodulation (PBM), uses low doses of light from a laser. Low-level laser has been applied in several experimental disease models [18][19][20] because of its ability to reduce inflammation. LLLT has been proposed to target mitochondrion and alter cellular responses through multilevel mechanisms, such as regulating the formation of reactive oxygen spices (ROS) and subsequently modulate transcription of several genes, including nuclear factor kappa B (NF-κB) 21 . ...
Macrophages and resident microglia play an import role in the secondary neuroinflammation response following spinal cord injury. Reprogramming of macrophage/microglia polarization is an import strategy for spinal cord injury restoration. Low-level laser therapy (LLLT) is a noninvasive treatment that has been widely used in neurotrauma and neurodegenerative diseases. However, the influence of low-level laser on polarization of macrophage/microglia following spinal cord injury remains unknown. The present study applied low-level laser therapy on a crush spinal cord injury rat model. Using immunofluorescence, flow cytometry, RT-qPCR, and western blot assays, we found that low-level laser therapy altered the polarization state to a M2 tendency. A greater number of neurons survived in the pare injury site, which was accompanied by higher BBB scores in the LLLT group. Furthermore, low-level laser therapy elevated expression of interleukin 4 (IL-4) and interleukin 13 (IL-13). Results from this study show that low-level laser therapy has the potential for reducing inflammation, regulating macrophage/microglia polarization, and promoting neuronal survival. These beneficial effects demonstrate that low-level laser therapy may be an effective candidate for clinical treatment of spinal cord injury.
... 98 Nevertheless, the relative success of at least some of these studies prompted researchers' continued investigations of the effects of LLLT in acute TBI in animal models. 99 From such work, a number of positive results have now been reported. There is building evidence to support that tNIR can stimulate neurogenesis as shown by induction of bromodeoxyuridine (BrdU)-positive neuroprogenitor cells in the dentate gyrus and subventricular zone of laboratory animals. ...
The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/treatment effect curves. Although trials are encouraging, elucidating the basic mechanisms of tDCS will accelerate validation and adoption. To this end, biomarkers (eg, clinical neuroimaging and findings from animal models) can support hypotheses linking neurobiological mechanisms and behavioral effects. Dosage can be optimized using computational models of current flow and understanding dose–response. Both biomarkers and dosimetry should guide individualized interventions with the goal of reducing variability. Insights from other applied energy domains, including ionizing radiation, transcranial magnetic stimulation, and low-level laser (light) therapy, can be prudently leveraged.
... PBM using red to NIR lights may cause photodissociation of NO from CCO and thus increase the respiration rate Hamblin, 2008). As NO is a vasodilator, released NO following light irradiation influences local blood flow and, therefore, improvement in perfusion (Huang et al., 2012;Hennessy and Hamblin, 2016). ...
Major depressive disorder is a common debilitating mood disorder that affects quality of life. Prefrontal cortex abnormalities, an imbalance in neurotransmitters, neuroinflammation, and mitochondrial dysfunction are the major factors in the etiology of major depressive disorder. Despite the efficacy of pharmacotherapy in the treatment of major depressive disorder, 30%–40% of patients do not respond to antidepressants. Given this, exploring the alternative therapies for treatment or prevention of major depressive disorder has aroused interest among scientists. Transcranial photobiomodulation therapy is the use of low-power lasers and light-emitting diodes in the far-red to near-infrared optical region for stimulation of neuronal activities. This non-invasive modality improves the metabolic capacity of neurons due to more oxygen consumption and ATP production. Beneficial effects of transcranial photobiomodulation therapy in the wide range of neurological and psychological disorders have been already shown. In this review, we focus on some issues relating to the application of photobiomodulation therapy for major depressive disorder. There is some evidence that transcranial photobiomodulation therapy using near-infrared light on 10-Hz pulsed mode appears to be a hopeful technique for treatment of major depressive disorder. However, further studies are necessary to find the safety of this method and to determine its effective treatment protocol.
Significance:
Transcranial photobiomodulation (tPBM) is a noninvasive neuromodulation method that facilitates the improvement of human cognition. However, limited information is available in the literature on the wavelength- and site-specific effects of prefrontal tPBM. Moreover, 2-channel broadband near-infrared spectroscopy (2-bbNIRS) is a new approach for quantifying infra-slow oscillations (ISO; 0.005 to 0.2 Hz) of neurophysiological networks in the resting human brain in vivo.
Aim:
We aim to prove the hypothesis that the hemodynamic and metabolic activities of the resting prefrontal cortex are significantly modulated by tPBM and that the modulation is wavelength- and site-specific in different ISO bands.
Approach:
Noninvasive 8-min tPBM with an 800- or 850-nm laser or sham was delivered to either side of the forehead of 26 healthy young adults. A 2-bbNIRS unit was used to record prefrontal ISO activity 7 min before and after tPBM/sham. The measured time series were analyzed in the frequency domain to determine the coherence of hemodynamic and metabolic activities at each of the three ISO frequency bands. Sham-controlled coherence values represent tPBM-induced effects on neurophysiological networks.
Results:
Prefrontal tPBM by either wavelength and on either lateral side of the forehead (1) increased ipsilateral metabolic-hemodynamic coupling in the endogenic band and (2) desynchronized bilateral activity of metabolism in the neurogenic band and vascular smooth-muscle hemodynamics in the myogenic band. Site-specific effects of laser tPBM were also observed with significant enhancement of bilateral hemodynamic and metabolic connectivity by the right prefrontal 800-nm tPBM.
Conclusions:
Prefrontal tPBM can significantly modulate neurophysiological networks bilaterally and coupling unilaterally in the human prefrontal cortex. Such modulation effects are site- and wavelength-specific for each ISO band.
In Bangladesh, accidents are happening frequently at the railway crossing due to the use of typical manual railway crossing systems/ boom gates. The main reasons are likely having these accidents in the railway crossings due to not possible to stop the train engine mechanism system automatically or instantly such as cars and other vehicles as well as for fewer safety measures in the railway crossing. Currently, there are very few automatic railway crossing systems (without any obstacle detector, just runs with the schedule of the trains crossing) are available, however, all of them are dependent on the national power grid that has no backup plan for any emergency cases. As Bangladesh is running a bit behind in the power generation of its consumption, hence it is not possible to have a continuous power supply at all times. This paper aims to design and develop a railway crossing system with a smart obstacle detector to prevent very common types of accidents in the railway crossing points in Bangladesh. In the railway system, time consumption is the biggest issue that leads to having most of the accidents in the railway crossings. In this research, we design to use two infrared (IR) sensors for opening and closing the railway crossing systems/ gates and the whole system to be controlled by the Arduino. To run the process without having any interruption, we propose to use renewable energy i.e., mainly the solar photovoltaic (PV) power systems which are economic friendly and apply under the national green energy policy towards achieving the sustainable goal.
Recent studies demonstrate that low-level light therapy (LLLT) modulates recovery in patients with traumatic brain injury (TBI). However, the impact of LLLT on brain activity following TBI has not been well described. Here we use a randomized, double-blind, placebo-controlled design to investigate the effect of LLLT on resting-state connectivity at acute (within 1-week), subacute (2–3 weeks), and late-subacute (3-month) time-points following moderate TBI. A characteristic connectivity profile was observed during TBI recovery in both sham- (n = 21) and LLLT-treated patients (n = 17) compared to healthy controls, with increased resting-state connectivity between frontal and parietal cortices. Temporal comparisons between LLLT- and sham-treated patients showed that the acute-to-subacute changes in resting-state connectivity were significantly greater in LLLT-treated patients. These results demonstrate that LLLT increased resting-state connectivity in the presence of a regional hyperconnectivity response to moderate TBI, suggesting that LLLT can modulate activity in the injured brain and encouraging its further exploration as a therapy for TBI.
Understanding the compartment fire behavior has a vital importance for fire protection
engineers. For design purposes, whether to use a prescriptive code or performance based on design, life safety and property protection issues are required to be assessed. The use of design fires in computer modelling is the general method to determine fire safety. However, these computer models are generally limited to the input of one design fire, with consideration of the complex interaction between fuel packages and the compartment environment being simplified. Of particular interest is the Heat Release Rate, HRR, as this is the commonly prescribed design parameter for fire modelling. If the HRR is not accurate then it can be subsequently argued that the design scenario may be flawed. Therefore, the selection of the most appropriate fire design scenario is critical, and an increased level of understanding of compartment behavior is an invaluable aid to fire engineering assumptions. This thesis studies 3 types of pool fire geometry to enhance the understanding of the impact and interaction that the size and location of pool fires within an enclosure have upon the compartment fire behavior, also Ethanol pool fires were used. In this present work, we have carried out to analysis the effect of water to extinguish the fire and it and it's tested in 4 different ways with and without water. Also in the result, we can see the effect of water to visibility and also the concentration
of air.
Transcranial photobiomodulation therapy (PBMT) also known as low-level laser therapy (LLLT) relies on the use of red/NIR light to stimulate, preserve and regenerate cells and tissues. In this review, we will present the most important laser types and sources used in the treatment of the brain, required energy densities to provide treatment, and laser delivery techniques to the brain through the cranium, eye, internal ear, and nostril. Various forms of light therapy have been practiced all over the world for many years. Among them, laser therapy has flourished in recent years. More and more laser equipment is being used in this area. The use of PBMT for neuronal stimulation has been studied in various animal and human models and has been shown to improve cerebral metabolic activity and blood flow and provide neuroprotection through anti-inflammatory and antioxidant pathways. In recent years, the concept of thermotherapy for the treatment of brain tumors has become more widespread. Traditionally, heat therapy is divided into hyperthermia, with a moderate increase in the temperature of the treated tissue above the physiological baseline level, and heat ablation, in which even higher temperatures are reached. Recently, intranasal light therapy, light delivery to the brain through the ear and other channels have become attractive and potential treatments for brain diseases. Here we summarize the various methods of delivering light through the nostrils and ear canals using lasers or light-emitting diodes (LEDs), which can be used alone or in combination with transcranial devices or (applied directly to the scalp) to treat a wide range of brain conditions such as the lungs cognitive impairment, Alzheimer's disease, Parkinson's disease, cerebrovascular disease, depression and anxiety, and insomnia. Evidence shows that low-intensity laser therapy improves blood rheology and cerebral blood flow, so there is no need to pierce blood vessels.
Photobiomodulation (PBM) is now over 50 years old and has recently started to gain more widespread acceptance within the medical community. Alleviation of the side effects of cancer therapy has so far been one of the most impressive applications of PBM and the focus of this chapter. I will cover the mechanism of action and ask whether the effects of PBM on cancer cells and tumors is more likely to be positive or negative. There are some ways that PBM could actually attack the cancer either directly or indirectly, or in combination with other cytotoxic therapies. Finally, I will summarize the clinical applications of PBM against such side effects as oral mucositis, radiation dermatitis, dysphagia, hyposalivation and xerostomia, taste alterations, trismus, head and neck lymphedema, and voice and speech alterations.
An overview of a noninvasive neurorehabilitation treatment for TBI and commonly associated neuropsychiatric problems: (1) Therapeutic effects of LED application on cognition, sleep, and PTSD; (2) Home-based TBI program, using noninvasive treatment modality, light emitting diodes (LED); (3) Virtual Care LED TBI Home Tx program for TBI and PTSD. We present the latest evidence and discuss how recent clinical research findings translate into current clinical practice. Summary: The results from the LED pilot RCT and LED clinical program evaluation showed that transcranial LED Home Tx improves cognitive (attention, executive function, learning/memory) and neuropsychiatric symptoms (mood, PTSD, sleep) in patients with chronic mild-moderate TBI. These results suggest that noninvasive, non-pharmacologic LED Home treatment with tele-health support improves daily function and neurobehavioral symptoms in chronic TBI. The LED TBI Home Tx Program, converted to Virtual Care following the COVID-19 pandemic restrictions, demonstrated higher treatment adherence and lower dropout rates, as compared to the standard In-office LED treatment. These results provide evidence that the twelve-week home-based treatment of chronic mild-moderate TBI with transcranial LEDs is safe and effective for clinical use.
Dry eye disease is one of the most common, chief-complaints presenting in clinical practice, with a prevalence of up to 50%. Evaporative dry eye, as a result of meibomian gland dysfunction, is thought to be the biggest component factor. Treatments for meibomian gland dysfunction aim to restore tear film homoeostasis and include warm compress therapy, eyelid hygiene, in-office meibomian gland expression and lipid-containing, artificial tears. A recent introduction to the in-office treatments available for meibomian gland dysfunction has been low-level light therapy, also known as photobiomodulation. The technique involves applying red, or near infra-red, radiation using low-power light sources and is suggested to promote tissue repair, decrease inflammation, and relieve pain. This work aims to review the available literature on the efficacy and safety of photobiomodulation in meibomian gland dysfunction and dry eye disease, as well as what is currently known about its mechanism of action.
Aim:
Previous studies on spinal cord injury (SCI) have confirmed that percutaneous photobiomodulation (PBM) therapy can ameliorate immunoinflammatory responses at sites of injury, accelerate nerve regeneration, suppress glial scar formation, and promote the subsequent recovery of locomotor function. The current study was performed to evaluate a large-animal model employing implanted optical fibers to accurately irradiate targeted spinal segments. The method's feasibility and irradiation parameters that do not cause phototoxic reaction were determined, and the methodology of irradiating the spinal cord with near-infrared light was investigated in detail.
Methods:
A diffusing optical fiber was implanted above the T9 spinal cord of Bama miniature pigs and used to transfer near-infrared light (810 nm) onto the spinal cord surface. After daily irradiation with 200, 300, 500, or 1000 mW for 14 days, both sides of the irradiated area of the spinal cord were assessed for temperature changes. The condition of the spinal cord and the position of optical fiber were investigated by magnetic resonance imaging (MRI), and different parameters indicating temperature increases or phototoxicity were measured on the normal spinal cord surface due to light irradiation (i.e., heat shock responses, inflammatory reactions, and neuronal apoptosis), and the animals' lower-limb neurological function and gait were assessed during the irradiation process.
Results:
The implanted device was stable inside the freely moving animals, and light energy could be directly projected onto the spinal cord surface. The screening of different irradiation parameters preliminary showed that direct irradiation onto the spinal cord surface at 200 and 300 mW did not significantly increase the temperature, stress responses, inflammatory reactions and neural apoptosis, whereas irradiation at 500 mW slightly increased these parameters, and irradiation at 1000 mW induced a significant temperature increase, heat shock, inflammation and apoptosis responses. HE staining of spinal cord tissue sections did not reveal any significant structural changes of the tissues compared to the control group, and the neurological function and gait of all irradiated animals were normal.
Conclusion:
In this study, we established an in-vivo optical fiber implantation method, which might be safe and stable and could be used to directly project light energy onto the spinal cord surface. This study might provide a new perspective for clinical applications of PBM in acute SCI. This article is protected by copyright. All rights reserved.
The main objective of this work is to quantify the impact of photodynamic/photothermal treatment by using visible LED and NIR laser irradiation through the skin of subcutaneous fat in vivo followed up by tissue sampling and histology. The optical method may provide reduction of regional or site‐specific accumulations of abdominal or subcutaneous adipose tissue precisely and least‐invasively by inducing cell apoptosis and controlled necrosis of fat tissue. As photodynamic/photothermal adipose tissue sensitizers Brilliant Green (BG) or Indocyanine Green (ICG) dyes were injected subcutaneously in rats. The CW LED device (625 nm) or CW diode laser (808 nm) were used as light sources, respectively. Biopsies of skin together with subcutaneous tissues were taken for histology. The combined action BG‐staining and LED‐irradiation (BG+LED) or ICG‐staining and NIR‐laser irradiation (ICG+NIR) causes pronounced signs of damage of adipose tissue haracterized by a strong stretching, thinning, folding and undulating of cell membranes, and appearance of necrotic areas. As a post‐treatment after 14 days only connective tissue was observed at the site of necrotic areas. The data obtained are important for safe light treatment of site‐specific fat accumulations, including cellulite. This work provides a basis for the development of fat lipolysis technologies and to move them to clinical applications. This article is protected by copyright. All rights reserved.
Background
Sympathetic neural activation plays a key role in the incidence and maintenance of acute myocardial infarction (AMI) induced ventricular arrhythmia (VA). Furthermore, previous studies showed that AMI might induce microglia and sympathetic activation and that microglial activation might contribute to sympathetic activation. Recently, studies showed that light emitting diode (LED) therapy might attenuate microglial activation. Therefore, we hypothesized that LED therapy might reduce AMI‐induced VA by attenuating microglia and sympathetic activation.
Methods
Thirty anesthetized rats were randomly divided into three groups: the Control group (n=6), AMI group (n=12) and AMI+LED group (n=12). ECG and LSG neural activity were continuously recorded. The incidence of VAs was recorded during the first hour after AMI. Furthermore, we sampled brain and myocardium tissue of the different groups to examine the microglial activation and expression of NGF, IL‐18 and IL‐1β, respectively.
Results
Compared to the AMI group, LED therapy significantly reduced the incidence of AMI‐induced VAs (VPB number: 85.08±13.91 vs. 27.5±9.168, P < 0.01; nSVT duration: 34.39±8.562 vs. 9.005±3.442, P < 0.05; nSVT number: 18.92±4.52 vs. 7.583±3.019, P < 0.05; incidence rate of SVT/VF: 58.33% vs. 8.33%, P < 0.05) and reduced the LSG neural activity (P < 0.01) in the AMI+LED group. Furthermore, LED significantly attenuated microglial activation and reduced IL‐18, IL‐1β and NGF expression in the peri‐infarct myocardium.
Conclusion
LED therapy may protect against AMI‐induced VAs by suppressing sympathetic neural activity and the inflammatory response.
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One of the challenges in transcranial low‐level laser therapy (LLLT) is to optimally choose illumination parameters, such as wavelength. However, there is sparse study on the wavelengths comparison especially on human transcranial LLLT. Here, we employed Monte Carlo modeling and visible human phantom to compute the penetrated photon fluence distribution within cerebral cortex. By comparing the fluence distribution, penetration depth, and the intensity of laser‐tissue‐interaction within brain among all candidate wavelengths, we found that 660, 810 nm performed much better than 980, 1064 nm with much stronger, deeper, and wider photon penetration into cerebral tissue. 660 nm was shown to be the best and slightly better than 810 nm. Our computational finding was in a surprising accordance with previous LLLT‐neurobehavioral studies on mice. This study not only offered quantitative comparison among wavelengths in the effect of LLLT light penetration effectiveness but also anticipated a delightful possibility of online, precise, and visible optimization of LLLT illumination parameters.
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Although photons have been repeatedly shown to affect the functioning of the nervous system, their effects on neurotransmitter release have never been investigated. We exploited in vitro models that allow effects involving neuron‐astrocyte network functioning to be detected (mouse cerebrocortical slices) and dissected these effects at cerebrocortical nerve endings and astrocyte processes. Infrared light proved able to induce glutamate release by stimulating glutamatergic nerve endings.
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Stroke is the second leading cause of death and disability worldwide. The incidence of hemorrhagic stroke increases dramatically with the increasingly aging population. Recently, technology of low-level light/laser therapy (LLLT) is emerging as a novel noninvasive therapeutic approach to treat stroke based on effective photobiomodulation. To obtain optimal therapeutic effects, several LLLT illumination parameters such as beam size and beam type need to be optimized. However, the quantitative optimization of LLLT illumination parameters for stroke therapeutics is impractical to test directly on human subjects. In this paper, we employed a precise voxelized 3-D Monte Carlo method (MCVM) to simulate photon propagation within Visible Chinese human (VCH) head at different level of stroke with varied parameters of beams. By evaluation with criteria of the total fluence flux in lesion region and the maximal penetration depth, we found that Gaussian beam with larger or the same size of hemorrhagic region generates the highest and relative homogeneous therapeutic outcomes, while the Top-hat beam performed better when hemorrhagic region is much bigger than beam size. These results demonstrate the great potential of using VCH and MCVM in optimizing LLLT treatment parameters for stroke and in guiding future instrumentation of LLLT on hemorrhagic stroke. OAPA
Thymic atrophy and the subsequent reduction in T cell production are the most noticeable age-related changes affecting lymphoid organs in the immune system. In fact thymic involution has been described as “programmed aging”. New therapeutic approaches such as photobiomodulation (PBM) may reduce or reverse these changes. PBM (also known as low-level laser therapy or LLLT) involves the delivery of non-thermal levels of red or near-infrared light that are absorbed by mitochondrial chromophores, in order to prevent tissue death and stimulate healing and regeneration. PBM may reverse or prevent thymic involution due to its ability to induce extrapineal melatonin biosynthesis via cyclic AMP or NF-kB activation, or alternatively by stimulating bone marrow stem cells that can regenerate the thymus. This perspective puts forward a hypotheses that PBM can alter thymic involution, improve immune functioning in aged people, and even extend lifespan.
The skin, which is the largest organ of the human body, serves as a protective barrier between the internal milieu and the environment. It functions as the body’s first line of defense against infection and regulates its temperature and fluid balance. Keratinocytes are present in all the layers of the epidermis, the outermost layer of the skin, and are essentially connected to the pathophysiology of skin diseases such as psoriasis and atopic dermatitis, and play a crucial role in skin wound healing. Keratinocytes are the first cells to be in contact when exposed with external stimuli and are consequently more amenable to non-invasive treatments such as PBM using blue light. The anti-microbial, anti-inflammatory and anti-proliferative effects of blue light are already used for different medical treatments like psoriasis, neonatal jaundice and back pain. However, little is known about the mechanisms transducing the light induced signals from target molecules over downstream processes and/or gene expression to the biological effects and therefore the aim of this project was to examine the photobiomodulary effect of blue light on the immortalized human keratinocyte cell line HaCaT in detail. Photobiomodulation using blue light irradiation induces a biphasic dose response curve of metabolism in HaCaT cells with an increase in metabolism and proliferation for low doses and a decrease in metabolism and proliferation for higher doses in vitro. For further tests, 7.5min (10.35J/cm²) respectively 30min (41.4J/cm²) were chosen for subsequent experiments to test the blue light effect after different harvesting times in the proliferative phase respectively the anti-proliferative phase of PBM. Gene expression evaluation of HaCaT cells after 30min (41.4J/cm²) of blue light irradiation revealed an upregulation of “AHR battery genes” leading to production of phase I and phase II enzymes of xenobiotic metabolism. One important action of this downstream process is to provide a delicate hormesis between promoting and preventing ROM-mediated oxidative stress, which is in agreement with our ROS measurements. H2O2 concentrations are increased 30min after blue light irradiation; however, already 1h after irradiation H2O2 is metabolized by the cells leading to an even lower ROS concentration. Furthermore, steroid hormone biosynthesis is activated as a downstream process of “AHR battery gene” expression already 1h after irradiation triggering anti-inflammatory responses. Additionally, inflammation is also decreased due to oxidative stress inhibited NF-κB signaling pathway and interaction with JunB. DNA replication pathway is downregulated resulting in a decrease in cell proliferation due to primary production of ROS, AHR-induced downregulation of CDKN1B and prolongation of S-phase. However, ROS concentrations are not reaching a damaging level as cell survival pathways are enhanced by crosstalk of AHR-ligand complex with EGFR. Moreover, reduction of TNF-signaling pathway and downregulation of TRADD gene expression, which are relevant for apoptotic signaling, are consistent with FACS analysis as 24h after blue light irradiation cells are not showing any sign of apoptosis. Finally, it can be concluded that gene expression after 30min (41.4J/cm²) of blue light irradiation shows a time course after blue light irradiation, with early response genes and pathways leading to the identification of AHR as a possible target for PBM with blue light via photo-oxidation of tryptophan resulting, when using this described dose, in a cell protective effect with decreased proliferation, production of steroid hormones and prevention of inflammatory responses. Moreover, the anti- proliferative effect can be prolonged by consecutive irradiations each 24h. Photobiomodulation with 7.5min (10.35J/cm²) blue light induced a proliferation increase in HaCaT cells until at least up to 24h after irradiation, which was documented in gene expression analysis with upregulation of DNA replication pathway and genes connected to cell cycle. H2O2 concentrations were increased 30min after blue light irradiation to an even higher level than after a 30min (41.4J/cm2) blue light irradiation; however, already 1h after irradiation H2O2 was metabolized by the cells. The hypothesis was set that even though H2O2 concentrations were higher after a 7.5min (10.35J/cm²) blue light irradiation compared to 30min (41.4J/cm2) the actual oxidative stress was lower. This was explained with the triphasic ROS production-curve induced by PBM described by Huang et al. 2011 and could be linked to gene expression analysis results, where for example oxidative stress dependent Nrf2 transcribed genes were not deregulated. It was not only shown that ROS production was not damaging the cells but even that cell survival pathways were enhanced by crosstalk of EGFR with the AHR-ligand complex. Furthermore, apoptotic signaling was downregulated as TRADD gene expression and TNF-signaling pathway were reduced. Comparable with 30min (41.4J/cm²) blue light irradiation, gene expression analysis revealed an upregulation of “AHR battery genes” after 7.5min (10.35J/cm²) blue light leading to production of phase I and phase II enzymes of xenobiotic metabolism and steroid hormone biosynthesis as a downstream process of “AHR battery gene” expression. However, deregulation of genes and pathways occurred to a smaller extent. Finally, it can be concluded that PBM with blue light, when using 7.5min (10.35J/cm²), activates AHR and results in a cell protective effect with increased proliferation, production of steroid hormones and induction of cell survival pathways. Furthermore, it is suggested not to use consecutive irradiations each 24h if a proliferative effect is desired.
Pain is a concept that is clinically and pathogenetically complex and heterogeneous. It varies in intensity, localization and subjective manifestations (shooting, pressing, pulsating, pricking, cutting, aching, etc.), can be permanent or periodic, which is largely due to localization and what causes it.
Some well-recognised types of pain include muscle or joint-muscle pain. An example of this type of pain is fibromyalgia, a rheumatic disease of unknown etiology, is characterized by generalized muscle
weakness and painful palpation in limited areas of the body, designated as trigger points. Effective methods
of treatment of patients with this disease have not yet been developed. Some medications allow the patient some form of short-term relief, however, even this is not always the case.
Using a complex approach, which involves a wide range of laser therapy methods, it allows the human body to restore itself and any abnormalities in the functioning of various organs and systems, which, as well as providing direct analgesia, ensures the elimination of the causes of the disease. In addition, laser
therapy methods are simple and safe, and unlike analgesics do not cause side effects, as well as there
being no contraindications.
Laser illumination doesn’t only affect one link of the painful reception, but essentially the whole hierarchy of mechanisms in the appearance of pain. Due to this, the curative effect persists for a long period of time. This “versatility” predetermines the exceptional effectiveness of laser therapy, all while using adequate techniques and appropriate equipment. Laser therapeutic devices in the LASMIK series have a frequency of up to 10.000Hz, and a unique set of laser emitting attachments and nozzles. These are the most suitable for implementing methods of pain management.
The book is intended for specialists in rehabilitation, rheumatologists, traumatologists, general practitioners
and physiotherapists.
Tissue engineering techniques, to replace wounded or missing tissue, are advancing rapidly to ensure the speedy recovery of patients. However, this field faces limitations of cells and biomaterials which prevents the acceleration of regeneration. Low level light therapy, a physical therapy, shows potential in enhancing and supporting the existing medicinal treatments. Visible light in the red and near-infrared range has shown to have positive stimulatory effects on various types of cells involved in wound healing and tissue regeneration. As angiogenesis is an essential part of this process, light therapy was investigated in multiple studies to see its beneficial effect on vessel formation. In vitro, in vivo, and in a clinical setup, LLLT therapy proved that it is capable of stimulating not only endothelial cells but other cells such as fibroblasts, smooth muscle cells, and lymphocytes which are involved in the vessel formation process. It triggers the activation of cytochrome c oxidase, which leads to the production of NO, ROS, and ATP in the mitochondria. These molecules appear to act as secondary messengers initiating ERK/Sp1 and PI3K signaling pathway, which in turn leads to proliferation, migration, and the synthesis of proangiogenic factors. This data indicates that LLLT could be a promising adjuvant treatment in the future.
Significance statement:
Controlling the differentiation of stem cells would support the development of promising brain regenerative therapies. Blue light transiently increased reactive oxygen species, resulting in neuronal differentiation and increased retinoic acid receptor (RARα) levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis, while offering a temporal and spatial control of RA release. In this sense, our approach relying on the modulation of endogenous stem cells for the generation of new neurons may support the development of novel clinical therapies.
We aimed to investigate the effects of low-level light emitting diode therapy (LED-T) on the long-term functional outcomes after cerebral ischemia, and the optimal timing of LED-T initiation for achieving suitable functional recovery. Focal cerebral ischemia was induced in mice via photothrombosis. These mice were assigned to a sham-operated (control), ischemic (vehicle), or LED-T group [initiation immediately (acute), 4 days (subacute) or 10 days (delayed) after ischemia, followed by once-daily treatment for 7 days]. Behavioral outcomes were assessed 21 and 28 days post-ischemia, and histopathological analysis was performed 28 days post-ischemia. The acute and subacute LED-T groups showed a significant improvement in motor function up to 28 days post-ischemia, although no brain atrophy recovery was noted. We observed proliferating cells (BrdU+) in the ischemic brain, and significant increases in BrdU+/GFAP+, BrdU+/DCX+, BrdU+/NeuN+, and CD31+ cells in the subacute LED-T group. However, the BrdU+/Iba-1+ cell count was reduced in the subacute LED-T group. Furthermore, the brain-derived neurotrophic factor (BDNF) was significantly upregulated in the subacute LED-T group. We concluded that LED-T administered during the subacute stage had a positive impact on the long-term functional outcome, probably via neuron and astrocyte proliferation, blood vessel reconstruction, and increased BDNF expression. Picture: The rotarod test for motor coordination showed that acute and subacute LED-T improves long-term functional recovery after cerebral ischemia.
Photostimulation with low-level light emitting diode therapy (LED-T) modulates neurological and psychological functions. The purpose of this study was to evaluate the effects of LED-T pretreatment on the mouse brain after ischemia/reperfusion and to investigate the underlying mechanisms. Ischemia/reperfusion brain injury was induced by middle cerebral artery occlusion. The mice received LED-T twice a day for 2 days prior to cerebral ischemia. After reperfusion, the LED-T group showed significantly smaller infarct and edema volumes, fewer behavioral deficits compared to injured mice that did not receive LED-T and significantly higher cerebral blood flow compared to the vehicle group. We observed lower levels of endothelial nitric oxide synthase (eNOS) phosphorylation in the injured mouse brains, but significantly higher eNOS phosphorylation in LED-T-pretreated mice. The enhanced phospho-eNOS was inhibited by LY294002, indicating that the effects of LED-T on the ischemic brain could be attributed to the upregulation of eNOS phosphorylation through the phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, no reductions in infarct or edema volume were observed in LED-T-pretreated eNOS-deficient (eNOS−/-) mice. Collectively, we found that pretreatment with LED-T reduced the amount of ischemia-induced brain damage. Importantly, we revealed that these effects were mediated by the stimulation of eNOS phosphorylation via the PI3K/Akt pathway.
Use of photostimulation including low‐level light emitting diode (LED) therapy has broadened greatly in recent years because it is compact, portable, and easy to use. Here, the effects of photostimulation by LED (610 nm) therapy on ischemic brain damage was investigated in mice in which treatment started after a stroke in a clinically relevant setting. The mice underwent LED therapy (20 min) twice a day for 3 days, commencing at 4 hours post‐ischemia. LED therapy group generated a significantly smaller infarct size and improvements in neurological function based on neurologic test score. LED therapy profoundly reduced neuroinflammatory responses including neutrophil infiltration and microglia activation in the ischemic cortex. LED therapy also decreased cell death and attenuated the NLRP3 inflammasome, in accordance with down‐regulation of pro‐inflammatory cytokines IL‐1β and IL‐18 in the ischemic brain. Moreover, the mice with post‐ischemic LED therapy showed suppressed TLR‐2 levels, MAPK signaling and NF‐kB activation. These findings suggest that by suppressing the inflammasome, LED therapy can attenuate neuroinflammatory responses and tissue damage following ischemic stroke. Therapeutic interventions targeting the inflammasome via photostimulation with LED may be a novel approach to ameliorate brain injury following ischemic stroke.
Effect of post‐ischemic low‐level light emitting diode therapy (LED‐T) on infarct reduction was mediated by inflammasome suppression.
A single-electron transistor (SET) comprising highly resistive Cr thin-film strips (sheet resistance ∼4 kΩ) instead of traditional tunnel barriers is reported. Two such strips (∼1 μm long) connect two Al outer electrodes to an Al island 1 μm in length equipped with a capacitively coupled gate. This transistor with a total asymptotic resistance of 110 kΩ showed a perfect Coulomb blockade and strictly e-periodic reproducible modulation by the gate in wide ranges of bias (V) and gate (Vg) voltages. In the Coulomb-blockade region (∣V∣⩽ about 0.5 mV), we observed a strong suppression of the transport current, allowing modulation curves V(Vg) with appreciable amplitude to be measured at a fixed bias current value I as low as 100 fA. The background-charge noise of our SET was found to be similar to that of typical Al/AlOx/Al tunnel-junction single-electron transistors, namely δQ≈5×10−4e/ at 10 Hz. The electron transport mechanism is discussed. © 2001 American Institute of Physics.
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.
Near-infrared transcranial laser therapy (TLT) has been found to modulate various biological processes including traumatic brain injury (TBI). Following TBI in mice, in this study we assessed the possibility of various near-infrared TLT modes (pulsed versus continuous) in producing a beneficial effect on the long-term neurobehavioral outcome and brain lesions of these mice. TBI was induced by a weight-drop device, and neurobehavioral function was assessed from 1 h to 56 days post-trauma using the Neurological Severity Score (NSS). The extent of recovery is expressed as the difference in NSS (dNSS), the difference between the initial score and that at any other later time point. An 808-nm Ga-Al-As diode laser was employed transcranially 4, 6, or 8 h post-trauma to illuminate the entire cortex of the brain. Mice were divided into several groups of 6-8 mice: one control group that received a sham treatment and experimental groups that received either TLT continuous wave (CW) or pulsed wave (PW) mode transcranially. MRI was taken prior to sacrifice at 56 days post-injury. From 5-28 days post-TBI, the NSS of the laser-treated mice were significantly lower (p<0.05) than those of the non-laser-treated control mice. The percentage of surviving mice that demonstrated full recovery at 56 days post-CHI (NSS=0, as in intact mice) was the highest (63%) in the group that had received TLT in the PW mode at 100 Hz. In addition, magnetic resonance imaging (MRI) analysis demonstrated significantly smaller infarct lesion volumes in laser-treated mice compared to controls. Our data suggest that non-invasive TLT of mice post-TBI provides a significant long-term functional neurological benefit, and that the pulsed laser mode at 100 Hz is the preferred mode for such treatment.
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.
Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation at a cellular level remain unclear.
In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810 nm laser radiation. Significant activation of NF-kB was observed at fluences higher than 0.003 J/cm(2) and was confirmed by Western blot analysis. NF-kB was activated earlier (1 hour) by LLLT compared to conventional lipopolysaccharide treatment. We also observed that LLLT induced intracellular reactive oxygen species (ROS) production similar to mitochondrial inhibitors, such as antimycin A, rotenone and paraquat. Furthermore, we observed similar NF-kB activation with these mitochondrial inhibitors. These results, together with inhibition of laser induced NF-kB activation by antioxidants, suggests that ROS play an important role in the laser induced NF-kB signaling pathways. However, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that LLLT also upregulates mitochondrial respiration.
We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive NFkB signaling via generation of ROS. Expression of anti-apoptosis and pro-survival genes responsive to NFkB could explain many clinical effects of LLLT.
The purpose of this study was to investigate the effect of 810-nm low level laser therapy (LLLT) on dendritic cells (DC) in vitro.
LLLT can enhance wound healing and increase cell proliferation and survival, and is used to treat inflammatory conditions. However there are reports that LLLT can stimulate leukocytes and could therefore be pro-inflammatory. Recently, DC have been found to play an important role in inflammation and immune response.
Murine bone-marrow-derived DC were isolated, stimulated with lipopolysaccharide (LPS) or CpG oligodeoxynucleotide and treated with 810-nm laser, using fluences of 0.3, 3, and 30 J/cm(2) delivered at irradiances of 1, 10, and 100 mW/cm(2) respectively. Confocal microscopy, flow cytometry for DC markers, viability using propidium iodide, enzyme-linked immunosorbent assays (ELISA) for secreted interleukin-12 (IL-12), and bioluminescence measurements in cells transduced with a reporter for toll-like receptor (TLR)-9/nuclear factor kappa B (NF-κB) activation, were performed.
LLLT changed the morphology of LPS-stimulated DC, increased their viability, and altered the balance of DC activation markers (major histocompatibility complex [MHC] class 2 up and CD86 down). LLLT reduced IL-12 secretion from DC stimulated by either LPS or CpG. LLLT reduced NF-κB activation in reporter cells stimulated with CpG. There was no obvious light dose response observed.
Taken together, these data suggest that 810-nm LLLT has an anti-inflammatory effect on activated DC, possibly mediated by cyclic adenosine monophosphate (cAMP) and reduced NF-κB signaling.
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.
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 cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and 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. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response.
Photodynamic therapy (PDT) was discovered over 100 years ago by observing the killing of microorganisms when harmless dyes and visible light were combined in vitro. Since then it has primarily been developed as a treatment for cancer, ophthalmologic disorders and in dermatology. However, in recent years interest in the antimicrobial effects of PDT has revived and it has been proposed as a therapy for a large variety of localized infections. This revival of interest has largely been driven by the inexorable increase in drug resistance among many classes of pathogen. Advantages of PDT include equal killing effectiveness regardless of antibiotic resistance, and a lack of induction of PDT resistance. Disadvantages include the cessation of the antimicrobial effect when the light is turned off, and less than perfect selectivity for microbial cells over host tissue. This review will cover the use of PDT to kill or inactivate pathogens in ex vivo tissues and in biological materials such as blood. PDT has been successfully used to kill pathogens and even to save life in several animal models of localized infections such as surface wounds, burns, oral sites, abscesses and the middle ear. A large number of clinical studies of PDT for viral papillomatosis lesions and for acne refer to its antimicrobial effect, but it is unclear how important this microbial killing is to the overall therapeutic outcome. PDT for periodontitis is a rapidly growing clinical application and other dental applications are under investigation. PDT is being clinically studied for other dermatological infections such as leishmaniasis and mycobacteria. Antimicrobial PDT will become more important in the future as antibiotic resistance is only expected to continue to increase.
Nitric oxide is an important messenger in numerous biological processes, such as angiogenesis, hypoxic vasodilation, and cardioprotection. Although nitric oxide synthases (NOS) produce the bulk of NO, there is increasing interest in NOS independent generation of NO in vivo, particularly during hypoxia or anoxia, where low oxygen tensions limit NOS activity. Interventions that can increase NO bioavailability have significant therapeutic potential. The use of far red and near infrared light (R/NIR) can reduce infarct size, protect neurons from methanol toxicity, and stimulate angiogenesis. How R/NIR modulates these processes in vivo and in vitro is unknown, but it has been suggested that increases in NO levels are involved. In this study we examined if R/NIR light could facilitate the release of NO from nitrosyl heme proteins. In addition, we examined if R/NIR light could enhance the protective effects of nitrite on ischemia and reperfusion injury in the rabbit heart. We show both in purified systems and in myocardium that R/NIR light can decay nitrosyl hemes and release NO, and that this released NO may enhance the cardioprotective effects of nitrite. Thus, the photodissociation to NO and its synergistic effect with sodium nitrite may represent a noninvasive and site-specific means for increasing NO bioavailability.
Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome. This review focuses on a number of such multifunctional compounds that have shown considerable success in experimental studies and that show maximum promise for success in clinical trials.
Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.
After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.
We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.
As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)
Methanol intoxication produces toxic injury to the retina and optic nerve, resulting in blindness. The toxic metabolite in methanol intoxication is formic acid, a mitochondrial toxin known to inhibit the essential mitochondrial enzyme, cytochrome oxidase. Photobiomodulation by red to near-IR radiation has been demonstrated to enhance mitochondrial activity and promote cell survival in vitro by stimulation of cytochrome oxidase activity. The present studies were undertaken to test the hypothesis that exposure to monochromatic red radiation from light-emitting diode (LED) arrays would protect the retina against the toxic actions of methanol-derived formic acid in a rodent model of methanol toxicity. Using the electroretinogram as a sensitive indicator of retinal function, we demonstrated that three brief (2 min, 24 s) 670-nm LED treatments (4 J/cm(2)), delivered at 5, 25, and 50 h of methanol intoxication, attenuated the retinotoxic effects of methanol-derived formate. Our studies document a significant recovery of rod- and cone-mediated function in LED-treated, methanol-intoxicated rats. We further show that LED treatment protected the retina from the histopathologic changes induced by methanol-derived formate. These findings provide a link between the actions of monochromatic red to near-IR light on mitochondrial oxidative metabolism in vitro and retinoprotection in vivo. They also suggest that photobiomodulation may enhance recovery from retinal injury and other ocular diseases in which mitochondrial dysfunction is postulated to play a role.
The influence of He-Ne laser radiation on the formation of new blood vessels in the bone marrow compartment of a regenerating area of the mid-cortical diaphysis of the tibiae of young adult rats was studied. A small hole was surgically made with a dentistry burr in the tibia and the injured area received a daily laser therapy over 7 or 14 days transcutaneously starting 24 h from surgery. Incident energy density dosages of 31.5 and 94.5 Jcm(-2) were applied during the period of the tibia wound healing investigated. Light microscopic examination of histological sections of the injured area and quantification of the newly-formed blood vessels were undertaken. Low-level energy treatment accelerated the deposition of bone matrix and histological characteristics compatible with an active recovery of the injured tissue. He-Ne laser therapy significantly increased the number of blood vessels after 7 days irradiation at an energy density of 94.5 Jcm(-2), but significantly decreased the number of vessels in the 14-day irradiated tibiae, independent of the dosage. These effects were attributed to laser treatment, since no significant increase in blood vessel number was detected between 8 and 15 non-irradiated control tibiae. Molecular mechanisms involved in low-level laser therapy of angiogenesis in post-traumatic bone regeneration needs further investigation.
Because photon energy delivered using a low-energy infrared laser may be useful to treat stroke, we determined whether transcranial laser therapy would improve behavioral deficits in a rabbit small clot embolic stroke model (RSCEM).
In this study, the behavioral and physiological effects of laser treatment were measured. The RSCEM was used to assess whether low-energy laser treatment (7.5 or 25 mW/cm2) altered clinical rating scores (behavior) when given to rabbits beginning 1 to 24 hours postembolization. Behavioral analysis was conducted from 24 hours to 21 days after embolization, allowing for the determination of the effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Using the RSCEM, a treatment is considered beneficial if it significantly increases the P50 compared with the control group.
In the present study, the P50 value for controls were 0.97+/-0.19 mg to 1.10+/-0.17 mg; this was increased by 100% to 195% (P50=2.02+/-0.46 to 2.98+/-0.65 mg) if laser treatment was initiated up to 6 hours, but not 24 hours, postembolization (P50=1.23+/-0.15 mg). Laser treatment also produced a durable effect that was measurable 21 days after embolization. Laser treatment (25 mW/cm2) did not affect the physiological variables that were measured.
This study shows that laser treatment improved behavioral performance if initiated within 6 hours of an embolic stroke and the effect of laser treatment is durable. Therefore, transcranial laser treatment may be useful to treat human stroke patients and should be further developed.
The detailed molecular mechanism for the reversible inhibition of mitochondrial respiration by NO has puzzled investigators: The rate constants for the binding of NO and O2 to the reduced binuclear center CuB/a3 of cytochrome oxidase (COX) are similar, and NO is able to dissociate slowly from this center whereas O2 is kinetically trapped, which altogether seems to favor the complex of COX with O2 over the complex of COX with NO. Paradoxically, the inhibition of COX by NO is observed at high ratios of O2 to NO (in the 40–500 range) and is very fast (seconds or faster). In this work, we used simple mathematical models to investigate this paradox and other important biological questions concerning the inhibition of COX by NO. The results showed that all known features of the inhibition of COX by NO can be accounted for by a direct competition between NO and O2 for the reduced binuclear center CuB/a3 of COX. Besides conciliating apparently contradictory data, this work provided an explanation for the so-called excess capacity of COX by showing that the COX activity found in tissues actually is optimized to avoid an excessive inhibition of mitochondrial respiration by NO, allowing a moderate, but not excessive, overlap between the roles of NO in COX inhibition and in cellular signaling. In pathological situations such as COX-deficiency diseases and chronic inflammation, an excessive inhibition of the mitochondrial respiration is predicted.
• mitochondrial respiration
• mathematical model
• cytochrome-oxidase-deficiency diseases
• inflammation
• excess capacity of cytochrome oxidase
Far red and near infrared (NIR) light promotes wound healing, but the mechanism is poorly understood. Our previous studies
using 670 nm light-emitting diode (LED) arrays suggest that cytochrome c oxidase, a photoacceptor in the NIR range, plays an important role in therapeutic photobiomodulation. If this is true, then
an irreversible inhibitor of cytochrome c oxidase, potassium cyanide (KCN), should compete with LED and reduce its beneficial effects. This hypothesis was tested on
primary cultured neurons. LED treatment partially restored enzyme activity blocked by 10–100 μm KCN. It significantly reduced neuronal cell death induced by 300 μm KCN from 83.6 to 43.5%. However, at 1–100 mm KCN, the protective effects of LED decreased, and neuronal deaths increased. LED significantly restored neuronal ATP content
only at 10 μm KCN but not at higher concentrations of KCN tested. Pretreatment with LED enhanced efficacy of LED during exposure to 10
or 100 μm KCN but did not restore enzyme activity to control levels. In contrast, LED was able to completely reverse the detrimental
effect of tetrodotoxin, which only indirectly down-regulated enzyme levels. Among the wavelengths tested (670, 728, 770, 830, and 880 nm), the most effective ones (830
nm, 670 nm) paralleled the NIR absorption spectrum of oxidized cytochrome c oxidase, whereas the least effective wavelength, 728 nm, did not. The results are consistent with our hypothesis that the
mechanism of photobiomodulation involves the up-regulation of cytochrome c oxidase, leading to increased energy metabolism in neurons functionally inactivated by toxins.
Low-energy visible light (LEVL) has been shown to stimulate cell functions. This is called "photobiostimulation" and has been used successfully over the last three decades for treating a range of conditions, including soft tissue injuries, severe wounds, chronic pain, and more. Nevertheless, the mechanism of photobiostimulative processes is still being debated. It is obvious that, in order to interact with the living cell, light has to be absorbed by intracellular chromophores. In a search for chromophores responsible for photobiostimulation, endogenous porphyrins, mitochondrial and membranal cytochromes, and flavoproteins were found to be suitable candidates. The above-mentioned chromophores are photosensitizers that generate reactive oxygen species (ROS) following irradiation. As the cellular redox state has a key role in maintaining the viability of the cell, changes in ROS may play a significant role in cell activation. In the present review, we summarize evidence demonstrating that various ROS and antioxidants are produced following LEVL illumination. We found that very little evidence for NO formation in illuminated non-vascular smooth muscle cells exists in the literature. We suggest that the change in the cellular redox state which plays a pivotal role in maintaining cellular activities leads to photobiostimulative processes.
Predicting the effects of polychromatic light on biological systems is a central goal of environmental photobiology. If the dose-response function for a process is a linear function of the light incident on a system at each wavelength within the spectrum, the effect of a polychromatic spectrum is obtained by integrating the product of the cross section for the reaction at each wavelength and the spectral irradiance at that wavelength over both wavelength and time. This procedure cannot be used, however, if the dose-response functions for an effect are not linear functions of photon dose. Although many photochemical reactions are linear within the biologically relevant range of doses, many biological end points are not. I describe procedures for calculating the effects of polychromatic irradiations on systems that exhibit certain classes of dose-response functions, including power law responses typical of mutation induction and exponential dose-responses typical of cell survival. I also present an approach to predict the effects of polychromatic spectra on systems in which the ultraviolet components form pyrimidine dimers, and the longer-wavelength ultraviolet and visible components remove them by photoreactivation, thus generating complex dose-response functions for these coupled light-driven reactions.
Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke.
METHODS:
The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS:
RESULTS:
In part 1, there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours, although a benefit was observed for the t-PA group at three months for all four outcome measures. In part 2, the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed (global odds ratio for a favorable outcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo (P < 0.001). Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group (P = 0.30).
CONCLUSIONS:
Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.
Photobiomodulation with near infrared light (NIR) provides cellular protection in various disease models. Previously, infrared light emitted by a low-energy laser has been shown to significantly improve recovery from ischemic injury of the canine heart. The goal of this investigation was to test the hypothesis that NIR (670 nm) from light emitting diodes produces cellular protection against hypoxia and reoxygenation-induced cardiomyocyte injury. Additionally, nitric oxide (NO) was investigated as a potential cellular mediator of NIR. Our results demonstrate that exposure to NIR at the time of reoxygenation protects neonatal rat cardiomyocytes and HL-1 cells from injury, as assessed by lactate dehydrogenase release and MTT assay. Similarly, indices of apoptosis, including caspase 3 activity, annexin binding and the release of cytochrome c from mitochondria into the cytosol, were decreased after NIR treatment. NIR increased NO in cardiomyocytes, and the protective effect of NIR was completely reversed by the NO scavengers carboxy-PTIO and oxyhemoglobin, but only partially blocked by the NO synthase (NOS) inhibitor L-NMMA. Mitochondrial metabolism, measured by ATP synthase activity, was increased by NIR, and NO-induced inhibition of oxygen consumption with substrates for complex I or complex IV was reversed by exposure to NIR. Taken together these data provide evidence for protection against hypoxia and reoxygenation injury in cardiomyocytes by NIR in a manner that is dependent upon NO derived from NOS and non-NOS sources.
Traumatic brain injury (TBI) affects millions worldwide and is without effective treatment. One area that is attracting growing interest is the use of transcranial low-level laser therapy (LLLT) to treat TBI. The fact that near-infrared light can penetrate into the brain would allow non-invasive treatment to be carried out with a low likelihood of treatment-related adverse events. LLLT may treat TBI by increasing respiration in the mitochondria, causing activation of transcription factors, reducing inflammatory mediators and oxidative stress, and inhibiting apoptosis.
We tested LLLT in a mouse model of closed-head TBI produced by a controlled weight drop onto the skull. Mice received a single treatment with continuous-wave 665, 730, 810, or 980 nm lasers (36 J/cm(2) delivered at 150 mW/cm(2)) 4-hour post-TBI and were followed up by neurological performance testing for 4 weeks.
Mice with moderate-to-severe TBI treated with 665 and 810 nm laser (but not with 730 or 980 nm) had a significant improvement in Neurological Severity Score that increased over the course of the follow-up compared to sham-treated controls. Morphometry of brain sections showed a reduction in small deficits in 665 and 810 nm laser treated mouse brains at 28 days.
The effectiveness of 810 nm agrees with previous publications, and together with the effectiveness of 660 nm and non-effectiveness of 730 and 980 nm can be explained by the absorption spectrum of cytochrome oxidase, the candidate mitochondrial chromophore in transcranial LLLT.
This study aimed to quantify the cerebral blood flow (CBF) after bilateral, transcranial near-infrared light-emitting diode (LED) irradiation to the forehead in a patient in a persistent vegetative state following severe head injury.
Positive behavioral improvement has been observed following transcranial near-infrared light therapy in humans with chronic traumatic brain injury and acute stroke. Methods: Single-photon emission computed tomography with N-isopropyl-[123I]p-iodoamphetamine (IMP-SPECT) was performed following a series of LED treatments.
IMP-SPECT showed unilateral, left anterior frontal lobe focal increase of 20%, compared to the pre-treatment value for regional CBF (rCBF) for this area, following 146 LED treatments over 73 days from an array of 23×850 nm LEDs, 13 mW each, held 5 mm from the skin, 30 min per session, the power density 11.4 mW/cm(2); the energy density 20.5 J/cm(2) at the skin. The patient showed some improvement in his neurological condition by moving his left arm/hand to reach the tracheostomy tube, post-LED therapy.
Transcranial LED might increase rCBF with some improvement of neurological condition in severely head-injured patients. Further study is warranted.
Low-level laser light therapy (LLLT) exerts beneficial effects on motor and histopathological outcomes after experimental traumatic brain injury (TBI), and coherent near-infrared light has been reported to improve cognitive function in patients with chronic TBI. However, the effects of LLLT on cognitive recovery in experimental TBI are unknown. We hypothesized that LLLT administered after controlled cortical impact (CCI) would improve post-injury Morris water maze (MWM) performance. Low-level laser light (800 nm) was applied directly to the contused parenchyma or transcranially in mice beginning 60-80 min after CCI. Injured mice treated with 60 J/cm² (500 mW/cm²×2 min) either transcranially or via an open craniotomy had modestly improved latency to the hidden platform (p<0.05 for group), and probe trial performance (p<0.01) compared to non-treated controls. The beneficial effects of LLLT in open craniotomy mice were associated with reduced microgliosis at 48 h (21.8±2.3 versus 39.2±4.2 IbA-1+ cells/200×field, p<0.05). Little or no effect of LLLT on post-injury cognitive function was observed using the other doses, a 4-h administration time point and 7-day administration of 60 J/cm². No effect of LLLT (60 J/cm² open craniotomy) was observed on post-injury motor function (days 1-7), brain edema (24 h), nitrosative stress (24 h), or lesion volume (14 days). Although further dose optimization and mechanism studies are needed, the data suggest that LLLT might be a therapeutic option to improve cognitive recovery and limit inflammation after TBI.
Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Survivors of TBI frequently suffer from long-term personality changes and deficits in cognitive and motor performance, urgently calling for novel pharmacological treatment options. To date, all clinical trials evaluating neuroprotective compounds have failed in demonstrating clinical efficacy in cohorts of severely injured TBI patients. The purpose of the present review is to describe the utility of animal models of TBI for preclinical evaluation of pharmacological compounds. No single animal model can adequately mimic all aspects of human TBI owing to the heterogeneity of clinical TBI. To successfully develop compounds for clinical TBI, a thorough evaluation in several TBI models and injury severities is crucial. Additionally, brain pharmacokinetics and the time window must be carefully evaluated. Although the search for a single-compound, ‘silver bullet’ therapy is ongoing, a combination of drugs targeting various aspects of neuroprotection, neuroinflammation and regeneration may be needed. In summary, finding drugs and prove clinical efficacy in TBI is a major challenge ahead for the research community and the drug industry. For a successful translation of basic science knowledge to the clinic to occur we believe that a further refinement of animal models and functional outcome methods is important. In the clinical setting, improved patient classification, more homogenous patient cohorts in clinical trials, standardized treatment strategies, improved central nervous system drug delivery systems and monitoring of target drug levels and drug effects is warranted.
LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4
A complex set of molecular and functional reactions is set into motion by traumatic brain injury (TBI). New research that extends beyond pathological effects on neurons suggests a key role for the blood-brain barrier, neurovascular unit, arginine vasopressin, and neuroinflammation in the pathophysiology of TBI. The prevalence of molecular derangements in TBI holds promise for the identification and use of biomarkers to assess severity of injury, determine prognosis, and perhaps direct therapy. Hopefully, improved knowledge of these elements of pathophysiology will provide the mechanistic clues that lead to improved treatment of TBI.
Brain injury is responsible for significant morbidity and mortality in trauma patients, but controversy still exists over therapeutic management for these patients. The objective of this study was to analyze the effect of phototherapy with low intensity lasers on local and systemic immunomodulation following cryogenic brain injury. Laser phototherapy was applied (or not-controls) immediately after cryogenic brain injury performed in 51 adult male Wistar rats. The animals were irradiated twice (3 h interval), with continuous diode laser (gallium-aluminum-arsenide (GaAlAs), 780 nm, or indium-gallium-aluminum-phosphide (InGaAlP), 660 nm) in two points and contact mode, 40 mW, spot size 0.042 cm(2), 3 J/cm(2) and 5 J/cm(2) (3 s and 5 s, respectively). The experimental groups were: Control (non-irradiated), RL3 (visible red laser/ 3 J/cm(2)), RL5 (visible red laser/5 J/cm(2)), IRL3 (infrared laser/3 J/cm(2)), IRL5 (infrared laser/5 J/cm(2)). The production of interleukin-1IL-1beta (IL-1beta), interleukin6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha) was analyzed by enzyme immunoassay technique (ELISA) test in brain and blood samples. The IL-1beta concentration in brain of the control group was significantly reduced in 24 h (p<0.01). This reduction was also observed in the RL5 and IRL3 groups. The TNF-alpha and IL-6 concentrations increased significantly (p<0.01 and p<0.05, respectively) in the blood of all groups, except by the IRL3 group. The IL-6 levels in RL3 group were significantly smaller than in control group in both experimental times. IL-10 concentration was maintained stable in all groups in brain and blood. Under the conditions of this study, it is possible to conclude that the laser phototherapy can affect TNF-alpha, IL-1beta and IL-6 levels in the brain and in circulation in the first 24 h following cryogenic brain injury.
Brain plasticity refers to changes in brain function and structure that arise in a number of contexts. One area in which brain plasticity is of considerable interest is recovery from stroke, both spontaneous and treatment-induced. A number of factors influence these poststroke brain events. The current review considers the impact of genetic factors. Polymorphisms in the human genes coding for brain-derived neurotrophic factor (BDNF) and apolipoprotein E (ApoE) have been studied in the context of plasticity and/or stroke recovery and are discussed here in detail. Several other genetic polymorphisms are indirectly involved in stroke recovery through their modulating influences on processes such as depression and pharmacotherapy effects. Finally, new genetic polymorphisms that have not been studied in the context of stroke are proposed as new directions for study. A better understanding of genetic influences on recovery and response to therapy might allow improved treatment after stroke.