Spatial correspondence of cortical activity measured with whole head fNIRS and fMRI: Toward clinical use within subject.

Functional near infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI) both measure the hemodynamic response, and so both imaging modalities are expected to have a strong correspondence in regions of cortex adjacent to the scalp. To assess whether fNIRS can be used clinically in a manner similar to fMRI, 22 healthy adult participants underwent same-day fMRI and whole-head fNIRS testing while they performed separate motor (finger tapping) and visual (flashing checkerboard) tasks. Analyses were conducted within and across subjects for each imaging approach, and regions of significant task-related activity were compared on the cortical surface. The spatial correspondence between fNIRS and fMRI detection of task-related activity was good in terms of true positive rate, with fNIRS overlap of up to 68 % of the fMRI for analyses across subjects (group analysis) and an average overlap of up to 47.25 % for individual analyses within subject. At the group level, the positive predictive value of fNIRS was 51 % relative to fMRI. The positive predictive value for within subject analyses was lower (41.5 %), reflecting the presence of significant fNIRS activity in regions without significant fMRI activity. This could reflect task-correlated sources of physiologic noise and/or differences in the sensitivity of fNIRS and fMRI measures to changes in separate (vs. combined) measures of oxy and de-oxyhemoglobin. The results suggest whole-head fNIRS as a noninvasive imaging modality with promising clinical utility for the functional assessment of brain activity in superficial regions of cortex physically adjacent to the skull.

Treatment of Cells and Tissues with Chromate Maximizes Mitochondrial 2Fe2S EPR Signals.

In a previous study on chromate toxicity, an increase in the 2Fe2S electron paramagnetic resonance (EPR) signal from mitochondria was found upon addition of chromate to human bronchial epithelial cells and bovine airway tissue ex vivo. This study was undertaken to show that a chromate-induced increase in the 2Fe2S EPR signal is a general phenomenon that can be used as a low-temperature EPR method to determine the maximum concentration of 2Fe2S centers in mitochondria. First, the low-temperature EPR method to determine the concentration of 2Fe2S clusters in cells and tissues is fully developed for other cells and tissues. The EPR signal for the 2Fe2S clusters N1b in Complex I and/or S1 in Complex II and the 2Fe2S cluster in xanthine oxidoreductase in rat liver tissue do not change in intensity because these clusters are already reduced; however, the EPR signals for N2, the terminal cluster in Complex I, and N4, the cluster preceding the terminal cluster, decrease upon adding chromate. More surprising to us, the EPR signals for N3, the cluster preceding the 2Fe2S cluster in Complex I, also decrease upon adding chromate. Moreover, this method is used to obtain the concentration of the 2Fe2S clusters in white blood cells where the 2Fe2S signal is mostly oxidized before treatment with chromate and becomes reduced and EPR detectable after treatment with chromate. The increase of the g = 1.94 2Fe2S EPR signal upon the addition of chromate can thus be used to obtain the relative steady-state concentration of the 2Fe2S clusters and steady-state concentration of Complex I and/or Complex II in mitochondria.

Using hyperbaric oxygen for autism treatment: A review and discussion of literature.

PURPOSE: To determine whether hyperbaric oxygen (HBO2) therapy should be used for the treatment of autism spectrum disorders (ASD). METHODS: A literature search was performed on PubMed, Cochrane Library and DynaMed for studies evaluating the use of HBO2 for ASD treatment. The studies were then reviewed for the highest quality evidence. RESULTS: The evidence is weak for the use of HBO2 in ASD, with only one, likely flawed, randomized control study showing treatment benefit. CONCLUSIONS: HBO2 should not be recommended for ASD treatment until more conclusive favorable results and long-term outcomes are demonstrated from well-designed controlled trials.

Haemodynamic response associated with both ictal and interictal epileptiform activity using simultaneous video electroencephalography/near infrared spectroscopy in a within-subject study.

This paper reports the findings from a pilot study of four patients with medically refractory epilepsy undergoing pre-surgical evaluation with ages ranging from 5 to 17 years. Video electroencephalography recordings and data from a near infrared spectroscopy cerebral/somatic oximeter were gathered and related to electrographic seizure onset and offset as determined by a paediatric epileptologist. All four patients showed haemodynamic changes associated with epileptiform activities. The increased blood flow clearly coincided with epileptiform activity and continued to increase as the epileptiform activity built up. Regional cerebral oxygen saturation increased in the epileptogenic focus, perhaps due to loss of cerebrovascular autoregulation. These findings reinforce that near infrared spectroscopy can potentially be used in a wide spectrum of patients with epilepsy regardless of the underlying brain pathology.

Ketogenic diet for high partial pressure oxygen diving.

INTRODUCTION: A ketogenic diet (KD) may decrease central nervous system oxygen toxicity symptoms in divers, and in view of this implication a feasibility/ toxicity pilot study was performed to demonstrate tolerance of KD while performing normal diving profiles. The exact mechanism of neuroprotection from the KD remains unknown; however, evidence to support the efficacy of the KD in reducing seizures is present in epilepsy and oxygen toxicity studies, and may provide valuable insight in diving activities. METHODS: Three divers (two males and one female ages 32-45 with a history of deep diving and high pO2 exposure) on the KD made dives to varying depths in Hawaii using fully closed-circuit MK-15 and Inspiration rebreathers. These rebreathers have an electronically controlled set point, allowing the divers to monitor and control the oxygen level in the breathing loop, which can be varied manually by the divers. Oxygen level was varied during descent, bottom depth and ascent (decompression). Divers fasted for 12-18 hours before diet initiation. The ketosis level was verified by urinating on a Ketostix (reagent strips for urinalysis). RESULTS/SUMMARY: Ketosis was achieved and was easily monitored with Ketostix in the simulated operational environment. The KD did not interfere with the diving mission; no seizure activity or signs or symptoms of CNS toxicity were observed, and there were no adverse effects noted by the divers while on the KD.

Risk factors for oxygen toxicity seizures in hyperbaric oxygen therapy: case reports from multiple institutions.

Oxygen toxicity seizures are a rare but recognized complication of hyperbaric oxygen (HBO2) therapy. Many patients undergoing HBO2 therapy have medical conditions or are taking medications that could contribute to seizures. Previous literature has not extensively reported on these factors in patients experiencing oxygen toxicity seizures. We conducted a chart review at several hyperbaric oxygen centers in the Milwaukee, Wisc., area to explore whether the patients who experienced seizures in the hyperbaric chamber had other medical comorbidities or were on medications which lowered their seizure threshold, thereby contributing to oxygen toxicity seizures. There were a total of seven cases of seizures in five patients. Each patient had risk factors for seizures, including hypercapnia secondary to chronic obstructive pulmonary disease, narcotic withdrawal, alcohol dependence, and antidepressant, tramadol or cephalosporin/ceftriaxone use. We hypothesize that patients who experience oxygen toxicity seizures may have other factors which contribute to the development of these seizures.

High-grade glioma/glioblastoma multiforme: is there a role for photodynamic therapy?

In the United States, the 5-year survival rate for patients of all ages with all types of brain tumors is approximately 20%, with the scale skewed toward even poorer survival in patients with gliomas. Although surgery and radiotherapy are primary treatment options, surgery is rarely curative and radiotherapy has had little impact on overall survival. Predominantly studied in adults with advanced high-grade gliomas, photodynamic therapy (PDT) represents a paradigmatic shift in the treatment of brain tumors. With no clear standard of care for brain tumors, PDT may emerge as a potential alternative, although challenges regarding its clinical use remain and studies confirming its promise are necessary.

The use of hyperbaric oxygen for treating delayed radiation injuries in gynecologic malignancies: a review of literature and report of radiation injury incidence.

PURPOSE: The purposes of this paper are to review the best evidence supporting the use of hyperbaric oxygen therapy (HBOT) in delayed radiation injuries in gynecologic malignancies and report the incidence of radiation injuries at two large medical centers in southeastern Wisconsin. METHODS: A literature search was performed on Google Scholar, PubMed, and Ovid for studies evaluating the use of HBOT radiation cystitis, proctitis, and necrosis. The studies were then reviewed for the highest quality evidence using American Academy of Neurology guidelines. To evaluate radiation injuries, cancer databases at Froedtert Memorial Lutheran Hospital (FMLH) and Aurora St. Luke's Hospital (ASLH) were accessed. RESULTS: Several studies support the use of HBOT in treating radiation cystitis, proctitis, and necrosis, with proctitis having the strongest evidence in its favor. The average annual incidence of radiation injury at FMLH was 13.8%. Patients with cervical cancer and vulvar cancer had rates of 23% each. The average annual incidence of radiation injury among gynecologic cancer patients at ASLH was 5.5%. CONCLUSIONS: There is level A evidence for using HBOT to treat radiation proctitis. There is level B evidence for using HBOT to treat radiation cystitis and necrosis. The incidence delayed radiation injuries can be as high as 23%. This has relevance in practice guidelines for the treatment of delayed radiation injuries in gynecologic malignancies.

Amelioration of oral mucositis pain by NASA near-infrared light-emitting diodes in bone marrow transplant patients.

PURPOSE: This study seeks to investigate the use of extra-orally applied near-infrared phototherapy for the reduction of oral pain secondary to chemotherapy- and radiation therapy-induced mucositis in adult and pediatric hematopoietic stem cell transplant (HSCT) patients. METHODS: Eighty HSCT patients were divided into regular (R) and low (L) risk groups, then to experimental (E) and placebo (P) groups, resulting in four groups (ER, EL, PR, PL). Experimental subjects received 670 (± 10) nm gallium-aluminum-arsinide light-emitting diode device for 80 s at ~50 mW/cm(2) energy density and power exposure of 4 J/cm(2). Placebo patients received the same procedures, but with a placebo phototherapy (identical device but <5 mW/cm(2) energy density). Patients received their respective light therapy once per day starting on the day of the HSCT (day 0) and continued through day +14. Blinded evaluators examined the patients three times per week and scored their oral tissues and patient-reported pain assessments at each evaluation utilizing the WHO, NCI-CTCAE, and OMAS scales. RESULTS: Analysis of the mean scores at each observation demonstrate that the extra-oral application of phototherapy resulted in a significant reduction in patient-reported pain between the ER and PR patients (p < 0.05) at day +14 when graded via the WHO criteria. The ER and EL patients were improved in almost all other categories and assessment scales, but the differences were not statistically significant. CONCLUSION: Phototherapy demonstrated a significant reduction in patient-reported pain as measured by the WHO criteria in this patient population included in this study. Improvement trends were noted in most other assessment measurements.

Effect of Red-to-Near Infrared Light and a Nitric Oxide Donor on the Oxygen Consumption of Isolated Cytochrome c Oxidase.

Objective: To study the effects of 670 and 830 nm irradiation on oxygen consumption by cytochrome c oxidase (CCO) in a Clark electrode type reaction chamber. To explore the effect of irradiation on the nitric oxide (NO) donor-induced inhibition of oxygen consumption. Background: Most theories of photobiomodulation (PBM) involve the enzyme CCO as a cellular target for red-to-near infrared light (R-NIR) irradiation. Attempts to measure the effect of irradiation on the kinetics of CCO have failed to demonstrate a significant effect. It remains to explore the effects of irradiation on the consumption of oxygen. NO has been proposed as a possible mediator for PBM due to its inhibitory effects on CCO. Studying the effect of R-NIR on NO-induced inhibition of oxygen consumption is needed to explore this thesis. Methods: Oxygen consumption assays at 22°C were performed in a Mitocell MT200A system equipped with a 1302 oxygen electrode. R-NIR irradiation at 670 nm (41 mW/cm2) or 830 nm (31 mW/cm2) was provided to the reaction mixture. Calculated second-order rate constants were compared with control runs at four cytochrome c concentrations. Assays were also performed with or without NO donor and/or light for two substrate concentrations. Results: Kinetics constants for oxygen consumption with or without R-NIR showed no significant differences with either wavelength at any substrate concentration. The NO donor showed significant inhibition that was not relieved by irradiation. Conclusions: This lack of effect by R-NIR calls into question both the CCO activity model and the NO inhibition relief model of PBM.

Comparison of Whole-Head Functional Near-Infrared Spectroscopy With Functional Magnetic Resonance Imaging and Potential Application in Pediatric Neurology.

BACKGROUND: Changes in cerebral blood flow in response to neuronal activation can be measured by time-dependent fluctuations in hemoglobin species within the brain; this is the basis of functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS). There is a clinical need for portable neural imaging systems, such as fNIRS, to accommodate patients who are unable to tolerate an MR environment. OBJECTIVE: Our objective was to compare task-related full-head fNIRS and fMRI signals across cortical regions. METHODS: Eighteen healthy adults completed a same-day fNIRS-fMRI study, in which they performed right- and left-hand finger tapping tasks and a semantic-decision tones-decision task. First- and second-level general linear models were applied to both datasets. RESULTS: The finger tapping task showed that significant fNIRS channel activity over the contralateral primary motor cortex corresponded to surface fMRI activity. Similarly, significant fNIRS channel activity over the bilateral temporal lobe corresponded to the same primary auditory regions as surface fMRI during the semantic-decision tones-decision task. Additional channels were significant for this task that did not correspond to surface fMRI activity. CONCLUSION: Although both imaging modalities showed left-lateralized activation for language processing, the current fNIRS analysis did not show concordant or expected localization at the level necessary for clinical use in individual pediatric epileptic patients. Future work is needed to show whether fNIRS and fMRI are comparable at the source level so that fNIRS can be used in a clinical setting on individual patients. If comparable, such an imaging approach could be applied to children with neurological disorders.

What Lies at the Heart of Photobiomodulation: Light, Cytochrome C Oxidase, and Nitric Oxide-Review of the Evidence.

Objective: The underlying mechanisms of photobiomodulation (PBM) remain elusive. The most attractive hypotheses revolve around the role of cytochrome c oxidase (CCO) and cellular energetics. Background: No reliable demonstration of any PBM-related light-induced mechanistic effect on CCO has been reported. Studies on PBM have proven to be either nonreproducible, of questionable relevance, or involve wavelengths unlikely to be operative in vivo. The literature reveals very few demonstrable mechanistic light effects of any sort on CCO. Nitric oxide (NO) is involved in a number of the reported light effects on CCO. NO inhibits CCO at high reductive pressures by binding to the heme a3 moiety. This complex is white light labile. Methods: The reported photolability of the heme-NO complex seems to be a prime target for PBM studies, as removal of inhibiting NO from the active site of CCO could restore normal activity to inhibited CCO. Another aspect of CCO-NO chemistry has been revealed that shows intriguing possibilities. Results: A novel nitrite reductase activity of solubilized mitochondria has been demonstrated attributable to CCO. NO production was optimal under hypoxic conditions. It was also found that 590 nm irradiation increased NO production by enhancing NO release. The presence of cellular NO has usually been considered metabolically detrimental, but current thinking has expanded the importance and the physiological roles of NO. Evidence shows that NO production is likely to play a role in cardioprotection and defenses against hypoxic damage. Conclusions: Studies combining PBM and hypoxia also point to a connection between light irradiation, hypoxia protection, and NO production. This leads the authors to the possibility that the intrinsic nature of PBM involves the production of NO. The combination of CCO and hemoglobin/myoglobin NO production with photorelease of NO may constitute the heart of PBM.

Functional Near-Infrared Spectroscopy and Its Clinical Application in the Field of Neuroscience: Advances and Future Directions.

Similar to functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS) detects the changes of hemoglobin species inside the brain, but via differences in optical absorption. Within the near-infrared spectrum, light can penetrate biological tissues and be absorbed by chromophores, such as oxyhemoglobin and deoxyhemoglobin. What makes fNIRS more advantageous is its portability and potential for long-term monitoring. This paper reviews the basic mechanisms of fNIRS and its current clinical applications, the limitations toward more widespread clinical usage of fNIRS, and current efforts to improve the temporal and spatial resolution of fNIRS toward robust clinical usage within subjects. Oligochannel fNIRS is adequate for estimating global cerebral function and it has become an important tool in the critical care setting for evaluating cerebral oxygenation and autoregulation in patients with stroke and traumatic brain injury. When it comes to a more sophisticated utilization, spatial and temporal resolution becomes critical. Multichannel NIRS has improved the spatial resolution of fNIRS for brain mapping in certain task modalities, such as language mapping. However, averaging and group analysis are currently required, limiting its clinical use for monitoring and real-time event detection in individual subjects. Advances in signal processing have moved fNIRS toward individual clinical use for detecting certain types of seizures, assessing autonomic function and cortical spreading depression. However, its lack of accuracy and precision has been the major obstacle toward more sophisticated clinical use of fNIRS. The use of high-density whole head optode arrays, precise sensor locations relative to the head, anatomical co-registration, short-distance channels, and multi-dimensional signal processing can be combined to improve the sensitivity of fNIRS and increase its use as a wide-spread clinical tool for the robust assessment of brain function.

Near infrared light protects cardiomyocytes from hypoxia and reoxygenation injury by a nitric oxide dependent mechanism.

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.

Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children.

BACKGROUND AND PURPOSE: A safe and effective tissue plasminogen activator (tPA) dose for childhood stroke has not been established. This article describes a Bayesian outcome-adaptive method for determining the best dose of an experimental agent and explains how this method was used to design a dose-finding trial for tPA in childhood. METHODS: The method assigns doses to successive cohorts of patients on the basis of each dose's desirability, quantified in terms of the tradeoff between efficacy and toxicity. The tradeoff function is constructed from several pairs of equally desirable (efficacy, toxicity) probabilities specified by the physicians planning the trial. Each cohort's dose is chosen adaptively, based on dose-outcome data from the patients treated previously in the trial, to optimize the efficacy-toxicity tradeoff. Application of the method to design the tPA trial is described, including a computer simulation study to establish design properties. A hypothetical cohort-by-cohort example is given to illustrate how the method works during trial conduct. RESULTS: Because only a dose that is both safe and efficacious may be selected and the method combines phase I and phase II by integrating efficacy and toxicity to choose doses, it avoids the more time-consuming and expensive conventional approach of conducting a phase I trial based on toxicity alone followed by a phase II trial based on efficacy alone. This is especially useful in settings with low accrual rates, such as trials of tPA for pediatric acute ischemic stroke.

Near-infrared spectroscopy muscle oximetry of patients with postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a disabling condition characterized by orthostatic intolerance with tachycardia in the absence of drop-in blood pressure. A custom-built near-infrared spectroscopy device (NIRS) is applied to monitor the muscle oxygenation, noninvasively in patients undergoing incremental head-up tilt table (HUT). Subjects (6 POTS patients and 6 healthy controls) underwent 30 mins of 70°on a HUT. The results showed a significant difference in deoxyhemoglobin (Hb), change-in-oxygenation (ΔOxy) and blood volume (ΔBV) between patients and healthy controls. However, oxyhemoglobin (HbO2) showed a significantly faster rate of change in the healthy controls during the first 10 mins of the tilt and during the recovery. This NIRS muscle oximetry tool provides quantitative measurements of blood oxygenation monitoring in diseases such as POTS.

Survivorship and mortality implications of developmental 670-nm phototherapy: dioxin co-exposure.

OBJECTIVE: We assessed the effect of 670-nm light therapy on dioxin-induced embryonic mortality in chickens (Gallus gallus). BACKGROUND DATA: Developmental photobiomodulation using 670-nm light-emitting diode (LED) arrays improves hatching success and increases body size in hatchling chickens. Photobiomodulation also stimulates signaling pathways resulting in improved energy metabolism, antioxidant production and cell survival. Dioxin causes embryonic mortality, including increases in the frequency of chicken embryos that pip but can't go to hatch. We hypothesized that 670-nm LED therapy would attenuate dioxin-induced embryo mortality. METHODS: Fertile chicken eggs were injected with control or 2, 20, or 200 ppt 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) prior to the start of incubation. Half of the eggs in each dose group were treated once per day from embryonic days 0-20 with 670-nm LED light at a fluence of 4 J/cm(2). In ovo survival and hatching success were compared between dose groups and LED treatment. RESULTS: LED therapy decreased the embryonic mortality rate by 41%, resulting in increased embryonic survival and improved hatching success in eggs exposed to 200 ppt dioxin. However, at sub-lethal dioxin concentrations and in oil-treated controls, LED therapy slightly increased mortality. CONCLUSION: Overall survivorship and hatching success of chicks developmentally exposed to dioxin concentrations above the lethality threshold (>100 ppt TCDD) is improved by 670-nm LED treatment administered throughout the gestation period, but the relationship may be complicated by an LED-oil interaction.

Brief report: embryonic growth and hatching implications of developmental 670-nm phototherapy and dioxin co-exposure.

OBJECTIVE: We assessed the effect of 670-nm light therapy on growth and hatching kinetics in chickens (Gallus gallus) exposed to dioxin. BACKGROUND DATA: Photobiomodulation has been shown to stimulate signaling pathways resulting in improved energy metabolism, antioxidant production, and cell survival. In ovo treatment with 670-nm light-emitting diode (LED) arrays improves hatching success and increases hatchling size in control chickens. Under conditions where developmental dioxin exposure is above the lethality threshold (100 ppt), phototherapy attenuates dioxin-induced early embryonic death. We hypothesized that 670-nm LED therapy would attenuate dioxin-induced developmental anomalies and increase hatching success. METHODS: Fertile chicken eggs were injected with control oil, 2, 20, or 200 ppt dioxin, or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prior to the start of incubation. Half of the eggs in each dose group were treated once per day from embryonic days 0-20 with 670-nm LED light at a fluence of 4 J/cm2. Hatchling size, organ weights, and energy parameters were compared between dose groups and LED treatment. RESULTS: LED therapy resulted in earlier pip times (small hole created 12-24 h prior to hatch), and increased hatchling size and weight in the 200 ppt dose groups. However, there appears to be an LED-oil interaction within the oil-treated controls that results in longer hatch times and decreased liver weight within the LED control dose groups in comparison to the non-LED control dose groups. CONCLUSION: Size and hatching times suggest that the hatching success and preparedness of chicks developmentally exposed to dioxin concentrations above the lethality threshold is improved by 670-nm LED treatment administered throughout the gestation period, but the relationship may be complicated by an LED-oil interaction.

Clinical and experimental applications of NIR-LED photobiomodulation.

This review presents current research on the use of far-red to near-infrared (NIR) light treatment in various in vitro and in vivo models. Low-intensity light therapy, commonly referred to as "photobiomodulation," uses light in the far-red to near-infrared region of the spectrum (630-1000 nm) and modulates numerous cellular functions. Positive effects of NIR-light-emitting diode (LED) light treatment include acceleration of wound healing, improved recovery from ischemic injury of the heart, and attenuated degeneration of injured optic nerves by improving mitochondrial energy metabolism and production. Various in vitro and in vivo models of mitochondrial dysfunction were treated with a variety of wavelengths of NIR-LED light. These studies were performed to determine the effect of NIR-LED light treatment on physiologic and pathologic processes. NIRLED light treatment stimulates the photoacceptor cytochrome c oxidase, resulting in increased energy metabolism and production. NIR-LED light treatment accelerates wound healing in ischemic rat and murine diabetic wound healing models, attenuates the retinotoxic effects of methanol-derived formic acid in rat models, and attenuates the developmental toxicity of dioxin in chicken embryos. Furthermore, NIR-LED light treatment prevents the development of oral mucositis in pediatric bone marrow transplant patients. The experimental results demonstrate that NIR-LED light treatment stimulates mitochondrial oxidative metabolism in vitro, and accelerates cell and tissue repair in vivo. NIR-LED light represents a novel, noninvasive, therapeutic intervention for the treatment of numerous diseases linked to mitochondrial dysfunction.