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.

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.

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.

Photodynamic Therapy for Benign Cutaneous Neurofibromas Using Aminolevulinic Acid Topical Application and 633 nm Red Light Illumination.

Background: Neurofibromatosis type 1 (NF1) has no current effective treatments beyond surgery. Topical photodynamic therapy (PDT) has the potential to provide a less invasive treatment modality. Objective: Based on murine data, we hypothesized PDT could be used for the treatment of cutaneous neurofibromas (cNF). Methods and results: We conducted a phase I trial to examine absorption and conversion of topical aminolevulinic acid (ALA) in cNF and determine safety in a dose escalation study. ALA or control vehicle was applied to neurofibromas through microneedle-assisted delivery (n = 4) and excised specimens were examined 24 h later for protoporphyrin IX fluorescence. Fluorescence was detected in the tumors at 304 ± 94 U/µm2, while adjacent paralesional normal skin and vehicle-treated tumors showed no fluorescence (p < 0.0001). Subsequently, neurofibromas (n = 27) were treated with ALA and irradiated with 633 nm red light 18 h later, at escalating dosages of 50 and 100 mJ/cm2. Maximum tolerable dose was established at 100 mJ/cm2. Light microscopy study of tumors biopsied 48 h after PDT (ALA n = 14 and vehicle n = 4) showed mixed inflammatory infiltrate in the ALA, but not in the vehicle-treated tumors or perilesional normal skin. TUNEL evaluation showed 42.5 ± 19.9 apoptotic cells per visual field for ALA-treated and 1.1 ± 1.4 for vehicle-treated tumors (p = 0.002). Conclusions: In the first reported clinical trial of PDT for NF1, PDT targeted neurofibromas specifically, and may offer a normal tissue-sparing treatment modality in the future. This study is registered at Clintrials.gov (NCT01682811).

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.

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.

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.

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.

Effect of near-infrared light on in vitro cellular ATP production of osteoblasts and fibroblasts and on fracture healing with intramedullary fixation.

OBJECTIVE: Evaluate the effect of near-infrared light (NIR) on immediate production of ATP by osteoblasts and fibroblasts in vitro, and the healing process of rat femur fractures with intramedullary fixation. BACKGROUND: NIR is one potential treatment option for complications of fracture healing, which has shown to stimulate cellular proliferation and to enhance the healing process. METHODS: Cell culture - MC3T3-E1 and 3T3-A31 cells were subjected to NIR at 660 nm, 830 nm, or both combined. ATP was assayed at 5, 10, 20, and 45 min after exposure. Animal study - 18 rats had surgery with retrograde intramedullary pins inserted into their femurs, which then underwent closed, transverse femur fracture. Rats were randomly divided into 3 study groups of 6 each: nonirradiated controls, 660 nm, and 830 nm NIR. Healing process was assessed by a blinded radiologist, assigning a healing score of 1-6 for radiographs taken on days 0, 7, 14, and 21. RESULTS: Cell culture - All groups gave significant increase in ATP within 5-10 min, with decay to baseline by 45 min. 660 nm NIR was significantly more effective than 830 nm with fibroblasts or either wavelength with osteoblasts. Animal study - A significant increase in the fracture healing grade in the 660 nm group at day 14, but with no differences at day 21. CONCLUSION: The study demonstrated an immediate increase in ATP production in vitro and an initial acceleration of callus formation in the fracture healing process, in the presence of NIR.

Effect of Red-to-Near Infrared Light on the Reaction of Isolated Cytochrome c Oxidase with Cytochrome c.

OBJECTIVE: Our primary hypothesis was that red-to-near infrared (R-NIR) irradiation would have an effect on the kinetics parameters of the reaction of cytochrome c with isolated cytochrome c oxidase (CCO), and that the magnitude and direction of these changes could be interpreted in the context of the reaction schemes proposed by other authors. New values for the milimolar extinction coefficients of cytochrome c were also determined. BACKGROUND DATA: Definitive answers to the fundamental processes involved in red-to-near infrared photobiomodulation (R-NIR-PBM) have not been obtained. The consensus is that the electron transport chain enzyme CCO is the target for R-NIR-PBM. This work was undertaken to explore the effect of R-NIR on the activity of isolated CCO. METHODS: Scans for cytochrome c were obtained in both reduced and oxidized states, and values for the extinction coefficients were calculated. Activity assays were performed by following the oxidation state of cytochrome c at 550 or 415 nm. R-NIR effects on CCO activity were evaluated by pre-irradiating the enzyme at 670 or 830 nm, or by irradiating the reaction mixture with 660 nm light. RESULTS: Milimolar extinction coefficients (L-1 cm-1) were: ɛ550red = 29.1 ± 0.4, ɛ550ox = 8.60 ± 0.15, ɛ415red = 140 ± 2, and ɛ415ox = 89.0 ± 1.1. Reduced-oxidized extinction coefficients were: δɛ550red-ox = 20.5 ± 0.2, and δɛ415red-ox = 51.0 ± 2.0. The second order rate constants k' for irradiated CCO did not show a statistically significant difference from controls. CONCLUSIONS: The oxidation of cytochrome c by isolated CCO has not been shown to be affected by R-NIR irradiation, whether applied prior to or concurrently with the enzymatic assays. This lack of effect by R-NIR calls into question the CCO activity model of R-NIR photobiomodulation.

Photodynamic therapy (PDT) for malignant brain tumors--where do we stand?

INTRODUCTION: What is the current status of photodynamic therapy (PDT) with regard to treating malignant brain tumors? Despite several decades of effort, PDT has yet to achieve standard of care. PURPOSE: The questions we wish to answer are: where are we clinically with PDT, why is it not standard of care, and what is being done in clinical trials to get us there. METHOD: Rather than a meta-analysis or comprehensive review, our review focuses on who the major research groups are, what their approaches to the problem are, and how their results compare to standard of care. Secondary questions include what the effective depth of light penetration is, and how deep can we expect to kill tumor cells. CURRENT RESULTS: A measurable degree of necrosis is seen to a depth of about 5mm. Cavitary PDT with hematoporphyrin derivative (HpD) results are encouraging, but need an adequate Phase III trial. Talaporfin with cavitary light application appears promising, although only a small case series has been reported. Foscan for fluorescence guided resection (FGR) plus intraoperative cavitary PDT results were improved over controls, but are poor compared to other groups. 5-Aminolevulinic acid-FGR plus postop cavitary HpD PDT show improvement over controls, but the comparison to standard of care is still poor. CONCLUSION: Continued research in PDT will determine whether the advances shown will mitigate morbidity and mortality, but certainly the potential for this modality to revolutionize the treatment of brain tumors remains. The various uses for PDT in clinical practice should be pursued.

The bactericidal effect of 470-nm light and hyperbaric oxygen on methicillin-resistant Staphylococcus aureus (MRSA).

It has been shown that, in vitro, hyperbaric oxygen (HBO) suppresses 28 % bacterial growth, while 470-nm blue light alone suppresses up to 92 % methicillin-resistant Staphylococcus aureus (MRSA) in one application in vitro. Therefore, we determined if combined 470-nm light (55 J/cm(2)) and HBO will yield 100 % bacterial suppression in experimental simulation of mild, moderate or severe MRSA infection. We cultured MRSA at 3 × 10(6), 5 × 10(6), 7 × 10(6), 8 × 10(6), or 12 × 10(6) CFU/ml and treated each concentration in four groups as follows: (1) control (no treatment) (2) photo-irradiation only, (3) photo-irradiation then HBO, (4) HBO only, and (5) HBO then photo-irradiation. Bacteria colonies were then quantified. The results showed that at each bacterial concentration, HBO alone was significantly less effective in suppressing MRSA than photo-irradiation or combined HBO and photo-irradiation (p < 0.0001). Similarly, at no bacterial concentration did combined HBO and 470-nm light treatment yield a statistically better result than 470-nm light alone (p > 0.05), neither did HBO treatment either before or after irradiation make a difference. Furthermore, at no bacterial concentration was 100 % MRSA suppression achieved. Indeed, the maximum bacterial suppression attained was in the mild infection model (3 × 10(6) CFU/ml), with blue light producing 97.3 ± 0.2 % suppression and HBO + 55 J/cm(2) yielding 97.5 ± 2.5 % suppression. We conclude that (1) HBO and 470-nm light individually suppress MRSA growth; (2) 470-nm blue light is more effective in suppressing MRSA than HBO; and (3) HBO did not act synergistically to heighten the bactericidal effect of 470-nm light.

Cardioprotection from ischemia-reperfusion injury by near-infrared light in rats.

UNLABELLED: Abstract Objective: Myocardial reperfusion injury can induce further cardiomyocyte death and contribute to adverse cardiovascular outcomes after myocardial ischemia, cardiac surgery, or circulatory arrest. Exposure to near-infrared (NIR) light at the time of reoxygenation protects neonatal rat cardiomyocytes and HL-1 cells from injury. We hypothesized that application of NIR at 670 nm would protect the heart against ischemia-reperfusion injury. METHODS: We assessed the protective role of NIR in in vivo and in vitro rat models of ischemia-reperfusion injury. RESULTS: NIR application had no effect on the function of the nonischemic isolated heart, and had no effect on infarct size when applied during global ischemia. In the in vivo model, NIR commencing immediately before reperfusion decreased infarct size by 40%, 33%, 38%, and 77%, respectively, after regional ischemic periods of 30, 20, 15, and 10 min. Serum cardiac troponin I (cTnI) was significantly reduced in the 15 min group, whereas creatine kinase (CK) and lactate dehydrogenase (LDH) levels were not affected. CONCLUSIONS: We have demonstrated the safety of NIR application in an in vitro rat isolated model. In addition, we have demonstrated safety and efficacy when using NIR for cardioprotection in an in vivo rat ischemia model, and that this cardioprotection is dependent upon some factor present in blood, but not in perfusion buffer. RESULTS show potential for cTnI, but not CK or LDH, as a biomarker for cardioprotection by NIR. NIR may have therapeutic utility in providing myocardial protection from ischemia-reperfusion injury.

Presumed hydrogen sulfide-mediated neurotoxicity after streptococcus anginosus group meningitis.

Hydrogen sulfide is an environmental toxicant and gaseous neurotransmitter. It is produced enterically by sulfur-reducing bacteria and invasive pathogens including Streptococcus anginosus group, Salmonella and Citrobacter. We describe putative focal hydrogen sulfide neurotoxicity after Streptococcus constellatus meningitis, treated with adjunctive sodium nitrite and hyperbaric oxygen therapy.

Near-infrared photobiomodulation in an animal model of traumatic brain injury: improvements at the behavioral and biochemical levels.

OBJECTIVE: The purpose of this was to evaluate the neuroprotective effects of near-infrared (NIR) light using an in-vivo rodent model of traumatic brain injury (TBI), controlled cortical impact (CCI), and to characterize changes at the behavioral and biochemical levels. BACKGROUND DATA: NIR upregulates mitochondrial function, and decreases oxidative stress. Mitochondrial oxidative stress and apoptosis are important in TBI. NIR enhanced cell viability and mitochondrial function in previous in-vitro TBI models, supporting potential NIR in-vivo benefits. METHODS: Sprague-Dawley rats were divided into three groups: severe TBI, sham surgery, and anesthetization only (behavioral response only). Cohorts in each group were administered either no NIR or NIR. They received two 670 nm LED treatments (5 min, 50 mW/cm(2), 15 J/cm(2)) per day for 72 h (chemical analysis) or 10 days (behavioral). During the recovery period, animals were tested for locomotor and behavioral activities using a TruScan device. Frozen brain tissue was obtained at 72 h and evaluated for apoptotic markers and reduced glutathione (GSH) levels. RESULTS: Significant differences were seen in the TBI plus and minus NIR (TBI+/-) and sham plus and minus NIR (S+/-) comparisons for some of the TruScan nose poke parameters. A statistically significant decrease was found in the Bax pro-apoptotic marker attributable to NIR exposure, along with lesser increases in Bcl-2 anti-apoptotic marker and GSH levels. CONCLUSIONS: These results show statistically significant, preclinical outcomes that support the use of NIR treatment after TBI in effecting changes at the behavioral, cellular, and chemical levels.

Therapeutic effect of near infrared (NIR) light on Parkinson's disease models.

Parkinson's disease (PD) is a neurodegenerative disorder that affects large numbers of people, particularly those of a more advanced age. Mitochondrial dysfunction plays a central role in PD, especially in the electron transport chain. This mitochondrial role allows the use of inhibitors of complex I and IV in PD models, and enhancers of complex IV activity, such as NIR light, to be used as possible therapy. PD models fall into two main categories; cell cultures and animal models. In cell cultures, primary neurons, mutant neuroblastoma cells, and cell cybrids have been studied in conjunction with NIR light. Primary neurons show protection or recovery of function and morphology by NIR light after toxic insult. Neuroblastoma cells, with a gene for mutant alpha-synuclein, show similar results. Cell cybrids, containing mtDNA from PD patients, show restoration of mitochondrial transport and complex I and IV assembly. Animal models include toxin-insulted mice, and alpha-synuclein transgenic mice. Functional recovery of the animals, chemical and histological evidence, and delayed disease progression show the potential of NIR light in treating Parkinson's disease.