The effect of photobiomodulation on hearing loss: A systematic review.

OBJECTIVES: To assess outcomes associated with photobiomodulation therapy (PBMT) for hearing loss in human and animal studies. DESIGN: Systematic review and narrative synthesis in accordance with PRISMA guidelines. SETTING: Data bases searched: MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov and Web of Science. No limits were placed on language or year of publication. Review conducted in accordance with the PRISMA 2020 statement. PARTICIPANTS: All human and animal subjects treated with PBMT for hearing loss. MAIN OUTCOME MEASURES: Pre- and post-PBMT audio metric outcomes. RESULTS: Searches identified 122 abstracts and 49 full text articles. Of these, 17 studies met the inclusion criteria, reporting outcomes in 327 animals (11 studies), 30 humans (1 study), and 40 animal specimens (5 studies). PBMT parameters included 6 different wavelengths: 908 nm (1 study), 810 nm (1 study), 532 & 635 nm (1 study), 830 nm (3 studies), 808 nm (11 studies). The duration ranged from 4 to 60 minutes in a session, and the follow-up ranged from 5-28 days. Outcomes improved significantly when wavelengths within the range of 800-830 nm were used, and with greater duration of PBMT exposure. Included studies predominantly consisted of non-randomized controlled trials (10 studies). CONCLUSIONS: Hearing outcomes following PBMT appear to be superior to no PBMT for subjects with hearing loss, although higher level evidence is required to verify this. PBMT enables concentrated, focused delivery of light therapy to the inner ear through a non-invasive manner with minimal side effects. As a result of heterogeneity in reporting PBMT parameters and outcomes across the included studies, direct comparison is challenging.

Early assessment of injury with optical markers in a piglet model of neonatal encephalopathy.

BACKGROUND: Opportunities for adjunct therapies with cooling in neonatal encephalopathy are imminent; however, robust biomarkers of early assessment are lacking. Using an optical platform of broadband near-infrared spectroscopy and diffuse correlation spectroscopy to directly measure mitochondrial metabolism (oxCCO), oxygenation (HbD), cerebral blood flow (CBF), we hypothesised optical indices early (1-h post insult) after hypoxia-ischaemia (HI) predicts insult severity and outcome. METHODS: Nineteen newborn large white piglets underwent continuous neuromonitoring as controls or following moderate or severe HI. Optical indices were expressed as mean semblance (phase difference) and coherence (spectral similarity) between signals using wavelet analysis. Outcome markers included the lactate/N-acetyl aspartate (Lac/NAA) ratio at 6 h on proton MRS and TUNEL cell count. RESULTS: CBF-HbD semblance (cerebrovascular dysfunction) correlated with BGT and white matter (WM) Lac/NAA (r2 = 0.46, p = 0.004, r2 = 0.45, p = 0.004, respectively), TUNEL cell count (r2 = 0.34, p = 0.02) and predicted both initial insult (r2 = 0.62, p = 0.002) and outcome group (r2 = 0.65 p = 0.003). oxCCO-HbD semblance (cerebral metabolic dysfunction) correlated with BGT and WM Lac/NAA (r2 = 0.34, p = 0.01 and r2 = 0.46, p = 0.002, respectively) and differentiated between outcome groups (r2 = 0.43, p = 0.01). CONCLUSION: Optical markers of both cerebral metabolic and vascular dysfunction 1 h after HI predicted injury severity and subsequent outcome in a pre-clinical model. IMPACT: This study highlights the possibility of using non-invasive optical biomarkers for early assessment of injury severity following neonatal encephalopathy, relating to the outcome. Continuous cot-side monitoring of these optical markers can be useful for disease stratification in the clinical population and for identifying infants who might benefit from future adjunct neuroprotective therapies beyond cooling.

Multimodal Measurements of Brain Tissue Metabolism and Perfusion in a Neonatal Model of Hypoxic-Ischaemic Injury.

This is the first multimodal study of cerebral tissue metabolism and perfusion post-hypoxic-ischaemic (HI) brain injury using broadband near-infrared spectroscopy (bNIRS), diffuse correlation spectroscopy (DCS), positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). In seven piglet preclinical models of neonatal HI, we measured cerebral tissue saturation (StO2), cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), changes in the mitochondrial oxidation state of cytochrome c oxidase (oxCCO), cerebral glucose metabolism (CMRglc) and tissue biochemistry (Lac+Thr/tNAA). At baseline, the parameters measured in the piglets that experience HI (not controls) were 64 ± 6% StO2, 35 ± 11 ml/100 g/min CBF and 2.0 ± 0.4 µmol/100 g/min CMRO2. After HI, the parameters measured were 68 ± 6% StO2, 35 ± 6 ml/100 g/min CBF, 1.3 ± 0.1 µmol/100 g/min CMRO2, 0.4 ± 0.2 Lac+Thr/tNAA and 9.5 ± 2.0 CMRglc. This study demonstrates the capacity of a multimodal set-up to interrogate the pathophysiology of HIE using a combination of optical methods, MRS, and PET.

Changes in Brain Tissue Oxygenation and Metabolism During Rewarming After Neonatal Encephalopathy are Related to Electrical Abnormality.

Hypoxic ischemic encephalopathy (HIE) leads to significant mortality and morbidity, and therapeutic hypothermia (TH) has become a standard of care following HIE. After TH, the body temperature is brought back to 37 °C. Early electroencephalography (EEG) is a reliable outcome biomarker following HIE. We hypothesized that changes in cerebral oxidative metabolism, measured as Δ[oxCCO], in relation to changes in brain tissue oxygenation (measured as Δ[HbD]) during rewarming will correlate with injury severity as evidenced on amplitude integrated EEG/EEG at initial presentation. Broadband near-infrared spectroscopy (NIRS) and systemic data were collected during rewarming from 14 infants following HIE over a mean period of 12.5 h. All infants were monitored with video EEG telemetry using a standard neonatal montage. aEEG and EEG background was classified into mild, moderate and severely abnormal groups based on the background pattern. Two infants had mild, 6 infants had moderate and another 6 infants had severe abnormality at presentation. The relationship between [oxCCO] and [HbD] was evaluated between two groups of infants with abnormal electrical activity (mild vs moderate to severe). A significant difference was noted between the groups in the relationship between [oxCCO] and [HbD] (as r2) (p = 0.02). This result indicates that the mitochondrial injury and deranged oxidative metabolism persists in the moderate to severely abnormal group during rewarming.

Correction to: Improvements in Skeletal Muscle Can Be Detected Using Broadband NIRS in First-Time Marathon Runners.

This chapter was inadvertently published as an open access chapter. However, the open access for this chapter has now been reverted.

Near-Infrared Spectroscopy Measured Cerebral Blood Flow from Spontaneous Oxygenation Changes in Neonatal Brain Injury.

Neonates with hypoxic-ischaemic (HI) brain injury were monitored using a broadband near-infrared spectroscopy (NIRS) system in the neonatal intensive care unit. The aim of this work is to use the NIRS cerebral oxygenation data (HbD = oxygenated-haemoglobin - deoxygenated-haemoglobin) combined with arterial saturation (SaO2) from pulse oximetry to calculate cerebral blood flow (CBF) based on the oxygen swing method, during spontaneous desaturation episodes. The method is based on Fick's principle and uses HbD as a tracer; when a sudden change in SaO2 occurs, the change in HbD represents a change in tracer concentration, and thus it is possible to estimate CBF. CBF was successfully calculated with broadband NIRS in 11 HIE infants (3 with severe injury) for 70 oxygenation events on the day of birth. The average CBF was 18.0 ± 12.7 ml 100 g-1 min-1 with a range of 4 ml 100 g-1 min-1 to 60 ml 100 g-1 min-1. For infants with severe HIE (as determined by magnetic resonance spectroscopy) CBF was significantly lower (p = 0.038, d = 1.35) than those with moderate HIE on the day of birth.

Improvements in Skeletal Muscle Can Be Detected Using Broadband NIRS in First-Time Marathon Runners.

Skeletal muscle metabolic function is known to respond positively to endurance exercise interventions, such as marathon training. Studies investigating skeletal muscle have typically used muscle biopsy samples or magnetic resonance spectroscopy (MRS) to interrogate metabolic function. We aimed to non-invasively detect exercise-training-induced improvements in muscle function using broadband near-infrared spectroscopy (NIRS). We used NIRS to determine concentration changes in oxygenated haemoglobin (HbO2) and the oxidation state of cytochrome-c-oxidase (oxCCO) in gastrocnemius during arterial occlusion in 14 volunteers. We also used a cardio-pulmonary exercise test (CPET) to assess peak total body oxygen uptake (peakVO2; a measure of fitness). Measurements were made at baseline (BL) which was prior to a period of at least 16 weeks of training for the 2017 London Marathon, and then within 3 weeks after completion of the marathon, follow-up (FU). We observed an increase in locally measured muscle oxygen consumption and rate of oxCCO concentration change, but not in cardio-respiratory fitness measured as whole-body peak oxygen consumption (peakVO2).

ABroAD: A Machine Learning Based Approach to Detect Broadband NIRS Artefacts.

Artefacts are a common and unwanted aspect of any measurement process, especially in a clinical environment, with multiple causes such as environmental changes or motion. In near-infrared spectroscopy (NIRS), there are several existing methods that can be used to identify and remove artefacts to improve the quality of collected data.We have developed a novel Automatic Broadband Artefact Detection (ABroAD) process, using machine learning methods alongside broadband NIRS data to detect common measurement artefacts using the broadband intensity spectrum. Data were collected from eight subjects, using a broadband NIRS monitoring over the frontal lobe with two sensors. Six different artificial artefacts - vertical head movement, horizontal head movement, frowning, pressure, ambient light, torch light - were simulated using movement and light changes on eight subjects in a block test design. It was possible to identify both light artefacts to a good degree, as well as pressure artefacts. This is promising and, by expanding this work to larger datasets, it may be possible to create and train a machine learning pipeline to automate the detection of various artefacts, making the analysis of collected data more reliable.

Broadband NIRS Cerebral Cytochrome-C-Oxidase Response to Anoxia Before and After Hypoxic-Ischaemic Injury in Piglets.

Perinatal hypoxic ischaemic (HI) encephalopathy is associated with severe neurodevelopment problems and mortality. This study uses broadband continuous-wave near-infrared spectroscopy (NIRS) to assess the early changes in cerebral oxygenation and metabolism after HI injury in an animal model using controlled anoxia events. Anoxia was induced before and 1 h after various levels of HI injury to assess the metabolic response via the changes in the oxidation state of cytochrome-c-oxidase (oxCCO), a marker of oxidative metabolism. The oxCCO responses to anoxia were classified into five categories: increase, no change, decrease, biphasic and triphasic responses. The most common response (54%) was a biphasic decrease in oxCCO. A change in the classification of the metabolic response to anoxia after HI injury indicated a severe injury, as determined by proton magnetic resonance spectroscopy, with 86% sensitivity. This shows that broadband NIRS can identify disturbances to cerebral metabolism in the first hours after severe HI injury.

Functional NIRS Measurement of Cytochrome-C-Oxidase Demonstrates a More Brain-Specific Marker of Frontal Lobe Activation Compared to the Haemoglobins.

Functional near-infrared spectroscopy (fNIRS) is an increasingly common neuromonitoring technique used to observe evoked haemodynamic changes in the brain in response to a stimulus. The measurement is typically in terms of concentration changes of oxy- (∆HbO2) and deoxy- (∆HHb) haemoglobin. However, noise from systemic fluctuations in the concentration of these chromophores can contaminate stimulus-evoked haemodynamic responses, leading to misinterpretation of results. Short-separation channels can be used to regress out extracerebral haemodynamics to better reveal cerebral changes, significantly improving the reliability of fNIRS. Broadband NIRS can be used to additionally monitor concentration changes of the oxidation state of cytochrome-c-oxidase (∆oxCCO). Recent studies have shown ∆oxCCO to be a depth-dependent and hence brain-specific signal. This study aims to investigate whether ∆oxCCO can produce a more robust marker of functional activation. Continuous frontal lobe NIRS measurements were collected from 17 healthy adult volunteers. Short 1 cm source-detector separation channels were regressed from longer separation channels in order to minimise the extracerebral contribution to standard fNIRS channels. Significant changes in ∆HbO2 and ∆HHb were seen at 1 cm channels but were not observed in ∆oxCCO. An improvement in the haemodynamic signals was achieved with regression of the 1 cm channel. Broadband NIRS-measured concentration changes of the oxidation state of cytochrome-c-oxidase has the potential to be an alternative and more brain-specific marker of functional activation.

In Vivo Measurement of Cerebral Mitochondrial Metabolism Using Broadband Near Infrared Spectroscopy Following Neonatal Stroke.

Neonatal stroke presents with features of encephalopathy and can result in significant morbidity and mortality. We investigated the cerebral metabolic and haemodynamic changes following neonatal stroke in a term infant at 24 h of life. Changes in oxidation state of cytochrome-c-oxidase (oxCCO) concentration were monitored along with changes in oxy- and deoxy- haemoglobin using a new broadband near-infrared spectroscopy (NIRS) system. Repeated transient changes in cerebral haemodynamics and metabolism were noted over a 3-h study period with decrease in oxyhaemoglobin (HbO2), deoxy haemoglobin (HHb) and oxCCO in both cerebral hemispheres without significant changes in systemic observations. A clear asymmetry was noted in the degree of change between the two cerebral hemispheres. Changes in cerebral oxygenation (measured as HbDiff=HbO2-HHb) and cerebral metabolism (measured as oxCCO) were highly coupled on the injured side of the brain.

Interrelationship Between Broadband NIRS Measurements of Cerebral Cytochrome C Oxidase and Systemic Changes Indicates Injury Severity in Neonatal Encephalopathy.

Perinatal hypoxic ischaemic encephalopathy (HIE) is associated with severe neurodevelopmental problems and mortality. There is a clinical need for techniques to provide cotside assessment of the injury extent. This study aims to use non-invasive cerebral broadband near-infrared spectroscopy (NIRS) in combination with systemic physiology to assess the severity of HIE injury. Broadband NIRS is used to measure the changes in haemodynamics, oxygenation and the oxidation state of cytochrome c oxidase (oxCCO). We used canonical correlation analysis (CCA), a multivariate statistical technique, to measure the relationship between cerebral broadband NIRS measurements and systemic physiology. A strong relationship between the metabolic marker, oxCCO, and systemic changes indicated severe brain injury; if more than 60 % of the oxCCO signal could be explained by the systemic variations, then the neurodevelopmental outcome was poor. This boundary has high sensitivity and specificity (100 and 83 %, respectively). Broadband NIRS measured concentration changes of the oxidation state of cytochrome c oxidase has the potential to become a useful cotside tool for assessment of injury severity following hypoxic ischaemic brain injury.

Relationship Between Cerebral Oxygenation and Metabolism During Rewarming in Newborn Infants After Therapeutic Hypothermia Following Hypoxic-Ischemic Brain Injury.

Therapeutic hypothermia (TH) has become a standard of care following hypoxic ischemic encephalopathy (HIE). After TH, body temperature is brought back to 37 °C over 14 h. Lactate/N-acetylasperatate (Lac/NAA) peak area ratio on proton magnetic resonance spectroscopy ((1)H MRS) is the best available outcome biomarker following HIE. We hypothesized that broadband near infrared spectroscopy (NIRS) measured changes in the oxidation state of cytochrome-c-oxidase concentration (Δ[oxCCO]) and cerebral hemodynamics during rewarming would relate to Lac/NAA. Broadband NIRS and systemic data were collected during rewarming from 14 infants following HIE over a mean period of 12.5 h. (1)H MRS was performed on day 5-9. Heart rate increased by 20/min during rewarming while blood pressure and peripheral oxygen saturation (SpO2) remained stable. The relationship between mitochondrial metabolism and oxygenation (measured as Δ[oxCCO] and Δ[HbD], respectively) was calculated by linear regression analysis. This was reviewed in three groups: Lac/NAA values <0.5, 0.5-1, >1. Mean regression coefficient (r (2)) values in these groups were 0.41 (±0.27), 0.22 (±0.21) and 0.01, respectively. The relationship between mitochondrial metabolism and oxygenation became impaired with rising Lac/NAA. Cardiovascular parameters remained stable during rewarming.

Investigation of cerebral autoregulation in the newborn piglet during anaesthesia and surgery.

The relationship between cerebral autoregulation (CA) and the neurotoxic effects of anaesthesia with and without surgery is investigated. Newborn piglets were randomly assigned to receive either 6 h of anaesthesia (isoflurane) or the same with an additional hour of minor surgery. The effect of the spontaneous changes in mean arterial blood pressure (MABP) on the cerebral haemodynamics (oxy- and deoxy-haemoglobin, HbO2 and Hb) was measured using transverse broadband near-infrared spectroscopy (NIRS). A marker for impaired CA, concordance between MABP and intravascular oxygenation (HbD = HbO2 - Hb) in the ultra-low frequency domain (0.0018-0.0083 Hz), was assessed using coherence analysis. Presence of CA impairment was not significant but found to increase with surgical exacerbation. The impairment did not correlate with histological outcome (presence of cell death, apoptosis and microglial activation in the brain).

Review of measurements and imaging of cytochrome-c-oxidase in humans using near-infrared spectroscopy: an update.

This review examines advancements in the measurement and imaging of oxidized cytochrome-c-oxidase (oxCCO) using near-infrared spectroscopy (NIRS) in humans since 2016. A total of 34 published papers were identified, with a focus on both adult and neonate populations. The NIRS-derived oxCCO signal has been demonstrated to correlate with physiological parameters and hemodynamics. New instrumentation, such as systems that allow the imaging of changes of oxCCO with diffuse optical tomography or combine the oxCCO measurement with diffuse correlation spectroscopy measures of blood flow, have advanced the field in the past decade. However, variability in its response across different populations and paradigms and lack of standardization limit its potential as a reliable and valuable indicator of brain health. Future studies should address these issues to fulfill the vision of oxCCO as a clinical biomarker.

Subject-specific information enhances spatial accuracy of high-density diffuse optical tomography.

Functional near-infrared spectroscopy (fNIRS) is a widely used imaging method for mapping brain activation based on cerebral hemodynamics. The accurate quantification of cortical activation using fNIRS data is highly dependent on the ability to correctly localize the positions of light sources and photodetectors on the scalp surface. Variations in head size and shape across participants greatly impact the precise locations of these optodes and consequently, the regions of the cortical surface being reached. Such variations can therefore influence the conclusions drawn in NIRS studies that attempt to explore specific cortical regions. In order to preserve the spatial identity of each NIRS channel, subject-specific differences in NIRS array registration must be considered. Using high-density diffuse optical tomography (HD-DOT), we have demonstrated the inter-subject variability of the same HD-DOT array applied to ten participants recorded in the resting state. We have also compared three-dimensional image reconstruction results obtained using subject-specific positioning information to those obtained using generic optode locations. To mitigate the error introduced by using generic information for all participants, photogrammetry was used to identify specific optode locations per-participant. The present work demonstrates the large variation between subjects in terms of which cortical parcels are sampled by equivalent channels in the HD-DOT array. In particular, motor cortex recordings suffered from the largest optode localization errors, with a median localization error of 27.4 mm between generic and subject-specific optodes, leading to large differences in parcel sensitivity. These results illustrate the importance of collecting subject-specific optode locations for all wearable NIRS experiments, in order to perform accurate group-level analysis using cortical parcellation.

A promising tool to explore functional impairment in neurodegeneration: A systematic review of near-infrared spectroscopy in dementia.

This systematic review aimed to evaluate previous studies which used near-infrared spectroscopy (NIRS) in dementia given its suitability as a diagnostic and investigative tool in this population. From 800 identified records which used NIRS in dementia and prodromal stages, 88 studies were evaluated which employed a range of tasks testing memory (29), word retrieval (24), motor (8) and visuo-spatial function (4), and which explored the resting state (32). Across these domains, dementia exhibited blunted haemodynamic responses, often localised to frontal regions of interest, and a lack of task-appropriate frontal lateralisation. Prodromal stages, such as mild cognitive impairment, revealed mixed results. Reduced cognitive performance accompanied by either diminished functional responses or hyperactivity was identified, the latter suggesting a compensatory response not present at the dementia stage. Despite clear evidence of alterations in brain oxygenation in dementia and prodromal stages, a consensus as to the nature of these changes is difficult to reach. This is likely partially due to the lack of standardisation in optical techniques and processing methods for the application of NIRS to dementia. Further studies are required exploring more naturalistic settings and a wider range of dementia subtypes.

Illuminating neurodegeneration: a future perspective on near-infrared spectroscopy in dementia research.

Significance: Dementia presents a global healthcare crisis, and neuroimaging is the main method for developing effective diagnoses and treatments. Yet currently, there is a lack of sensitive, portable, and low-cost neuroimaging tools. As dementia is associated with vascular and metabolic dysfunction, near-infrared spectroscopy (NIRS) has the potential to fill this gap. Aim: This future perspective aims to briefly review the use of NIRS in dementia to date and identify the challenges involved in realizing the full impact of NIRS for dementia research, including device development, study design, and data analysis approaches. Approach: We briefly appraised the current literature to assess the challenges, giving a critical analysis of the methods used. To assess the sensitivity of different NIRS device configurations to the brain with atrophy (as is common in most forms of dementia), we performed an optical modeling analysis to compare their cortical sensitivity. Results: The first NIRS dementia study was published in 1996, and the number of studies has increased over time. In general, these studies identified diminished hemodynamic responses in the frontal lobe and altered functional connectivity in dementia. Our analysis showed that traditional (low-density) NIRS arrays are sensitive to the brain with atrophy (although we see a mean decrease of 22% in the relative brain sensitivity with respect to the healthy brain), but there is a significant improvement (a factor of 50 sensitivity increase) with high-density arrays. Conclusions: NIRS has a bright future in dementia research. Advances in technology - high-density devices and intelligent data analysis-will allow new, naturalistic task designs that may have more clinical relevance and increased reproducibility for longitudinal studies. The portable and low-cost nature of NIRS provides the potential for use in clinical and screening tests.

Introduction to the Biophotonics Congress 2022 feature issue.

A feature issue is being presented by a team of guest editors containing papers based on studies presented at the Optica Biophotonics Congress: Biomedical Optics held on April 24-27, 2022 in Fort Lauderdale, Florida, USA.

The effect of photobiomodulation on tinnitus: a systematic review.

OBJECTIVE: To establish outcomes following photobiomodulation therapy for tinnitus in humans and animal studies. METHODS: A systematic review and narrative synthesis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The databases searched were: Medline, Embase, Cochrane Central Register of Controlled Trials ('Central'), ClinicalTrials.gov and Web of Science including the Web of Science Core collection. There were no limits on language or year of publication. RESULTS: The searches identified 194 abstracts and 61 full texts. Twenty-eight studies met the inclusion criteria, reporting outcomes in 1483 humans (26 studies) and 34 animals (2 studies). Photobiomodulation therapy parameters included 10 different wavelengths, and duration ranged from 9 seconds to 30 minutes per session. Follow up ranged from 7 days to 6 months. CONCLUSION: Tinnitus outcomes following photobiomodulation therapy are generally positive and superior to no photobiomodulation therapy; however, evidence of long-term therapeutic benefit is deficient. Photobiomodulation therapy enables concentrated, focused delivery of light therapy to the inner ear through a non-invasive manner, with minimal side effects.