Measures of resting state EEG rhythms for clinical trials in Alzheimer's disease: Recommendations of an expert panel.

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes.

Modifying Alzheimer's disease pathophysiology with photobiomodulation: model, evidence, and future with EEG-guided intervention.

This manuscript outlines a model of Alzheimer's Disease (AD) pathophysiology in progressive layers, from its genesis to the development of biomarkers and then to symptom expression. Genetic predispositions are the major factor that leads to mitochondrial dysfunction and subsequent amyloid and tau protein accumulation, which have been identified as hallmarks of AD. Extending beyond these accumulations, we explore a broader spectrum of pathophysiological aspects, including the blood-brain barrier, blood flow, vascular health, gut-brain microbiodata, glymphatic flow, metabolic syndrome, energy deficit, oxidative stress, calcium overload, inflammation, neuronal and synaptic loss, brain matter atrophy, and reduced growth factors. Photobiomodulation (PBM), which delivers near-infrared light to selected brain regions using portable devices, is introduced as a therapeutic approach. PBM has the potential to address each of these pathophysiological aspects, with data provided by various studies. They provide mechanistic support for largely small published clinical studies that demonstrate improvements in memory and cognition. They inform of PBM's potential to treat AD pending validation by large randomized controlled studies. The presentation of brain network and waveform changes on electroencephalography (EEG) provide the opportunity to use these data as a guide for the application of various PBM parameters to improve outcomes. These parameters include wavelength, power density, treatment duration, LED positioning, and pulse frequency. Pulsing at specific frequencies has been found to influence the expression of waveforms and modifications of brain networks. The expression stems from the modulation of cellular and protein structures as revealed in recent studies. These findings provide an EEG-based guide for the use of artificial intelligence to personalize AD treatment through EEG data feedback.

Traumatic Brain Injury Recovery with Photobiomodulation: Cellular Mechanisms, Clinical Evidence, and Future Potential.

Traumatic Brain Injury (TBI) remains a significant global health challenge, lacking effective pharmacological treatments. This shortcoming is attributed to TBI's heterogeneous and complex pathophysiology, which includes axonal damage, mitochondrial dysfunction, oxidative stress, and persistent neuroinflammation. The objective of this study is to analyze transcranial photobiomodulation (PBM), which employs specific red to near-infrared light wavelengths to modulate brain functions, as a promising therapy to address TBI's complex pathophysiology in a single intervention. This study reviews the feasibility of this therapy, firstly by synthesizing PBM's cellular mechanisms with each identified TBI's pathophysiological aspect. The outcomes in human clinical studies are then reviewed. The findings support PBM's potential for treating TBI, notwithstanding variations in parameters such as wavelength, power density, dose, light source positioning, and pulse frequencies. Emerging data indicate that each of these parameters plays a role in the outcomes. Additionally, new research into PBM's effects on the electrical properties and polymerization dynamics of neuronal microstructures, like microtubules and tubulins, provides insights for future parameter optimization. In summary, transcranial PBM represents a multifaceted therapeutic intervention for TBI with vast potential which may be fulfilled by optimizing the parameters. Future research should investigate optimizing these parameters, which is possible by incorporating artificial intelligence.

Raman Spectroscopy Reveals Photobiomodulation-Induced α-Helix to ß-Sheet Transition in Tubulins: Potential Implications for Alzheimer's and Other Neurodegenerative Diseases.

In small clinical studies, the application of transcranial photobiomodulation (PBM), which typically delivers low-intensity near-infrared (NIR) to treat the brain, has led to some remarkable results in the treatment of dementia and several neurodegenerative diseases. However, despite the extensive literature detailing the mechanisms of action underlying PBM outcomes, the specific mechanisms affecting neurodegenerative diseases are not entirely clear. While large clinical trials are warranted to validate these findings, evidence of the mechanisms can explain and thus provide credible support for PBM as a potential treatment for these diseases. Tubulin and its polymerized state of microtubules have been known to play important roles in the pathology of Alzheimer's and other neurodegenerative diseases. Thus, we investigated the effects of PBM on these cellular structures in the quest for insights into the underlying therapeutic mechanisms. In this study, we employed a Raman spectroscopic analysis of the amide I band of polymerized samples of tubulin exposed to pulsed low-intensity NIR radiation (810 nm, 10 Hz, 22.5 J/cm2 dose). Peaks in the Raman fingerprint region (300-1900 cm-1)-in particular, in the amide I band (1600-1700 cm-1)-were used to quantify the percentage of protein secondary structures. Under this band, hidden signals of C=O stretching, belonging to different structures, are superimposed, producing a complex signal as a result. An accurate decomposition of the amide I band is therefore required for the reliable analysis of the conformation of proteins, which we achieved through a straightforward method employing a Voigt profile. This approach was validated through secondary structure analyses of unexposed control samples, for which comparisons with other values available in the literature could be conducted. Subsequently, using this validated method, we present novel findings of statistically significant alterations in the secondary structures of polymerized NIR-exposed tubulin, characterized by a notable decrease in α-helix content and a concurrent increase in ß-sheets compared to the control samples. This PBM-induced α-helix to ß-sheet transition connects to reduced microtubule stability and the introduction of dynamism to allow for the remodeling and, consequently, refreshing of microtubule structures. This newly discovered mechanism could have implications for reducing the risks associated with brain aging, including neurodegenerative diseases like Alzheimer's disease, through the introduction of an intervention following this transition.

Photobiomodulation Treatment with a Home-Use Device for COVID-19: A Randomized Controlled Trial for Efficacy and Safety.

Background: Photobiomodulation therapy (PBMT) using devices to deliver red and/or near-infrared light to tissues has shown promising effects in clinical settings for respiratory diseases, including potential benefits in managing symptoms associated with COVID-19. Objective: To determine if at-home self-administered PBMT for patients with COVID-19 is safe and effective. Methods: This was a randomized controlled trial (RCT) carried out at home during the COVID-19 pandemic (September 2020 to August 2021). The treatment group self-administered the Vielight RX Plus PBMT device (635 nm intranasal and 810 nm chest LEDs) and were monitored remotely. Eligible patients scored 4-7 (out of 7) for severity on the Wisconsin Upper Respiratory Symptom Survey (WURSS-44). Patients were randomized equally to Control group receiving standard-of-care (SOC) only or Treatment group receiving SOC plus PBMT. The device was used for 20 min 2X/day for 5 days and, subsequently, once daily for 30 days. The primary end-point was time-to-recovery (days) based on WURSS-44 question 1, "How sick do you feel today?". Subgroup analysis was performed, and Kaplan-Meier and Cox Proportional Hazards analysis were employed. Results: One hundred and ninety-nine eligible patients (18-65 years old) were divided into two subgroups as follows: 136 patients with 0-7 days of symptoms at baseline and 63 patients with 8-12 days of symptoms. Those with 0-7 days of symptoms at baseline recovered significantly faster with PBMT. The median for Treatment group was 18 days [95% confidence interval (CI), 13-20] versus the Control group 21 days (95% CI, 15-28), p = 0.050. The treatment:control hazard ratio was 1.495 (95% CI, 0.996-2.243), p = 0.054. Patients with symptom duration ≥7 days did not show any significant improvement. No deaths or severe adverse events (SAEs) occurred in the Treatment group, whereas there was 1 death and 3 SAEs requiring hospitalization in the Control group. Conclusions: Patients with ≤7 days of COVID-19 symptoms recovered significantly faster with PBMT compared to SOC. Beyond 7 days, PBMT showed no superiority over SOC. Trial Registration: ClinicalTrials.gov NCT04418505.

Near-Infrared Photobiomodulation of Living Cells, Tubulin, and Microtubules In Vitro.

We report the results of experimental investigations involving photobiomodulation (PBM) of living cells, tubulin, and microtubules in buffer solutions exposed to near-infrared (NIR) light emitted from an 810 nm LED with a power density of 25 mW/cm2 pulsed at a frequency of 10 Hz. In the first group of experiments, we measured changes in the alternating current (AC) ionic conductivity in the 50-100 kHz range of HeLa and U251 cancer cell lines as living cells exposed to PBM for 60 min, and an increased resistance compared to the control cells was observed. In the second group of experiments, we investigated the stability and polymerization of microtubules under exposure to PBM. The protein buffer solution used was a mixture of Britton-Robinson buffer (BRB aka PEM) and microtubule cushion buffer. Exposure of Taxol-stabilized microtubules (~2 µM tubulin) to the LED for 120 min resulted in gradual disassembly of microtubules observed in fluorescence microscopy images. These results were compared to controls where microtubules remained stable. In the third group of experiments, we performed turbidity measurements throughout the tubulin polymerization process to quantify the rate and amount of polymerization for PBM-exposed tubulin vs. unexposed tubulin samples, using tubulin resuspended to final concentrations of ~ 22.7 µM and ~ 45.5 µM in the same buffer solution as before. Compared to the unexposed control samples, absorbance measurement results demonstrated a slower rate and reduced overall amount of polymerization in the less concentrated tubulin samples exposed to PBM for 30 min with the parameters mentioned above. Paradoxically, the opposite effect was observed in the 45.5 µM tubulin samples, demonstrating a remarkable increase in the polymerization rates and total polymer mass achieved after exposure to PBM. These results on the effects of PBM on living cells, tubulin, and microtubules are novel, further validating the modulating effects of PBM and contributing to designing more effective PBM parameters. Finally, potential consequences for the use of PBM in the context of neurodegenerative diseases are discussed.

Changes in Brain Function and Structure After Self-Administered Home Photobiomodulation Treatment in a Concussion Case.

Traumatic brain injury (TBI) is a common neurological disorder among athletes. Although there are no widely accepted treatments for TBI, new investigational approaches, such as photobiomodulation (PBM), are being tested. PBM is a light therapy that uses red to near-infrared (NIR) light to stimulate, heal, and protect tissue that has been injured or is at risk of dying. Benefits following transcranial PBM treatments in animal models of acute TBI and a small number of chronic TBI patients have been reported. However, the human PBM TBI studies published to date have been based on behavioral assessments. This report describes changes in behavioral and neuroimaging measures after 8 weeks of PBM treatments. The subject was a 23-year professional hockey player with a history of concussions, presumed to have caused his symptoms of headaches, mild anxiety, and difficulty concentrating. He treated himself at home with commercially available, low-risk PBM devices that used light-emitting diodes (LEDs) to emit 810-nm light pulsing at 10 or 40 Hz delivered by an intranasal and four transcranial modules that targeted nodes of the default mode network (DMN) with a maximum power density of 100 mW/cm2. After 8 weeks of PBM treatments, increased brain volumes, improved functional connectivity, and increased cerebral perfusion and improvements on neuropsychological test scores were observed. Although this is a single, sport-related case with a history of concussions, these positive findings encourage replication studies that could provide further validation for this non-invasive, non-pharmacological modality as a viable treatment option for TBI.

Pulsed Near Infrared Transcranial and Intranasal Photobiomodulation Significantly Modulates Neural Oscillations: a pilot exploratory study.

Transcranial photobiomodulation (tPBM) is the application of low levels of red or near-infrared (NIR) light to stimulate neural tissues. Here, we administer tPBM in the form of NIR light (810 nm wavelength) pulsed at 40 Hz to the default mode network (DMN), and examine its effects on human neural oscillations, in a randomized, sham-controlled, double-blinded trial. Using electroencephalography (EEG), we found that a single session of tPBM significantly increases the power of the higher oscillatory frequencies of alpha, beta and gamma and reduces the power of the slower frequencies of delta and theta in subjects in resting state. Furthermore, the analysis of network properties using inter-regional synchrony via weighted phase lag index (wPLI) and graph theory measures, indicate the effect of tPBM on the integration and segregation of brain networks. These changes were significantly different when compared to sham stimulation. Our preliminary findings demonstrate for the first time that tPBM can be used to non-invasively modulate neural oscillations, and encourage further confirmatory clinical investigations.

Significant Improvement in Cognition in Mild to Moderately Severe Dementia Cases Treated with Transcranial Plus Intranasal Photobiomodulation: Case Series Report.

OBJECTIVE: This study investigated whether patients with mild to moderately severe dementia or possible Alzheimer's disease (AD) with Mini-Mental State Exam (MMSE) Baseline scores of 10-24 would improve when treated with near-infrared photobiomodulation (PBM) therapy. BACKGROUND: Animal studies have presented the potential of PBM for AD. Dysregulation of the brain's default mode network (DMN) has been associated with AD, presenting the DMN as an identifiable target for PBM. MATERIALS AND METHODS: The study used 810 nm, 10 Hz pulsed, light-emitting diode devices combining transcranial plus intranasal PBM to treat the cortical nodes of the DMN (bilateral mesial prefrontal cortex, precuneus/posterior cingulate cortex, angular gyrus, and hippocampus). Five patients with mild to moderately severe cognitive impairment were entered into 12 weeks of active treatment as well as a follow-up no-treatment, 4-week period. Patients were assessed with the MMSE and Alzheimer's Disease Assessment Scale (ADAS-cog) tests. The protocol involved weekly, in-clinic use of a transcranial-intranasal PBM device; and daily at-home use of an intranasal-only device. RESULTS: There was significant improvement after 12 weeks of PBM (MMSE, p < 0.003; ADAS-cog, p < 0.023). Increased function, better sleep, fewer angry outbursts, less anxiety, and wandering were reported post-PBM. There were no negative side effects. Precipitous declines were observed during the follow-up no-treatment, 4-week period. This is the first completed PBM case series to report significant, cognitive improvement in mild to moderately severe dementia and possible AD cases. CONCLUSIONS: Results suggest that larger, controlled studies are warranted. PBM shows potential for home treatment of patients with dementia and AD.