A multimodal evaluation of transcranial photobiomodulation in mild cognitive impairment: Cognitive, metabolic, and neuroimaging outcomes of a pilot randomized controlled trial

Abstract

Background

Mild cognitive impairment (MCI), a prodromal stage of Alzheimer’s disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicated in neurodegeneration, most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM) delivers near-infrared light to enhance mitochondrial respiration.
Objective
We hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default mode network (DMN) functional connectivity (FC).
Methods
We conducted a single-blind, randomized, sham-controlled pilot trial (NCT05563298) in adults ≥50 years with MCI. Twenty participants were randomized 1:1 to active or sham devices. Active devices delivered pulsed 810-nm light for 20 min per session; shams emitted light for 2 seconds. Stimulation targeted DMN hubs and the olfactory bulb. Participants self-administered treatment at home six days per week for six weeks.
Results
Adherence was high (active 96.9%; sham 94.2%). Adverse events (AEs) were reported by 10 of 20 participants (4 active, 6 sham). No serious AEs occurred. Compared with sham, active tPBM produced greater improvement in global cognition (Mini-Mental State Examination; p = 0.03, d = 1.05) and episodic memory (California Verbal Learning Test-II long-delay recognition; p = 0.02, d = 1.09). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate (L/P) ratio (p = 0.007, d = -1.37). DMN FC increased (p = 0.014, d = 1.25), and plasma IL-6 declined (p = 0.02, r = -0.52).
Conclusions
Home-based tPBM was safe, well tolerated, and feasible, with high adherence and mild AEs. Cognitive, metabolic, and network-level findings are consistent with enhanced mitochondrial efficiency and anti-inflammatory effects. These results support larger, double-blind, multicenter trials to evaluate tPBM as a mitochondria-targeted therapy in early ADRD.

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Clinical Stability and Functional Improvement in Amyotrophic Lateral Sclerosis Following Extended Brain-Gut Photobiomodulation Therapy: A Case Report

Abstract

Background

Amyotrophic lateral sclerosis (ALS) is a form of motor neuron disease (MND), a progressive neurodegenerative disorder with limited therapeutic options. Photobiomodulation (PBM) therapy has demonstrated neuroprotective properties in preclinical models, yet clinical evidence in human ALS patients remains sparse.

Methods

We present a 39-year-old male with bulbar-onset, upper motor neuron-predominant ALS who commenced twice-daily CeraThrive (Light Tree Ventures, Den Haag, Netherlands) red and near-infrared light therapy (630-1070 nm, 40 Hz) in January 2023, applied to the motor cortex, anterior neck, and abdomen.

Results

The clinician-administered ALSFRS-R score improved from 32 at baseline (February 2020) to 37 (February 2025), representing a cumulative 5-point improvement. Peripheral oxygen saturation also improved, rising from 89% (February 2020) to 96% (February 2026).The patient reported subjective improvements in ambulation, spasticity, swallowing, and general wellbeing.

Conclusions

While the case report methodology has limitations, functional improvement in a disease characterised by rapid progressive decline provides rationale for controlled clinical trials investigating PBM in ALS.

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Modulating cerebrospinal fluid dynamics using pulsed photobiomodulation

Abstract

Introduction: The use of photobiomodulation (PBM) to enhance brain health, specifically glymphatic drainage and thus neurotoxic waste clearance, may make it a promising therapeutic tool against neurodegenerative diseases such as Alzheimer’s disease.
Material and method: This study investigates whether PBM can modulate cerebrospinal fluid (CSF) flow in 45 healthy young adults. We conducted forehead transcranial PBM (tPBM) and intranasal PBM (iPBM) at the nostril, and measured CSF dynamics using blood-oxygenation level-dependent (BOLD) functional MRI (fMRI). Our data demonstrates 4 min of PBM-induced increases in CSF flow.
Conclusion and result: Our data shows that (1) even a short PBM of 4 min can induce a change in CSF dynamics, in the form of an immediate increase in intracranial CSF volume and a reduction in CSF inflow; (2) skin melanin had a significant effect on the CSF response in tPBM, with lighter skin associated with higher responses; (3) both iPBM and tPBM displayed a dose-dependent effect on CSF dynamics in terms of a wavelength-irradiance interaction; (4) intranasal PBM (iPBM) can be used to produce a significant change in CSF dynamics that is equivalent to forehead transcranial PBM (tPBM) with a small fraction of the irradiance. The most likely explanation for the observed fMRI signal changes in CSF regions of interest for both tPBM and iPBM is an increased CSF outflow pressure due to PBM-induced vasodilation that transiently increases intracranial CSF volume and reduces net CSF inflow.
Impact: This study establishes that PBM can modulate CSF flow in the healthy human brain in real time. This study also suggests that iPBM may be more efficient in CSF modulation due to the proximity to the olfactory system and the lack of melanin dependence. The influence of melanin on tPBM, the feasibility of iPBM and the dose dependence of both will require further investigation in healthy and patient populations.
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Transcranial photobiomodulation for reducing symptoms of autism spectrum disorder and modulating brain electrophysiology in children aged 2–7: an open label study

Abstract

Background

Small pilot studies have indicated that transcranial photobiomodulation (tPBM) may help alleviate symptoms of neurological conditions like depression, traumatic brain injury and Autism Spectrum Disorder (ASD).

Objective

To examine the effect of tPBM on the behavioral symptoms of ASD and brain electrophysiology in children aged 2–7.

Methods

We conducted an open label, one-arm study with 23 participants, aged 2–7, previously diagnosed with ASD. We delivered non-invasively to all participants pulses of near-infrared light (wavelength 850 nm, pulse 40 Hz) to cortical nodes of Default Mode Network, Broca and Wernicke areas, and occipital lobe of the brain, twice weekly for 10 weeks. The tPBM was delivered using an investigational medical device designed for this purpose. Changes in ASD symptoms were measured using pre- and post-intervention scores on the Childhood Autism Rating Scale (CARS-2, 2nd Edition). We collected electroencephalogram (EEG) data after each treatment session from all children who tolerated wearing the EEG cap to monitor changes in brain activity.

Results

The intervention resulted in a significant 7-point reduction in average CARS-2 scores (t = 10.23, p < .0001), along with decreased delta power and increased gamma and beta power in EEG readings. The increase in gamma power was statistically significant [t(14) = 2.30, p = 0.047]. Changes in EEG power were significantly correlated with the number of sessions (delta: r(192) = −0.18, p = .013; gamma: r(192) = .19, p = .007; beta: r(192) = .15, p = .04). Improvements in CARS-2 scores were negatively correlated with changes in delta and beta power (delta: r(15) = −.59, p = .020; beta: r(15) = −.54, p = .037). No moderate or severe side effects were reported.

Conclusion

This study supports the potential of tPBM as a safe and effective treatment for ASD, and it suggests that EEG measurements may serve as a useful biomarker for future research.

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Modifying Alzheimer’s Disease Pathophysiology with Photobiomodulation: Model, Evidence, and Future with EEG-Guided Intervention

Abstract:

Alzheimer’s disease (AD) is a major public health problem all over the world. Therapeutic strategies have been explored for several decades, but no curative treatment has been developed (1). Although the FDA has recently approved lecanemab (Leqembi) and donanemab (Kisunla) for treating cognitive decline in early Alzheimer’s disease, their efficacy is modest, with potential side effects like amyloid-related imaging abnormalities (ARIA), and their long-term impact on disease progression remains uncertain, particularly in advanced stages (2, 3). However, these drugs represent a significant advancement by objectively reducing amyloid beta (Aβ) markers, which purportedly slow disease progression in patients with early-stage AD, marking an important first step toward more effective therapies.

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Unleashing light’s healing power: an overview of photobiomodulation for Alzheimer’s treatment

Abstract:

Aim: Photobiomodulation involves the use of low-level light therapy or near-infrared light therapy found to be useful in the treatment of a wide range of neurological diseases.

Objective: The aim is to review the mechanism and clinical applications of photobiomodulation therapy (PBMT) in managing Alzheimer’s disease. Methods: To ensure that the consensus statement accurately reflects both the experts’ viewpoint and the most recent developments in the field, the expert opinions were recorded and thoroughly reviewed.

Results: PBMT elicits reduction of beta-amyloid plaque, restoration of mitochondrial function, anti-inflammatory and antioxidant properties with a stimulation in ATP synthesis.

Conclusion: The PBMT could be helpful in patients non-responsive to traditional pharmacological therapy providing significant aid in the management of Alzheimer’s disease when introduced into the medical field.

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Transcranial photobiomodulation in children aged 2–6 years: a randomized sham-controlled clinical trial assessing safety, efficacy, and impact on autism spectrum disorder symptoms and brain electrophysiology

Abstract

Background

Small pilot studies have suggested that transcranial photobiomodulation (tPBM) could help reduce symptoms of neurological conditions, such as depression, traumatic brain injury, and autism spectrum disorder (ASD).

Objective

To examine the impact of tPBM on the symptoms of ASD in children aged two to six years.

Method

We conducted a randomized, sham-controlled clinical trial involving thirty children aged two to six years with a prior diagnosis of ASD. We delivered pulses of near-infrared light (40 Hz, 850 nm) noninvasively to selected brain areas twice a week for eight weeks, using an investigational medical device designed for this purpose (Cognilum™, JelikaLite Corp., New York, United States). We used the Childhood Autism Rating Scale (CARS, 2nd Edition) to assess and compare the ASD symptoms of participants before and after the treatment course. We collected electroencephalogram (EEG) data during each session from those participants who tolerated wearing the EEG cap.

Results

The difference in the change in CARS scores between the two groups was 7.23 (95% CI 2.357 to 12.107, p = 0.011). Seventeen of the thirty participants completed at least two EEGs and time-dependent trends were detected. In addition, an interaction between Active versus Sham and Scaled Time was observed in delta power (Coefficient = 7.521, 95% CI -0.517 to 15.559, p = 0.07) and theta power (Coefficient = −8.287, 95% CI -17.199 to 0.626, p = 0.07), indicating a potential trend towards a greater reduction in delta power and an increase in theta power over time with treatment in the Active group, compared to the Sham group. Furthermore, there was a significant difference in the condition (Treatment vs. Sham) in the power of theta waves (net_theta) (Coefficient = 9.547, 95% CI 0.027 to 19.067, p = 0.049). No moderate or severe side effects or adverse effects were reported or observed during the trial.

Conclusion

These results indicate that tPBM may be a safe and effective treatment for ASD and should be studied in more depth in larger studies.

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Effects of Photobiomodulation Therapy on Muscle Function in Individuals with Multiple Sclerosis

Abstract

Background: In people with multiple sclerosis (pwMS), muscle fatigue and weakness are common issues that can interfere with daily activities. Photobiomodulation therapy (PBMT), comprising light in a 600-1100 nm bandwidth, is a low-level laser therapy thought to improve muscle performance in non-disease populations, in part, by improving mitochondrial function and thus, might be beneficial in pwMS. Given this potential, we aimed to investigate the effects of PBMT on muscle performance in pwMS, both in the short-term and over an extended period.

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Transcranial Photobiomodulation for the Brain: A Wide Range of Clinical Applications

Photobiomodulation therapy (PBMT) is a rapidly growing approach to the healing, stimulation, protection, and regeneration of many human organs and tissue types. PBMT started in the 1960s as low-level laser therapy for wound healing, but since then the introduction of light-emitting diodes (LEDs) has dramatically increased the number of applications and reports of positive results. PBMT generally uses red (620–700 nm) and/or near-infrared (780–1270 nm) wavelengths of light at an intensity that causes no tissue heating, and its activity is based on well-established biological and cellular mechanisms (de Freitas and Hamblin, 2016). While laser therapists continue to use various types of laser in their office practice, LEDs are ideally suited for home use devices because they are completely safe and without any known significant adverse effects. Among the various body parts on which PBMT has been shown to exert beneficial effects, the brain stands out as perhaps the most promising overall. PBMT has been shown to reduce neuroinflammation, while increasing mitochondrial function, oxygen consumption, and blood flow within the brain (Hamblin, 2016). Moreover, PBMT can stimulate the processes of synaptogenesis, neurogenesis, and neuroplasticity thus helping the brain to heal itself. PBMT has neuroprotective activity and can prevent brain damage in the acute phase after traumatic brain injury or stroke, because it inhibits apoptosis and upregulates the expression of anti-apoptotic proteins, as well as improving brain metabolism and oxygenation. In the chronic phase, PBMT can improve memory, cognitive function, mood, and sleep quality. In degenerative brain disorders (dementia, Alzheimer’s disease, and Parkinson’s disease), PBMT can improve motor, cognitive and social functioning (at least for some time). In a range of psychiatric disorders (depression, anxiety, autism spectrum disorder, and opioid addiction), PBMT can lead to significant improvements (Salehpour et al., 2018). This perspective will outline the mechanisms of action of PBMT on cells and tissues, and summarize the wide range of current applications to the brain, while proposing some new directions in psychiatry.

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