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| ID | Type | Description | Link |
|---|---|---|---|
| 128958 | Other Grant/Funding Number | Presbyterian Health Foundation |
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The goal of this clinical trial is to test whether transcranial photobiomodulation (tPBM), a non-invasive brain stimulation technique using near-infrared light, can improve brain blood flow regulation (neurovascular coupling) and cognitive function in people with mild cognitive impairment (MCI). The main questions it aims to answer are:
Participants will:
Cognitive impairment represents a major source of disability, with vascular pathologies playing a critical role in the development and progression of cognitive dysfunction. In particular, vascular cognitive impairment (VCI) is a common and clinically relevant contributor to cognitive decline in individuals with MCI. Despite substantial advances in understanding the underlying mechanisms of VCI, effective therapeutic interventions remain limited. Neurons require continuous energy supply, which is provided by the physiological process, called Neurovascular coupling (NVC), a dynamical redistribution of local cerebral blood flow to meet neuronal activity. NVC is essential to maintain optimal brain function. Evidence from our preclinical and clinical work, in line with findings from other research groups, increasingly implicates NVC dysregulation as a key mechanism underlying cognitive deficits in MCI, underscoring the need for targeted interventions aimed at restoring neurovascular function.
Transcranial photobiomodulation has emerged as a promising, non-invasive approach with the potential to support both neuronal and vascular health. By delivering near-infrared light to cortical tissue, tPBM has the potential to enhance mitochondrial activity, reduce oxidative stress, and improve cerebral hemodynamics. A growing body of literature demonstrates the beneficial effects of red and near-infrared light across a range of neurological, cardiovascular, and cerebrovascular conditions. However, the neurophysiological mechanisms underlying these effects remain insufficiently characterized in humans, and the therapeutic potential of tPBM has yet to be fully explored in clinical populations such as individuals with MCI. Optical imaging modalities, including near-infrared spectroscopy (NIRS), provide an opportunity to assess tPBM-induced changes in cerebral oxygenation and hemodynamics in real-world settings, thereby improving the feasibility and translational relevance of studies investigating cerebrovascular mechanisms in MCI. Further practical advantages of tPBM lie in its documented safe application, affordability, and simplicity of use; these factors support the utilization of tPBM in potential home-based interventions.
Recent studies have demonstrated a close association between cognitive performance and NVC responses both in healthy individuals and in patients with MCI. Neuronal activity-induced vasodilation is largely mediated by nitric oxide, whose bioavailability is enhanced by tPBM through its dissociation from cytochrome c oxidase. In addition, tPBM has been shown to exert anti-inflammatory effects within the brain, a mechanism that is particularly relevant given evidence of elevated neuroinflammatory processes in MCI. Despite these promising findings, clinical evidence directly examining the effects of tPBM on NVC remains limited. Existing studies have primarily focused on cognitive outcomes, with relatively little emphasis on underlying neurophysiological or hemodynamic changes and minimal integration of these measures. Addressing this gap, the present study aims to employ advanced multimodal neuroimaging techniques to investigate tPBM-induced modulation of NVC in individuals with MCI and to examine its relationship with cognitive performance.
Preclinical and early clinical studies indicate that tPBM enhances microvascular perfusion and tissue oxygenation while concurrently reducing neuroinflammation and oxidative stress. These complementary effects highlight tPBM as a multifaceted intervention capable of targeting both neural and vascular dysfunction. To date, tPBM has demonstrated a favorable safety profile across diverse populations, with transient and mild headache being the most commonly reported adverse effect. Its non-pharmacological nature and compatibility with existing therapeutic strategies further support its potential role in cognitive rehabilitation.
The significance of this project lies in its potential to advance a novel, non-invasive intervention for cognitive impairment in patients with MCI, as well as in its capacity to elucidate the neurovascular mechanisms through which tPBM exerts its effects. By clarifying how tPBM modulates NVC and related cognitive outcomes, this research will provide a foundation for future mechanism-driven and combination therapeutic approaches aimed at mitigating cognitive decline associated with MCI.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active near-infrared light therapy | Active Comparator | Participants in this arm will receive 20-minute active transcranial photobiomodulation sessions six times a week for 12 weeks during their participation in the study. The intervention will be administered using an active Vielight Neuro RX-Duo, a research version of a commercially available light therapy device categorized as a wellness product with non-significant risk. During these sessions, biologically effective near-infrared light will be administered. |
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| Sham near-infrared light therapy | Sham Comparator | Participants in this arm will receive 20-minute sham transcranial photobiomodulation sessions six times a week for 12 weeks during their participation in the study. The intervention will be administered using a sham Vielight Neuro RX-Duo, a research version of a commercially available light therapy device categorized as a wellness product with non-significant risk. During these sessions, biologically effective near-infrared light will not be administered. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Active Vielight Neuro RX-Duo device -Active transcranial photobiomodulation | Device | The active Vielight Neuro RX-Duo devices (© Vielight Inc.) will be used to transmit pulsed near-infrared (NIR) energy through the cranium. The device emits NIR photons at an 810-nm wavelength, generating ~250 mW/cm² of pulsed NIR power modulated at 10 and 40 Hz frequencies (Alpha and Gamma modes). The six NIR light sources are positioned along the midline over the frontal, parietal, and occipital cortices, bilaterally over the temporal cortices, and intranasally. Because of their portable design, Vielight Neuro RX-Duo instruments can be used in the laboratory, at the bedside, or in the participant's home. Active photobiomodulation sessions will last 20 minutes and will be administered in a laboratory, home, or office setting, depending on participant preference. TPBM will be delivered once per day, six times per week, for 12 weeks. Participants will complete an adverse-events questionnaire after each session. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in cortical neurovascular coupling | Functional near infrared spectroscopy (fNIRS) and electroencephalography (EEG) will be performed during the cognitive n-back task. fNIRS approach generates data that represent a relative change in oxygenated and deoxygenated hemoglobin measured over the cortical brain tissues. EEG records electrical potential changes in the brain cortex. Neurovascular coupling will be evaluated as a change in oxy- and deoxy-hemoglobin between before and after treatment, normalized to change in EEG. The change in regression coefficient reflecting change in neurovascular coupling responses is a dimensionless measure. | From baseline visit to the follow-up visit after completing a 12 week intervention protocol |
| Measure | Description | Time Frame |
|---|---|---|
| Change in fluid cognition composite score | NIH Toolbox will be used to assess fluid cognitive performance by calculating a composite score based on subscores from select tests targeting relevant domains, including attention, working memory, and executive function, as described in other pre-specified outcomes. Units of measure - score (from 0 to 200, the bigger the number, the better). Reported as a %change from baseline, before and after intervention. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in neurovascular coupling in the middle cerebral arteries | Transcranial Doppler sonography will be used to measure the change in the blood flow velocities during the cognitive n-back task between before and after treatment. Blood flow velocity will be expressed in cm/s. Task-induced increase in blood flow will be divided by resting state average, and the change in increase will be compared between baseline and follow-up visits and expressed as percentages. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Peter Mukli | Contact | +1 (405) 271-8001 | 37745 | peter-mukli@ou.edu |
| Leslie Guthery | Contact | +1 (405) 271-4113 | leslie-guthery@ou.edu |
| Name | Affiliation | Role |
|---|---|---|
| Peter Mukli, MD, PhD | Department of Neurosurgery, University of Oklahoma Health Campus, Oklahoma, USA | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Oklahoma Health Campus | Recruiting | Oklahoma City | Oklahoma | 73104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | Rashidi-Ranjbar N, Churchill NW, Graham SJ, Schneider R, Rajji TK, Andreazza AC, Lim L, Coull J, Munoz DG, Fornazzari LR, Schweizer TA, Fischer CE. A pilot study evaluating the feasibility, safety, and efficacy of transcranial photobiomodulation (tPBM) for the treatment of mild cognitive impairment (MCI): preliminary findings. Alzheimers Dement. 2024;20(Suppl 8). Epub 20250109. doi: 10.1002/alz.095049; PMCID: PMC11713276. | ||
| 33293556 | Background | Apaijai N, Sriwichaiin S, Phrommintikul A, Jaiwongkam T, Kerdphoo S, Chansirikarnjana S, Thongmung N, Mahantassanapong U, Vathesatogkit P, Kitiyakara C, Sritara P, Chattipakorn N, Chattipakorn SC. Cognitive impairment is associated with mitochondrial dysfunction in peripheral blood mononuclear cells of elderly population. Sci Rep. 2020 Dec 8;10(1):21400. doi: 10.1038/s41598-020-78551-4. | |
| 38861125 |
| Label | URL |
|---|---|
| Transcranial photobiomodulation research using Vielight | View source |
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To ensure compliance, investigators will establish data management and sharing practices that align with NIH standards, including the timely submission of datasets to public repositories such as SenNet consortium, Figshare, SPARC portal and OpenNeuro. Invetigators will also publish findings in peer-reviewed journals registered in PubMed centrals to prevent unintentional duplication of research. All data generated in this project and the detailed description of the methods will be published in journals accessible through NIH databases.
01/01/2027-01/01/2032
Deidentified IPD will be available from approved public repositories, such as OpenNeuro. Deidentified data will also be provided by the PI through direct contact via email, upon reasonable request.
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| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| D000544 | Alzheimer Disease |
| D000090862 | Neuroinflammatory Diseases |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D003704 | Dementia |
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This is a randomized, parallel-group, double-blind, sham-controlled trial. Adult (55-85 years of age) participants with MCI will be randomized in a 1:1 ratio to receive either active transcranial photobiomodulation or sham stimulation. Participants in both groups will complete one 20 minutes long session per day , 6 times per week for 12 weeks. Cognitive and physiological outcomes will be measured at baseline and post-intervention follow-up.
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Unblinded and do not participate in outcome assessment and statistical analysis. Blinded outcome assessors and blinded investigators perform these procedures.
|
|
| Sham Vielight Neuro RX-Duo device -Sham transcranial photobiomodulation | Device | Sham Vielight Neuro RX-Duo devices (© Vielight Inc.) will be used. These devices are identical in appearance to the active devices; however, they do not emit near-infrared (NIR) light at an 810-nm wavelength. The six light sources are positioned along the midline over the frontal, parietal, and occipital cortices; bilaterally over the temporal cortices; and intranasally. Because of their portable design, Vielight Neuro RX-Duo instruments can be used in the laboratory, at the bedside, or in the participant's home. Sham photobiomodulation sessions will last 20 minutes and will be administered in a laboratory, home, or office setting, depending on participant preference. TPBM will be delivered once per day, six times per week, for 12 weeks. Participants will complete an adverse-events questionnaire after each session. |
|
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| From baseline visit to the follow-up visit after completing a 12 week intervention protocol. |
| From baseline visit to the follow-up visit after completing a 12 week intervention protocol. |
| Change in neurovascular coupling in the retinal vessels | Flicker light-induced dilation of the retinal vessels (percentage increase over baseline diameter) will be measured in the right or left eye of each study participant using the Dynamic Vessel Analyzer (DVA, IMEDOS Systems, Jena, Germany). The change in retinal vessel diameters is tracked and reported as a %change from baseline, before and after treatment. | From baseline visit to the follow-up visit after completing a 12 week intervention protocol. |
| Change in the band-limited power of brain waves | Band limited power in delta-, theta-, alpha-, beta- and gamma-bands during resting and task state measured by electroencephalography (EEG). Units of measure: μ V²/Hz. | From baseline visit to the follow-up visit after completing a 12 week intervention protocol. |
| Change in neuronal functional connectivity | EEG will record cortical potential changes from multiple brain cortex regions simultaneously. Phase synchronization of these signals will be calculated to reveal neuronal functional connectivity, which is a dimensionless outcome measure. | From baseline visit to the follow-up visit after completing a 12 week intervention protocol. |
| Change in hemodynamic functional connectivity | fNIRS will be used to record cerebral hemodynamics from multiple brain regions simultaneously. Correlation of simultaneously recorded cerebral hemodynamics will reveal hemodynamic functional connectivity, which is a dimensionless outcome measure. | From baseline visit to the follow-up visit after completing a 12 week intervention protocol. |
| Change in Attention | The allocation of one's limited capacities to deal with an abundance of environmental stimulation will be measured in a combined "Flanker Inhibitory Control and Attention Test".Units of measure - score (from 0 to 10, bigger number is better). Reported as a %change from baseline, before and after treatment. | From baseline visit to the follow-up visit after completing a 12 week intervention protocol. |
| Change in Episodic Memory | Cognitive processes involved in the acquisition, storage, and retrieval of new information will be measured using the "Picture Sequence Memory Test". Unit of measure - overall score (bigger number is better). Reported as a %change from baseline, before and after treatment. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in Working Memory | The ability to store information until the amount of information to be stored exceeds one's capacity to hold that information will be measured using the "List Sorting Working Memory Test". Unit of measure - overall score (bigger number is better). Reported as a %change from baseline, before and after treatment. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in Executive Function | The capacity to plan, organize, and monitor the executive of behaviors that are strategically directed in a goal-oriented manner will be measured using the "Dimensional Change Card Sort Test". Units of measure - score (from 0 to 10, the bigger the number, the better). Reported as a %change from baseline, before and after treatment. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in Processing Speed (non-verbal) | The Pattern Comparison Processing Speed Test assesses the amount of information that can be processed within a certain unit of time. Items are simple to purely measure processing speed. Units of measure - score (from 0 to 130, bigger number is better). Reported as a %change from baseline, before and after treatment. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in Processing Speed and Sustained Attention | The Oral Symbol Digit Test assesses the amount of information that can be processed within a certain unit of time. Participants are asked to orally call out the number that corresponds to each symbol in a provided master key table. Units of measure - score: number of symbols correctly identified within 120 seconds. Reported as a %change from baseline, before and after treatment. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in Extracellular vesicles of neuronal origin | Extracellular vesicles of neuronal origin will be isolated from platelet poor plasma obtained from the participant, and their concentrations (count / microliter) will be determined reflecting the health of neurovascular unit. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in Extracellular vesicles of astrocytic origin | Extracellular vesicles of astrocytic origin will be isolated from platelet poor plasma obtained from the participant, and their concentrations (count/microliter) will be determined reflecting the health of the neurovascular unit. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in Extracellular vesicles of cerebrovascular endothelial origin | Extracellular vesicles of cerebrovascular endothelial origin will be isolated from platelet poor plasma obtained from the participant, and their concentrations (count/microliter) will be determined reflecting the health of the neurovascular unit. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in expression of pro-inflammatory cytokine IL-6 | To characterize anti-inflammatory activity of tPBM among study participants, commercially available human cerebromicrovascular endothelial cells (CMVEC) will be used and expression of interleukin-6 will be determined and expressed as cycle threshold, a dimensionless unit yielded by real-time quantitative PCR experiments. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in expression of pro-inflammatory cytokine TNF-alpha | To characterize the anti-inflammatory activity of tPBM among study participants, commercially available human cerebromicrovascular endothelial cells (CMVEC) will be used, and expression of tumor necrosis factor alpha will be determined and expressed as cycle threshold, a dimensionless unit yielded by real-time quantitative PCR experiments. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Change in expression of anti-inflammatory cytokine IL-10 | To characterize the anti-inflammatory activity of tPBM among study participants, commercially available human cerebromicrovascular endothelial cells (CMVEC) will be used, and expression of interleukin-10 will be determined and expressed as cycle threshold, a dimensionless unit yielded by real-time quantitative PCR experiments. | From baseline visit to the follow-up visit after completing a 12-week intervention protocol. |
| Background |
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| D001927 |
| Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |