Using Light Therapy for Mild Cognitive Impairment

Official title

Neurovascular and Mitochondrial Mechanisms of Transcranial Photobiomodulation in Vascular Mild Cognitive Impairment

Overview

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: * Does tPBM enhance cognitive function and cerebral hemodynamic responses during memory and finger tapping tasks? * Does tPBM reduce oxidative stress, inflammation, and mitigate brain cell damage? * Is cognitive improvement linked to amyloid status, greater cerebral hemodynamic response, and lower levels of brain inflammation and oxidative stress? Researchers will compare an active tPBM treatment arm to a sham treatment arm to see if tPBM leads to measurable improvements in brain activity and cognitive function compared to no active stimulation. Participants will: * Receive a 20-minute-long active tPBM or sham stimulation session once per day, 6 times per week, for 12 weeks. * Complete questionnaires and an iPad-based cognitive testing protocol. * Complete memory and motor tasks while their brain activity is measured using non-invasive techniques: simultaneous functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG). Dynamic analysis of the vessels in the eye will also be performed based on eligibility. Transcranial Doppler (TCD) flowmetry is optionally performed. * Provide blood samples to test for biomarkers of inflammation, oxidative stress, and brain cell damage.

Detailed description

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.

Interventions

• Device Active Vielight Neuro RX-Duo device -Active transcranial photobiomodulation
  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 desig
• Device Sham Vielight Neuro RX-Duo device -Sham transcranial photobiomodulation
  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 p

Primary outcome measures

• Change in cortical neurovascular coupling [Time frame: From baseline visit to the follow-up visit after completing a 12 week intervention protocol]

Secondary outcome measures (1)

• Change in fluid cognition composite score [Time frame: From baseline visit to the follow-up visit after completing a 12 week intervention protocol.]

Eligibility criteria

Inclusion criteria

• Age: 55-95 years of age
• Clinical Dementia Rating (CDR) equal to 0.5 and/or Montreal Cognitive Assessment (MoCA) <26 and ≥19
• Adequate hearing and visual acuity to participate in the examinations
• English speaker
• Presence of cerebrovascular pathology confirmed by structural brain imaging method

Exclusion criteria

• Active CNS disease including multiple sclerosis, uncontrolled seizures, active brain cancer
• Cerebrovascular accident other than TIA within 60 days prior to Visit 0
• Diagnosis of amyloid angiopathy
• Major psychiatric disease, including major depression not controlled on medications, alcohol or drug abuse
• Neurodegenerative diseases, e.g: Parkinson's, any kind of dementia
• Patients currently using commercial brain stimulation / neuromodulation device as part of a research study
• Patients currently take dietary supplements with an expected cerebrovascular benefit such as NAD- or NR-supplementum, L-citrullin, urolithin
• Unstable medical condition, including uncontrolled diabetes, chronic heart issues, heart failure, chronic obstructive pulmonary disease, hypertension uncontrolled by medication (>160/100 mmHg)
• Any other medical condition or medication which, in the opinion of investigator, would render the patient too unstable to complete the study protocol
• Severe sensory deficits interfering with the testing

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Oklahoma Health Campus — Oklahoma City

Publications

• 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.09
• 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. PMID 33293556
• Rodriguez-Fernandez L, Zorzo C, Arias JL. Photobiomodulation in the aging brain: a systematic review from animal models to humans. Geroscience. 2024 Dec;46(6):6583-6623. doi: 10.1007/s11357-024-01231-y. Epub 2024 Jun 11. PMID 38861125
• Lee TL, Ding Z, Chan AS. Can transcranial photobiomodulation improve cognitive function? A systematic review of human studies. Ageing Res Rev. 2023 Jan;83:101786. doi: 10.1016/j.arr.2022.101786. Epub 2022 Nov 9. PMID 36371017
• Cassano P, Petrie SR, Hamblin MR, Henderson TA, Iosifescu DV. Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis. Neurophotonics. 2016 Jul;3(3):031404. doi: 10.1117/1.NPh.3.3.031404. Epub 2016 Mar 4. PMID 26989758
• Spera V, Sitnikova T, Ward MJ, Farzam P, Hughes J, Gazecki S, Bui E, Maiello M, De Taboada L, Hamblin MR, Franceschini MA, Cassano P. Pilot Study on Dose-Dependent Effects of Transcranial Photobiomodulation on Brain Electrical Oscillations: A Potential Therapeutic Target in Alzheimer's Disease. J Alzheimers Dis. 2021;83(4):1481-1498. doi: 10.3233/JAD-210058. PMID 34092636
• Salehpour F, Mahmoudi J, Kamari F, Sadigh-Eteghad S, Rasta SH, Hamblin MR. Brain Photobiomodulation Therapy: a Narrative Review. Mol Neurobiol. 2018 Aug;55(8):6601-6636. doi: 10.1007/s12035-017-0852-4. Epub 2018 Jan 11. PMID 29327206
• Csiszar A, Ungvari A, Patai R, Gulej R, Yabluchanskiy A, Benyo Z, Kovacs I, Sotonyi P, Kirkpartrick AC, Prodan CI, Liotta EM, Zhang XA, Toth P, Tarantini S, Sorond FA, Ungvari Z. Atherosclerotic burden and cerebral small vessel disease: exploring the link through microvascular aging and cerebral microhemorrhages. Geroscience. 2024 Oct;46(5):5103-5132. doi: 10.1007/s11357-024-01139-7. Epub 2024 Apr PMID 38639833

Identifiers

NCT: NCT07651787 · 19237 · 128958

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗