A multimodal evaluation of transcranial photobiomodulation in mild cognitive impairment: Cognitive,metabolic,and neuroimaging outcomes of a pilot randomized controlled trial
Restricted accessResearch articleFirst published online 2026
A multimodal evaluation of transcranial photobiomodulation in mild cognitive impairment: Cognitive,metabolic,and neuroimaging outcomes of a pilot randomized controlled trial
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.
SperlingRAAisenPSBeckettLA, et al.Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement2011; 7: 280–292.
3.
CummingsJApostolovaLRabinoviciGD, et al.Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis2023; 10: 362–377.
4.
LivingstonGHuntleyJLiuKY, et al.Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet2024; 404: 572–628.
5.
WardATardiffSDyeC, et al.Rate of conversion from prodromal Alzheimer’s disease to Alzheimer's dementia: a systematic review of the literature. Dement Geriatr Cogn Dis Extra2013; 3: 320–332.
6.
FangEFHouYPalikarasK, et al.Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci2019; 22: 401–412.
7.
CummingsJZhouYLeeG, et al.Alzheimer’s disease drug development pipeline: 2023. Alzheimers Dement (N Y)2023; 9: e12385.
8.
KolyvaCTachtsidisIGhoshA, et al.Systematic investigation of changes in oxidized cerebral cytochrome c oxidase concentration during frontal lobe activation in healthy adults. Biomed Opt Express2012; 3: 2550–2566.
9.
HamblinMR. Mechanisms and mitochondrial redox signaling in photobiomodulation. Photochem Photobiol2018; 94: 199–212.
10.
De TaboadaLYuJEl-AmouriS, et al.Transcranial laser therapy attenuates amyloid-β peptide neuropathology in amyloid-β protein precursor transgenic mice. J Alzheimers Dis2011; 23: 521–535.
11.
PurushothumanSJohnstoneDMNandasenaC, et al.Near infrared light mitigates cerebellar pathology in transgenic mouse models of dementia. Neurosci Lett2015; 591: 155–159.
12.
BaikJSLeeTYKimNG, et al.Effects of photobiomodulation on changes in cognitive function and regional cerebral blood flow in patients with mild cognitive impairment: a pilot uncontrolled trial. J Alzheimers Dis2021; 83: 1513–1519.
13.
SaltmarcheAENaeserMAHoKF, et al.Significant improvement in cognition in mild to moderately severe dementia cases treated with transcranial plus intranasal photobiomodulation: case series report. Photomed Laser Surg2017; 35: 432–441.
14.
ChaoLL. Effects of home photobiomodulation treatments on cognitive and behavioral function, cerebral perfusion, and resting-state functional connectivity in patients with dementia: a pilot trial. Photobiomodul Photomed Laser Surg2019; 37: 133–141.
15.
ZebhauserPTBertheleAGoldhardtO, et al.Cerebrospinal fluid lactate levels along the Alzheimer’s disease continuum and associations with blood-brain barrier integrity, age, cognition, and biomarkers. Alzheimers Res Ther2022; 14: 61.
16.
Rashidi-RanjbarNMirandaDButtersMA, et al.Evidence for structural and functional alterations of frontal-executive and corticolimbic circuits in late-life depression and relationship to mild cognitive impairment and dementia: a systematic review. Front Neurosci2020; 14: 253.
17.
AlbertMSDeKoskySTDicksonD, et al.The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement2011; 7: 270–279.
18.
WhiteheadALJuliousSACooperCL, et al.Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res2016; 25: 1057–1073.
19.
TedfordCEDeLappSJacquesS, et al.Quantitative analysis of transcranial and intraparenchymal light penetration in human cadaver brain tissue. Lasers Surg Med2015; 47: 312–322.
20.
RajjiTKBowieCRHerrmannN, et al.Design and rationale of the PACt-MD randomized clinical trial: prevention of Alzheimer’s dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression. J Alzheimers Dis2020; 76: 733–751.
21.
BaumgartnerPCHaynesRBHersbergerKE, et al.A systematic review of medication adherence thresholds dependent of clinical outcomes. Front Pharmacol2018; 9: 1290.
22.
FolsteinMFFolsteinSEMcHughPR. Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res1975; 12: 189–198.
23.
ArnettJALabovitzSS. Effect of physical layout in performance of the Trail Making Test. Psychol Assess1995; 7: 220–221.
24.
WoodsSPDelisDCScottJC, et al.The California Verbal Learning Test–second edition: test-retest reliability, practice effects, and reliable change indices for the standard and alternate forms. Arch Clin Neuropsychol2006; 21: 413–420.
25.
BuysseDJReynoldsCF3rdMonkTH, et al.The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res1989; 28: 193–213.
26.
IsmailZAgüera-OrtizLBrodatyH, et al.The Mild Behavioral Impairment Checklist (MBI-C): a rating scale for neuropsychiatric symptoms in pre-dementia populations. J Alzheimers Dis2017; 56: 929–938.
27.
PsychogiosNHauDDPengJ, et al.The human serum metabolome. PLoS One2011; 6: e16957.
28.
SaudeEJSlupskyCMSykesBD. Optimization of NMR analysis of biological fluids for quantitative accuracy. Metabolomics2006; 2: 113–123.
29.
RoutMLipfertMLeeBL, et al.Magmet: a fully automated web server for targeted nuclear magnetic resonance metabolomics of plasma and serum. Magn Reson Chem2023; 61: 681–704.
30.
HenekaMTCarsonMJEl KhouryJ, et al.Neuroinflammation in Alzheimer’s disease. Lancet Neurol2015; 14: 388–405.
31.
MondesertEDelabyCDe La CruzE, et al.Comparative performances of 4 serum NfL assays, pTau181, and GFAP in patients with amyotrophic lateral sclerosis. Neurology2025; 104: e213400.
32.
ChurchillNWHutchisonMGGrahamSJ, et al.Post-concussion changes in the functional brain connectome relative to pre-injury baseline: a prospective observational study. J Neurotrauma2025; 42: 1287–1301.
33.
SchaeferAKongRGordonEM, et al.Local-global parcellation of the human cerebral cortex from intrinsic functional connectivity MRI. Cereb Cortex2018; 28: 3095–3114.
34.
TianYMarguliesDSBreakspearM, et al.Topographic organization of the human subcortex unveiled with functional connectivity gradients. Nat Neurosci2020; 23: 1421–1432.
35.
FischlBvan der KouweADestrieuxC, et al.Automatically parcellating the human cerebral cortex. Cereb Cortex2004; 14: 11–22.
36.
FischlBDaleAM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A2000; 97: 11050–11055.
37.
DesikanRSSégonneFFischlB, et al.An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage2006; 31: 968–980.
38.
ChurchillNWHutchisonMGGrahamSJ, et al.Post-concussion brain changes relative to pre-injury white matter and cerebral blood flow: a prospective observational study. Neurology2025; 104: e213374.
39.
WangZAguirreGKRaoH, et al.Empirical optimization of ASL data analysis using an ASL data processing toolbox: ASLtbx. Magn Reson Imaging2008; 26: 261–269.
40.
WinklerAMRidgwayGRWebsterMA, et al.Permutation inference for the general linear model. Neuroimage2014; 92: 381–397.
41.
PapiSAllahverdipourHJahanA, et al.The effect of transcranial photobiomodulation on cognitive function and attentional performance of older women with mild cognitive impairment: a randomized controlled trial. Prz Menopauzalny2022; 21: 157–164.
42.
LansdallCJMcDougallFButlerLM, et al.Establishing clinically meaningful change on outcome assessments frequently used in trials of mild cognitive impairment due to Alzheimer’s disease. J Prev Alzheimers Dis2023; 10: 9–18.
43.
WolkDASignoffEDDekoskyST. Recollection and familiarity in amnestic mild cognitive impairment: a global decline in recognition memory. Neuropsychologia2008; 46: 1965–1978.
44.
GonzalezSVNguyenNHTRiseF, et al.Brain metabolism of exogenous pyruvate. J Neurochem2005; 95: 284–293.
45.
MoffettJRRossBArunP, et al.N-acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol2007; 81: 89–131.
46.
HuangMYuHCaiX, et al.A comparative study of posterior cingulate metabolism in patients with mild cognitive impairment due to Parkinson’s disease or Alzheimer's disease. Sci Rep2023; 13: 14241.
47.
KanetaTKatsuseOHiranoT, et al.Head-to-head visual comparison between brain perfusion SPECT and arterial spin-labeling MRI with different postlabeling delays in Alzheimer disease. AJNR Am J Neuroradiol2017; 38: 1562–1568.
48.
NawashiroHWadaKNakaiK, et al.Focal increase in cerebral blood flow after treatment with near-infrared light to the forehead in a patient in a persistent vegetative state. Photomed Laser Surg2012; 30: 231–233.
49.
UozumiYNawashiroHSatoS, et al.Targeted increase in cerebral blood flow by transcranial near-infrared laser irradiation. Lasers Surg Med2010; 42: 566–576.
50.
PekalaJPatkowska-SokołaBBodkowskiR, et al.L-carnitine: metabolic functions and meaning in humans life. Curr Drug Metab2011; 12: 667–678.
51.
TanasATozluÖÖGezmişT, et al.In vitro and in vivo neuroprotective effects of sarcosine. Biomed Res Int2022; 2022: 5467498.
52.
RobergsRAGriffinSE. Glycerol: biochemistry, pharmacokinetics and clinical and practical applications. Sports Med1998; 26: 145–167.
53.
MarashianSMHashemianMPourabdollahM, et al.Photobiomodulation improves serum cytokine response in mild to moderate COVID-19: the first randomized, double-blind, placebo controlled, pilot study. Front Immunol2022; 13: 929837.
54.
RieckmannAJohnsonKASperlingRA, et al.Dedifferentiation of caudate functional connectivity and striatal dopamine transporter density predict memory change in normal aging. Proc Natl Acad Sci U S A2018; 115: 10160–10165.
55.
WangZZhangDGuanM, et al.Increased thalamic gray matter volume induced by repetitive transcranial magnetic stimulation treatment in patients with major depressive disorder. Front Psychiatry2023; 14: 1163067.
56.
FitzsimmonsSMDDOostraEPostmaTS, et al.Repetitive transcranial magnetic stimulation-induced neuroplasticity and the treatment of psychiatric disorders: state of the evidence and future opportunities. Biol Psychiatry2024; 95: 592–600.
57.
LuJYangQXZhangH, et al.Disruptions of the olfactory and default mode networks in Alzheimer’s disease. Brain Behav2019; 9: e01296.
58.
HendersonTAMorriesLD. Near-infrared photonic energy penetration: can infrared phototherapy effectively reach the human brain?Neuropsychiatr Dis Treat2015; 11: 2191–2208.
59.
LinALFoxPTHardiesJ, et al.Nonlinear coupling between cerebral blood flow, oxygen consumption, and ATP production in human visual cortex. Proc Natl Acad Sci U S A2010; 107: 8446–8451.
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