Background: Alzheimer’s disease’s (AD) prevalence is projected to increase as the population ages and current treatments are minimally effective. Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light penetrates into the cerebral cortex, stimulates the mitochondrial respiratory chain, and increases cerebral blood flow. Preliminary data suggests t-PBM may be efficacious in improving cognition in people with early AD and amnestic mild cognitive impairment (aMCI). Methods: In this randomized, double-blind, placebo-controlled study with aMCI and early AD participants, we will test the efficacy, safety, and impact on cognition of 24 sessions of t-PBM delivered over 8 weeks. Brain mechanisms of t-PBM in this population will be explored by testing whether the baseline tau burden (measured with ¹⁸F-MK6240), or changes in mitochondrial function over 8 weeks (assessed with ³¹P-MRSI), moderates the changes observed in cognitive functions after t-PBM therapy. We will also use changes in the fMRI Blood-Oxygenation-Level-Dependent (BOLD) signal after a single treatment to demonstrate t-PBM-dependent increases in prefrontal cortex blood flow. Conclusion: This study will test whether t-PBM, a low-cost, accessible, and user-friendly intervention, has the potential to improve cognition and function in an aMCI and early AD population.

Down syndrome (DS) is the leading genetic cause of intellectual disability globally, affecting about 1 in every 800 births. Individuals with DS often face various neuropsychiatric conditions alongside intellectual disabilities due to altered brain development. Despite the diverse phenotypic expressions of DS, typical physical characteristics frequently influence language development and acquisition. EEG studies have identified abnormal oscillatory patterns in individuals with DS. Emerging interventions targeting the enhancement of gamma (40 Hz) neuronal oscillations show potential for improving brain electrical activity and cognitive functions in this population. However, effective cognitive interventions for DS remain scarce. Extensive research indicates that transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light can penetrate deeply into the cerebral cortex, modulate cortical excitability, and enhance cerebral perfusion and oxygenation. Furthermore, t-PBM has been shown to improve cognitive functions such as language, attention, inhibition, learning, and memory, including working memory. This study presents the rationale and design of an ongoing randomized, sham-controlled clinical trial aimed at assessing the effectiveness of t-PBM using NIR light in enhancing the language abilities of individuals with DS.

Background: Transcranial photobiomodulation (t-PBM) is a promising non-invasive therapy for Major Depressive Disorder (MDD). MDD is associated with altered brain metabolism, including changes in N-acetylaspartate (NAA), choline (Cho), and creatine (Cr). This study assessed the effects of varying t-PBM doses on neurometabolite levels in the dorsolateral prefrontal cortex (dlPFC) and their correlations with clinical outcomes. Methods: In this randomized, sham-controlled, cross-over study, 33 adults with MDD received one session of t-PBM at low, medium, and high doses and a sham treatment. Proton magnetic resonance spectroscopy (1H-MRS) measured NAA, Cho, and Cr pre- and post-treatment. Clinical outcomes were assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Symptoms of Depression Questionnaire (SDQ). Statistical analyses included paired t-tests or Wilcoxon signed-rank tests for neurometabolite changes, and linear mixed-effects regression models for t-PBM dose, neurometabolites, and time effects. Results: NAA levels increased significantly (7.52 ± 0.777 to 8.12 ± 1.05 mmol/L for one session; 7.36 ± 0.85 to 7.85 ± 0.68 mmol/L across all sessions); however, these changes were not associated with specific t-PBM doses or sham. No significant changes were observed for Cho and Cr levels. Positive correlations were found between Cho levels and MADRS scores (r = 0.59, p = 0.017), and negative correlations between Cr levels and SDQ scores at the medium dose (r = −0.91, p = 0.011). Conclusions: While NAA levels increased, and correlations between neurometabolites and clinical outcomes were observed, these findings do not suggest a specific effect of t-PBM. Larger randomized controlled trials with optimized dosing protocols, extended follow-up, and advanced spectroscopy are needed to clarify the neurometabolic therapeutic potential of t-PBM in MDD.