Amnestic mild cognitive impairment (aMCI) is associated with early disruptions in large-scale brain networks, including the default mode network (DMN), which often shows inefficient or abnormally high connectivity in individuals at increased risk for Alzheimer's disease. Human studies examining the impact of transcranial photobiomodulation (t-PBM) on DMN connectivity and cognitive performance in aMCI remain limited, and few controlled trials have assessed Group × Time interaction effects. This study was designed to address this gap by evaluating whether t-PBM produces measurable changes in resting-state functional connectivity and cognitive outcomes when combined with cognitive rehabilitation.
The trial uses a randomized, sham-controlled, pretest-posttest design. Participants with aMCI were randomly assigned to receive either active t-PBM paired with a cognitive rehabilitation program or sham t-PBM with the same cognitive rehabilitation. The intervention was delivered across eight sessions. Cognitive assessments and resting-state fMRI scans were conducted before the first session and after the final session to evaluate changes in cognitive performance and DMN connectivity. The experimental model allows for the direct evaluation of treatment-related neural changes while accounting for natural variation and practice effects.
To minimize confounding factors, dietary stability was monitored. All participants completed a dietitian visit at baseline and follow-up to document eating habits and reduce the influence of diet-related changes on cognitive or imaging outcomes. In addition, peripheral venous blood samples were collected at baseline for genetic analysis. Genotyping targeted APOE alleles (rs429358, rs7412) and the COMT Val158Met (rs4680) polymorphism. DNA extraction followed silica membrane-based protocols, and allelic discrimination was performed using TaqMan-based real-time PCR. Quality assurance included blinded laboratory processing, random duplicates, call rate thresholds (\>95%), and Hardy-Weinberg equilibrium criteria. These genetic data were incorporated into exploratory models to examine whether genotype moderated baseline brain connectivity or response to the intervention.
Neuroimaging was conducted using a GE SIGNA Hero 3.0 Tesla MRI system. High-resolution T1-weighted structural images were acquired using an axial MPRAGE sequence (TR = 2745 ms, TE = 3.01 ms, TI = 1020 ms, flip angle = 8°, 1 mm slice thickness, voxel size 0.44 × 0.44 × 1 mm, 225 slices). Resting-state functional MRI data were collected using an axial multiband echo-planar imaging sequence (TR = 2000 ms, TE = 22 ms, flip angle = 20°, voxel size 3.125 × 3.125 × 3 mm, 45 slices, matrix 64 × 64, 200 volumes; approximately 6 minutes 40 seconds). Participants were instructed to remain still, keep their eyes closed, and avoid focused mental activity during the scan. These data enable reliable estimation of DMN functional connectivity before and after the intervention.
The study integrates cognitive rehabilitation outcomes, functional neuroimaging, dietary monitoring, and genetic profiling to explore neurobiological and behavioral effects of t-PBM in aMCI. By evaluating network-level changes and potential individual differences in treatment response, the trial aims to improve understanding of whether t-PBM can serve as a network-targeted adjunctive intervention for individuals with early cognitive impairment.
