Effectiveness and safety of high-definition transcranial direct current stimulation in patients with mild cognitive impairment: A randomized, triple-blind, sham-controlled trial

BackgroundHigh-definition transcranial direct current stimulation (HD-tDCS), a non-invasive brain stimulation technique, has shown potential for improving cognition in patients with mild cognitive impairment (MCI).ObjectiveTo evaluate whether HD-tDCS enhances cognitive function in individuals with MCI.MethodsThis was a triple-blind, randomized, sham-controlled study. The anodal electrode was placed over the left dorsolateral prefrontal cortex (DLPFC) and surrounded by four cathode electrodes (2 mA for 25 min, daily for 10 sessions). Tests were performed at baseline, after 2-week stimulation, at 1 month, and at 3 months. The primary outcome was global cognition measured by Cognitive Abilities Screening Instrument and secondary outcomes included memory, language, executive function, and attention tests. Group differences were analyzed using linear mixed model (LMM).ResultsFifty patients with MCI were randomized to the sham (n = 25) and HD-tDCS groups (n = 25). No significant differences were observed between the HD-tDCS and sham groups in global cognition or other neuropsychological measures. However, subgroup analysis revealed a significant three-way interaction between apolipoprotein E (<i>APOE</i>) allele 4 status, tDCS condition, and time. <i>APOE4</i>-positive patients receiving HD-tDCS showed significantly greater improvement in language function, as measured by the Wechsler Adult Intelligence Scale Fourth Edition vocabulary, compared to <i>APOE4</i>-negative patients in the sham group (p = 0.028). Adverse effects were mild and comparable between groups.ConclusionsHD-tDCS did not enhance global cognition in MCI patients overall. Preliminary findings demonstrated a potential language benefit was observed in <i>APOE4</i>-postitive individuals. These exploratory findings warrant further investigation in larger, biomarker-stratified studies.<b>Trial registration</b>The study was registered at ClinicalTrial.gov under NCT04121156.