High Definition Transcranial Direct Current Stimulation (HD-tDCS) for Early Alzheimer's Disease

Overview

This completed randomized trial evaluated the clinical and neural effects of high-definition transcranial direct current stimulation (HD-tDCS) combined with computerized cognitive training in patients with Alzheimer's disease. Participants were assigned to active HD-tDCS plus computerized cognitive training, computerized cognitive training control, or active HD-tDCS control. The study assessed whether combined neuromodulation and cognitive training produced greater cognitive and clinical benefit than either component condition, and whether treatment-related benefit was associated with changes in brain network organization.

Upon meeting the inclusion criteria and providing informed consent, each participant completed a series of cognitive, neuropsychological, and neuroimaging assessments at the hospital outpatient clinics or inpatient department before receiving the assigned intervention. Participants were randomly allocated to one of three parallel intervention arms: active anodal high-definition transcranial direct current stimulation (HD-tDCS) combined with computerized cognitive training, active anodal HD-tDCS combined with control cognitive training, or sham HD-tDCS combined with computerized cognitive training. Approximately 20 participants were assigned to each group. Participants were studied using a masked randomized design. Study participants and personnel responsible for clinical and neuropsychological outcome assessments remained masked to the assigned stimulation condition and allocation parameters. Only trained tDCS administrators had access to the randomization list; they had minimal contact with participants and had no role in cognitive or clinical assessments. Each participant received the assigned intervention for 10 sessions over 2 weeks. Active HD-tDCS was delivered using an anodal stimulation protocol. In the combined intervention arm, active HD-tDCS was paired with computerized cognitive training. In the active HD-tDCS control arm, active stimulation was paired with control cognitive training. Control cognitive training consisted of structured computer-based cognitive activities matched for session duration, computer exposure, task instructions, and participant contact, but used fixed or minimally adaptive task difficulty and did not include individualized performance-based progression. In the sham stimulation arm, computerized cognitive training was paired with sham HD-tDCS. Before intervention, trained investigators obtained baseline cognitive and neuropsychological assessments. The assessment battery included the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Montreal Cognitive Assessment (MoCA), associative memory measures, and additional tasks and questionnaires assessing general cognition, attention, executive function, language, memory, mood, and daily functioning. These measures included Digit Span, Stroop test, verbal fluency test, Symbol Digit Modalities Test, Auditory Verbal Learning Test, associative memory tasks, working memory tasks, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and other executive-function tasks. Stimulation tolerability and adverse events were also assessed. The baseline assessment was completed over approximately 2 days. Participants also underwent multimodal magnetic resonance imaging and electroencephalography recording to assess neural mechanisms related to the intervention. Follow-up evaluations were conducted after the intervention course, including clinical and neuropsychological assessments, stimulation tolerability assessment, and adverse-event monitoring. Post-intervention assessments, neuropsychological testing, multimodal MRI, and EEG recording were completed within 24 hours after the last stimulation session whenever feasible. Additional follow-up assessments were conducted approximately 1 month and 3 months after the last stimulation session using the same or comparable clinical and cognitive assessment battery. Participants were instructed to answer symptom and function questionnaires based on the relevant recent assessment period.