As populations age, Alzheimer's disease (AD) is increasing while disease-modifying drugs remain elusive, making early diagnosis and intervention essential. Building on advances in neuromodulation and virtual reality (VR), we target amnestic mild cognitive impairment (aMCI)-the prodromal stage of AD-as a key window for prevention. Preliminary evidence shows disrupted theta-delta phase-amplitude coupling in prefrontal and temporal cortices in aMCI, whereas olfactory enrichment can enhance hippocampal synaptic function, improve cognition, and potentially lower AD risk. We will conduct a large-scale clinical cohort study to test the neural mechanisms and clinical efficacy of multi-site, cross-frequency transcranial alternating current stimulation (tACS) combined with multisensory (visual-olfactory-auditory) VR. A comprehensive database spanning demographic, neuropsychological, biochemical, neuroimaging, and neuromodulation parameters will guide optimal protocols and provide objective evidence for non-pharmacological interventions, informing development of a microcurrent brain stimulator and a portable VR device.
With the accelerating pace of population aging, the prevalence of Alzheimer's disease (AD) continues to rise, yet effective disease-modifying pharmacotherapies remain unavailable. Early diagnosis and intervention are critical to slowing cognitive decline and reducing disease burden. In recent years, rapid advances in neuromodulation and virtual reality (VR) have opened new avenues for mechanistic studies and functional brain rehabilitation in AD and other neurodegenerative disorders. Amnestic mild cognitive impairment (aMCI) is widely regarded as the prodromal stage of AD and represents a key window for prevention and treatment. Developing innovative non-pharmacological therapies for individuals at this early stage has therefore become an urgent clinical priority. Preliminary studies indicate that people with aMCI exhibit a significant loss of phase-amplitude coupling (PAC) between theta and delta rhythms in the prefrontal cortex and temporal lobe, whereas olfactory-enriched environmental stimulation can enhance hippocampal synaptic function, improve cognition, and lower AD risk. Accordingly, we propose a large-scale clinical cohort study to investigate the neural-circuit mechanisms and clinical efficacy of multi-site, cross-frequency transcranial alternating current stimulation (tACS) and multisensory VR integrating visual, olfactory, and auditory inputs for the treatment of aMCI. We will establish a comprehensive database encompassing demographic, neuropsychological, biochemical, neuroimaging, and neuromodulation parameters. Ultimately, this work will provide optimal theoretical parameters and objective evidence to guide the development of non-pharmacological interventions for AD-specifically, a microcurrent brain stimulator and a portable VR device.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
300
Olfactory stimulation were set as follows: Essential oil types: yuzu, lavender, lemon, and mint. Concentration: 158 μL of essential oil + 50 mL of water. The mixed solution was poured into the test tubes of the olfactory instrument, ensuring that the liquid levels of the four solutions were kept at the same height. Each scent was released for 30 seconds, followed by a 10-second air interval, with each cycle lasting 20 minutes.
During stimulation, the parameters were set as follows: Δf=40Hz (2000Hz vs. 2040Hz) 2mA Stimulation duration: 20min We fixed the stimulation protocol and used a standard head to simulate stimulation of the entorhinal region.
During stimulation, the parameters were set as follows: Δf=40Hz (2000Hz vs. 2040Hz) 2mA Stimulation duration: 20min We fixed the stimulation protocol and used a standard head to simulate stimulation of the entorhinal region. Olfactory stimulation were set as follows: Essential oil types: yuzu, lavender, lemon, and mint. Concentration: 158 μL of essential oil + 50 mL of water. The mixed solution was poured into the test tubes of the olfactory instrument, ensuring that the liquid levels of the four solutions were kept at the same height. Each scent was released for 30 seconds, followed by a 10-second air interval, with each cycle lasting 20 minutes.
During stimulation, the parameters were set as follows: Δf=0Hz (2000Hz vs. 2000Hz) 2mA Stimulation duration: 20min. Olfactory stimulation were set as follows: Essential oil types: air. lasting 20 minutes.
Change in Olfactory Sensitivity (TDI score)
Change in olfactory function measured with the Sniffin' Sticks Threshold-Discrimination-Identification (TDI) composite score. Unit of Measure: TDI score, 1-48 (higher scores indicate better olfactory function).
Time frame: Baseline; 30 minutes after Session 1; 30 minutes after Session 5; 30 minutes after Session 10; 1 week after Session 10.
Path Integration - Angle Deviation
Absolute angular error during the path-integration task. Lower values indicate better performance. Unit of Measure: Degrees (°); lower is better.
Time frame: Baseline; 5 minutes after Session 1; 5 minutes after Session 5; 5 minutes after Session 10.
Path Integration - Distance Deviation
Difference between actual and ideal path length during the path-integration task. Lower values indicate better performance. Unit of Measure: Meters (m); lower is better.
Time frame: Baseline; 5 minutes after Session 1; 5 minutes after Session 5; 5 minutes after Session 10.
Path Integration - Composite Accuracy (M_ROC_AUC)
Area under the ROC curve computed from multivariate PI features to quantify task accuracy/reliability across sessions. Unit Measure: AUC, 0.00-1.00 (higher values indicate better accuracy/stability).
Time frame: Baseline; 5 minutes after Session 1; 5 minutes after Session 5; 5 minutes after Session 10.
Change in Cognitive Performance (MoCA-B)
Change in global cognition using the Montreal Cognitive Assessment-Basic (MoCA-B). Unit of Measure: MoCA-B score, 0-30 (higher scores indicate better cognition).
Time frame: Baseline; 5 minutes after Session 10.
Activities of Daily Living (ADL - Barthel Index)
Change in functional ability using the Barthel Index. Unit of Measure: Barthel Index, 0-100 (higher scores indicate greater independence).
Time frame: Baseline; 30 minutes after Session 1; 30 minutes after Session 5; 30 minutes after Session 10; 1 week after Session 10.
Adverse Events Related to Intervention
Incidence of device- or procedure-related adverse events (e.g., skin irritation, headache, dizziness, nausea). Unit of Measure: Number of participants with ≥1 adverse event (count).
Time frame: Baseline; 5 minutes after Session 1; 5 minutes after Session 5; 5 minutes after Session 10.
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