Development of a Novel Multidimensional Therapeutic Intervention Protocol for MCI

NCT ID: NCT07196592

Last Updated: 2025-09-29

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-10-01
• Study Completion Date: 2026-12-01

Brief Summary

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.

Detailed Description

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.

Conditions

MCI-AD, Early Stage Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Olfactory Stimulation Group

Group Type: EXPERIMENTAL

Olfactory stimulation

Intervention Type: BEHAVIORAL

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.

TI Stimulation Group

Group Type: EXPERIMENTAL

Temporal Interference,TI

Intervention Type: BIOLOGICAL

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-TI Stimulation Group

Group Type: EXPERIMENTAL

Olfactory-TI Stimulation

Intervention Type: COMBINATION_PRODUCT

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.

Sham Control Group

Group Type: SHAM_COMPARATOR

Sham Control

Intervention Type: COMBINATION_PRODUCT

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.

Interventions

Olfactory stimulation

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.

Intervention Type: BEHAVIORAL

Temporal Interference,TI

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.

Intervention Type: BIOLOGICAL

Olfactory-TI Stimulation

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.

Intervention Type: COMBINATION_PRODUCT

Sham Control

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.

Intervention Type: COMBINATION_PRODUCT

Eligibility Criteria

Inclusion Criteria

Inclusion Criteria:

Baseline screening inclusion criteria: a) Age ≤ 65 years and ≤ 85 years; b) Education duration ≥ 1 year; c) Normal cognitive function at enrollment: MMSE total score: non-illiterate (primary school or below) ≥ 20 points, primary school or above ≥ 24 points; d) Corrected vision and hearing are basically normal, and able to complete cognitive assessment.

Exclusion Criteria:

Baseline screening exclusion criteria: a) Neurological/psychiatric disorders affecting cognitive function: depression, schizophrenia, mental retardation, Parkinson's disease, etc.; b) Severe physical illnesses: cardiovascular disease, cerebrovascular disease, tumors, diabetes, kidney disease, and hypertension stage III or above; c) Autoimmune inflammatory diseases such as rheumatoid arthritis, lupus erythematosus, osteoarthritis, and multiple sclerosis.

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Shanghai Mental Health Center

OTHER

Sponsor Role: collaborator

Yuan Shen

OTHER

Sponsor Role: lead

Responsible Party

Yuan Shen

MD., Ph.D.

Responsibility Role: SPONSOR_INVESTIGATOR

Other Identifiers

B20250001I

Identifier Type: -

Identifier Source: org_study_id