Investigating the Effectiveness of Personalized Optimal Gamma Auditory Frequency Stimulation Intervention on Cognitive Function Enhancement

Previous studies have shown that 40-Hz gamma-band sensory stimulation can reduce Aβ and p-tau burden and improve memory performance in AD mouse models. However, findings from human studies remain inconsistent due to differences in intervention duration and stimulation protocols. Recent studies further suggest that the optimal frequency for inducing gamma-band neural entrainment varies across individuals. In addition, a pilot study conducted in our laboratory found that the optimal auditory stimulation frequency was not necessarily 40 Hz for all participants. Therefore, the present study aims to investigate the effects of optimal auditory frequency stimulation on cognitive performance and its relationship with electrophysiological changes measured by EEG.

The study will recruit 20 cognitively healthy adults. Participants who are willing to join the study will first undergo a screening session to determine whether they meet the inclusion and exclusion criteria and whether auditory stimulation can induce significant neural entrainment. Those who meet the eligibility criteria will proceed to the intervention stage.

This study will adopt a crossover design. All participants will receive two stages of auditory stimulation intervention. Prior to the intervention, participants will be randomly assigned in a 1:1 ratio to one of two experimental groups. One group will receive optimal auditory frequency stimulation during the first stage, while the other group will receive non-optimal auditory frequency stimulation (i.e., the frequency producing the weakest neural entrainment effect). Each group will include 10 participants. During the second intervention stage, the two groups will switch experimental conditions (optimal/non-optimal auditory frequency stimulation).

Each stage will last for one month, with stimulation lasts five days per week and one hour per day. After each intervention session, participants will complete an experimental log form to record adverse effects. A one-month washout period will be implemented between the two intervention stages.

EEG recordings will be conducted before and after each intervention stage, including resting-state EEG, optimal auditory stimulation EEG recordings, and cognitive tasks.

• Personalized optimal gamma auditory frequency stimulation (Device): Participants will receive personalized optimal gamma auditory frequency stimulation using our app downloaded in the mobile device to play the sound for 1 hour per day, 5 days a week, over 1 month.
• Non-optimal gamma auditory frequency stimulation (Device): Participants will receive non-optimal gamma auditory frequency stimulation using our app downloaded in the mobile device to play the sound for 1 hour per day, 5 days a week, over 1 month.

Primary outcomes

• changes in neurophysiological function [Stage 1 baseline (T1), post one-month intervention of stage 1 (T2), stage 2 baseline (T3), post one-month intervention of stage 2 (T4)]: EEG oscillation within the gamma band obtained during resting-state and the periods of optimal and non-optimal auditory stimulation will be analyzed to evaluate and compare the neurophysiological changes.
• changes in working memory performance [Stage 1 baseline (T1), post one-month intervention of stage 1 (T2), stage 2 baseline (T3), post one-month intervention of stage 2 (T4)]: Behavioral performance and electrophysiological activity will be evaluated via a working memory task.
• changes in inhibitory control performance [Stage 1 baseline (T1), post one-month intervention of stage 1 (T2), stage 2 baseline (T3), post one-month intervention of stage 2 (T4)]: Behavioral performance and electrophysiological activity will be evaluated via an inhibitory control task.

Sex: All, ages: 18 Years to 40 Years, accepts healthy volunteers

Inclusion Criteria:

1. Age between 18 to 40 years old.
2. The Cognitive Abilities Screening Instrument (CASI) score is within normal ranges adjusted for age and education.
3. Participants have no history of severe neurological or psychiatric disorders (such as stroke, epilepsy, depression, migraine, etc.) that could affect cognitive function.
4. Participants have not used drugs that may affect cognitive function (e.g., benzodiazepines, anticholinergic medications, etc.).
5. Participants with normal or corrected vision (e.g., glasses or contact lenses) to normal levels.
6. Auditory stimuli induce significant neural entrainment.
7. Self-reported normal hearing

Exclusion Criteria:

1. Participants enrolled in any cognitive enhancement study within the past two months.
2. Participants with a history of disease that could affect cognitive function (e.g., cancer, autoimmune diseases, etc.).
3. Individuals with tinnitus or hyperacusis