Efficacy of auricular point-vagus nerve stimulation in adolescent insomnia patients and the brain function regulation mechanisms: a study protocol for an experimental, randomized, controlled clinical trial

On August 6, 2024, the study was registered in the Chinese Clinical Trial Registry.1 This research is a randomized controlled prospective single-blind clinical trial. A total of 174 participants were sought in Zhejiang Province. The dynamic randomization method of a central randomization system was used to randomly group the subjects who met the inclusion criteria. The placebo group is selected as the control group. Electroacupuncture will be used to stimulate bilateral auricular point-vagus nerve locations in the treatment group and bilateral non-auricular-vagus distribution areas in the control group. The evaluation of therapeutic indicators is carried out by personnel who are unaware of the grouping situation, and the separation of researchers, operators, and statisticians is implemented. The 8-week trial is divided into 4 weeks of therapy and 4 weeks of follow-up. The Chinese Guidelines for the Diagnosis and Treatment of Insomnia Disorders, which were compiled by the Chinese Sleep Research Society in 2019, provided the relevant criteria used to develop the study protocol (No.1.0, Date: 2024.01.15). Further details are provided in Figures 1, 2.

The study is conducted at Third Affiliated Hospital of Zhejiang Chinese Medical University, which leads the group and provides the medical resources and expert staff required to support the project’s execution. The Department of Acupuncture and Moxibustion, which has skilled medical personnel and cutting-edge therapeutic equipment suitable for undertaking the study of auricular-vagus nerve stimulation therapy, hosts the investigation. The intervention is administered to participants in a hospital treatment room that has been reserved. To ensure the safety and effectiveness of the therapy, the treatment room is equipped with the necessary electroacupuncture and monitoring equipment. The hospital creates a calm, cozy environment that encourages participant relaxation and minimizes the impact of external factors on the treatment’s efficacy. The humidity, light, and temperature of the treatment room is controlled to the appropriate degree.

This trial protocol had been approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine (ZSLL-KY-2024-018-01), and registered in https://www.chictr.org.cn↗ (Identifier: ChiCTR2400087889). This research complies with the Helsinki Declaration. Prior to the start of the study, hospital authorization had been secured. The ethics committee supervises and evaluates the design and execution of the trial procedures.

Non-inferiority sample size estimation for two independent samples was conducted via the Powerandsamplesize.com↗ network. Using the PSQI score as the primary outcome, the sample size was calculated to require a minimum of 78 individuals in each group. Considering the 10% dropout rate in outpatient clinics, the sample size for each group would need to be expanded to 87, totaling 174 people. The specific calculation formula is as follows:nA=κnB,nB=(1+1κ)(σz1−α+z1−βμA−μB−δ)21−β=Φ(z−z1−α)+Φ(−z−z1−α),z=μA−μB−δσ1nA+1nB

The recruitment period for participants ran from September 1, 2024, to March 31, 2025, following registration and ethical approval. A formal informed consent form must be signed for eligible participants to take part and the written consent of their legal guardian must be obtained.

This study adopted the relevant standards stipulated in the “Guidelines for the Diagnosis and Treatment of Insomnia Disorders in China” compiled by the Chinese Sleep Research Society in 2019. Diagnostic criteria: (a) Chief complaints: inability to fall asleep, persistent inability to fall asleep, waking up earlier than intended, refusal to go to bed at the appointed hour, and inability to go asleep on one’s own without assistance from a parent or caregiver. (b) Deficits in daytime functioning: weariness or low energy; difficulty focusing, paying attention, or remembering things; impairment in social, familial, professional, or academic functioning; agitation or irritability of mood; daytime sleepiness; behavioral issues (such as hyperactivity, impulsivity, or aggression); lack of drive, energy, or motivation; vulnerability to errors or mishaps; and anxiety regarding the quality of sleep. (c) Inappropriate sleep opportunities (e.g., adequate sleep periods) or sleep surroundings (e.g., dark, quiet, safe, pleasant places) cannot account for all of these irregularities in sleep and wakefulness. (d) Chronic insomnia: >3 episodes per week for at least 3 months; unrelated to other sleep problems.

Patients were included if they simultaneously met all seven of the criteria: (1) Individuals who meet the diagnostic standards listed above for insomnia. (2) Age: 13–17 years old; no restrictions on gender (2). (3) A score of at least seven on the Pittsburgh Sleep Quality Index Rating Scale (PSQI). (4) Signed informed consent was obtained and obtained the written consent of their legal guardian. (5) Individuals who are able to strictly comply with the treatment requirements. (6) No major illnesses affecting the blood system, immunity, or internal organs illnesses, without any mental health issues. (7) Within 1–3 weeks, no related drugs such as benzodiazepines and melatonin were taken (based on the elimination half-life).

The exclusion criteria are as follows: (1) Patients who were inadvertently registered despite not meeting the eligibility requirements. (2) Patients who are under 13 years old or over 17 years old. (3) Individuals with a history of head trauma, neurological conditions, and other objective environmental causes of insomnia. (4) Individuals with severe underlying illnesses, such as endocrine, hematologic, or digestive system cancers, and patients whose conditions vagal nerve stimulation, such as hyperthyroidism and heart failure. (5) Patients with a PSQI score <7. (6) History of drug abuse or alcoholism. (7) Skin allergy, injury or inflammation at the site of auricular application. Women who are pregnant or preparing for pregnancy, or women who are breastfeeding. (8) Participation in other clinical trials in the last 6 months, or patients who have taken anticholinergic drugs or hormonal drugs in the recent past, or patients who are taking drugs to inhibit the cerebral cortex or the nervous system on an irregular basis.

This trial carries out compliance evaluation, analyzes the causes of dropouts, assesses adverse events, and conducts safety evaluations. These measures are designed to ensure the safety of the patients as well as the scientific validity and reliability of the trial results.

We are committed to conducting this trial in strict accordance to the protocol. However, should any issues arise during the trial necessitating adjustments to certain factors, we will promptly apply for ethical review and notify all relevant parties. Any such adjustments will be disclosed in a transparent and detailed manner. We will exercise utmost with each modification to ensure the scientific rigor and reliability of the trial results.

Single-blind study (Investigator, Outcomes Assessor): Individuals who evaluate the results will remain blind to the condition of the participants (intervention or control group). After the study participants were included in the TransHealth study, they received online access to the e-health platform. First, they were asked to complete questionnaires for baseline assessment (T0). Only after completing the T0 assessment, a 1:1 randomization for intervention and control group was carried out using a computer-based code with variable block length generated by the Institute for Medical Biometry and Epidemiology (Figures 1, 2). At the end of study participation, participants will complete the T1 assessment. Against this background, we do not expect any loss of data.

The Case Report Form (CRF) will be used to collect study data, and EXCEL software will be employed for data collection or recording. Junying Du will be responsible for data management. At the end of the study, the investigator will submit the CRFs of all enrolled patients to the data management center, which should be complete and signed. A professional data management company will be commissioned for clinical data management. Data will be analyzed using the statistical software SPSS 19.0. Uniform testing SOPs will be developed by the subject group.

The study prevents a novel approach to addressing teenage insomnia by integrating modern neurophysiological strategies with traditional acupuncture. Utilizing a Randomized Controlled Trial design enhances the reliability of the results and minimizes bias. Objective measures, including polysomnography (PSG), HRV, and fMRI, are employed to comprehensively evaluate the treatment effects. By exploring the neural mechanisms underlying the treatment outcomes, the study aims to advance understanding of insomnia and its management. With a focus on non-pharmacological interventions due to concerns regarding medication side effects in adolescents, the generalizability of the findings may be limited to the teenage population. Conducted in a specific cultural context, the study’s findings may have restricted applicability beyond this setting. Despite efforts to recruit an adequate number of participants, the sample size limitations could affect the study’s ability to detect smaller effects. While the treatment and follow-up durations are clearly defined, the sustainability and long-term benefits of the intervention remain uncertain. Various factors contributing to insomnia may not have been fully considered in this study.

To ensure compliance with ethical standards and protect participants’ rights, the Ethics Committee must approve the project before implementation. Prior to commencing the study, participants and their legal guardians must provide informed consent by signing a formal document. All collected data will be treated confidentially, with information anonymized or coded to maintain privacy. Immediate action should be taken in response to any adverse events to uphold the accuracy and integrity of the gathered data. Researchers are required to disclose any potential conflicts of interest that may affect the study’s impartiality. For scientific rigor and validity, the research protocol, methodology, and results must be disseminated to the academic and broader communities through appropriate channels. The study outcomes should be published in peer-reviewed scientific journals. Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.