Aim
To examine the impact of HTWPE on subthreshold depression in college students in order to provide stronger evidence regarding the treatment of this condition.
Study design and setting
This is a two-armed, single-center, randomized clinical trial with a parallel design that will be conducted at the Tianjin University of Traditional Chinese Medicine(Tianjin, China). In total, 62 eligible participants will be randomized into an HTWPE treatment group and a waiting-list control group at a 1:1 ratio. Prior to treatment, all participants must provide written informed consent. Interventions will be performed twice per day (14 times per week) for 16 weeks. For further details regarding the clinical procedures involved in this trial, see Figure 1. The current protocol (version 2.0, Apr. 6th, 2022) was performed in accordance with the principles of the Declaration of Helsinki, and was in accordance with the standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist shown in Additional file 1.
Participants
Questionnaires pertaining to depression were distributed to undergraduate students at Tianjin University of Traditional Chinese Medicine through posters and contact with counselors. Subjects will be screened based on established inclusion/exclusion criteria, and research assistants will introduce subjects to the study, provide detailed consent forms, and discuss the treatment plants for appropriate groups. Eligible participants will be invited to sign an informed consent form, after which they will undergo baseline assessment.
Inclusion Criteria
1. The standard score of SDS >52 and the score of BDI-II >13;
2. No sex limitations;18 ≤ age ≤ 25 years old;
3. Normal or corrected vision, hearing and intelligence;
4. No antidepressant therapy interventions;
5. No other brain-related diseases;
6. Right-handed individuals;
7. Subjects voluntarily signed the informed consent form.
Exclusion Criteria
1. Patients with MDD meeting the ICD-10 diagnostic criteria;
2. Individuals with comorbid anxiety symptoms;
3. Individuals with any prior history of depression, mental illness, organic mental disorder, or depression caused by psychoactive or addictive substances;
4. Patients with brain diseases and impaired judgment (Wechsler scale < 90 points);
5. Individuals that had participated in other clinical trials within 4 weeks prior to the start of the present study;
6. Individuals with suicidal tendencies.
Withdrawal Criteria
1. Any individuals not meeting with inclusion criteria that are unintentionally accepted;
2. Individuals exhibiting poor compliance who voluntarily withdraw from researchers;
Suspension Criteria
1. fNIRS monitoring cannot be conducted as a result of excess anxiety, tension, or other factors;
2. Serious adverse events or critical illnesses arise during the study that precludes continued clinical trial participation, requiring urgent interventional measures.
Sample size estimation
Power calculations for this study were conducted with the G*Power3.1 software. At a type I error of 5% (α = 0.05), a power value of 0.8, an effect size of 0.8, and an assumed 20% withdrawal rate, 62 subjects were identified as being necessary for this study, including 31 each in the control and intervention groups.
Randomization
Experimenters not involved in result evaluation will generate random numbers using R 3.6.3. These numbers were placed in sealed opaque envelopes and assigned to participants meeting with study inclusion criteria following a complete baseline evaluation. Subjects will be randomized into groups by another experimenter based on the appropriate requirements.
Blinding
Experimenters responsible for evaluating and analyzing study data will be blinded to group assignments, as will study participants. Experimenters responsible for subject group assignments and experimenters supervising HTWPE will not be blinded.
Intervention
All researchers will be trained in professional massage and acupuncture techniques and will undergo standard HTWPE training developed by Professor Guo Yi of Tianjin University of Traditional Chinese Medicine. This training includes discussions of both the standard movement flow of HTWPE and provides an understanding of the efficacy of this technique. Training will include a video of the HTWPE approach and a booklet on curative efficacy and how to perform it. All study participants will be taught standard HTWPE protocols and related practices via video.
HTWPE intervention group
The HTWPE intervention includes five exercises named: "Pat the fingertip area (A)", "Rub nail roots of the fingers (B)", "Flip nails (C)", "Pinch the Jing-well point (D-H)", and "Roc spreads its wings (Fingers spread outward with force)(I)", with the fourth of these interventions being the most important, with pinching being performed to the maximum level of pain that subjects are capable of tolerating group. All subjects in the intervention group will perform this HTWPE regimen two times per day (~5 minutes/time) for four months. Results will be assessed after 4 and 16 weeks. For further details regarding the HTWPE intervention process, see Figure 2.
Waiting-list control group
Individuals in the control group will not be subjected to any specific interventions. Results will be assessed after 4 and 16 weeks. Individuals in the control group will be taught the HTWPE practices when the experiment is complete.
Outcomes
Primary outcomes
The primary outcomes for this study will be participant self-rating depression scale (SDS) and Beck Depression Inventory-II (BDI-II) scores. The SDS is composed of 20 items separated into four grades, with both forward- and reverse-scored items. Scores for all items are summed together and multiplied by 1.25 to produce a standard score (T), with scores of 53-62, 63-72, and >72 respectively corresponding to mild, moderate, and severe depression[20]. The BDI-II scale consists of 21 items scored from 0-3, with total scores of 14-19, 20-28, and 29-63 respectively corresponding to mild, moderate, and severe depression[21].
Secondary outcomes
PSQI
The Pittsburgh Sleep Quality Index (PSQI) consists of seven components, each of which is scored from 0-3. The sum of these sores ranges from 0-21, with higher scores corresponding to lower quality sleep[22]. Outcomes and time points for data collection during this trial are summarized in Table 1.
Table1 Outcomes and Measurement Time points
Time
|
Week-1
|
Week 0
|
Week 4
|
Week 16
|
Period assessment
|
Screening
|
Baseline
|
Intervention
|
Intervention
|
Patients diagnosis
|
Inclusion criteria
|
✔️
|
|
|
|
Exclusion criteria
|
✔️
|
|
|
|
Informed consent
|
✔️
|
|
|
|
Randomization
|
✔️
|
|
|
|
Intervention
|
HTWPE group
n=31
|
|
|
Intervention
2 times/day for 16 weeks
|
Wait-list control group
n=31
|
|
|
No intervention
|
Outcomes
|
SDS
|
✔️
|
✔️
|
✔️
|
✔️
|
BDI-II
|
✔️
|
✔️
|
✔️
|
✔️
|
PIQS
|
|
✔️
|
✔️
|
✔️
|
Reward-processing task
|
|
✔️
|
✔️
|
✔️
|
fNIRS
|
|
✔️
|
✔️
|
✔️
|
Data collection and statistical analysis
|
Adverse event
|
|
|
✔️
|
✔️
|
Causes of dropout
|
|
|
✔️
|
✔️
|
Safety analysis
|
|
|
✔️
|
✔️
|
Analysis
|
✔️
|
✔️
|
✔️
|
✔️
|
(SDS: Self-rating Depression; BDI-II: Scale Beck Depression Inventory-II; PSQI: Pittsburgh Sleep Quality Index; HTWPE: hand twelve Jing-well points exercise; fNIRS: functional Near-Infrared Spectroscopy)
Reward processing tasks
Task types will include both monetary incentive delay (MID) and social incentive delay (SID) tasks[23,24]. In total, 60 trials will be implemented per task type, including 20 trials each with blank, first-class, and second-class rewards. Each trial will be 7 s in duration and will be implemented through event-related design, with a 15 s interval between these trials. The presentation order will consist of 30 MID task trials (10 with no reward, 10 with first-class rewards, 10 with second-class rewards), followed by SID tasks, SID tasks, and the remaining MID tasks, requiring 45 minutes in total to complete. MID tasks will utilize one dime and one yuan as first- and second-level rewards, respectively. SID tasks will use emoticon images from The NimStim Set of Facial Expressions[25]. For examples of these reward processing task protocols, see Figure 3.
Neuroimaging evaluations
Functional near-infrared brain imaging (fNIRS) will be utilized to assess changes in cerebral cortex activity in study subjects over time[26]. The changes of oxygen-containing (HbO2) and deoxidized (HbR) hemoglobin will be assessed in a continuous waveform with LABNIRS (Shimadzu, Japan), a device containing 7 emitters (light sources) and 8 detectors (probes) in a 5*3 arrangement (Figure 4).
Safety assessments
If participants experience any hand pain, headaches, nausea, dizziness, or other adverse effects during the study they will be recorded, and appropriate members of the steering committee will be notified.
Statistical analysis
Scale data
Repeated measures analyses of variance (ANOVAs) will be used to analyze data in SPSS 25.0, with P < 0.05 as the significance level. Normally and non-normally distributed continuous data will be reported as means with standard deviation and medians with the interquartile range, respectively.
fNIRS data
The MatLab (R2018a) NIRS_KIT toolkit will be used to process fNIRS data and to eliminate any drift and noise in these data[27]. A general linear model will be established for each subject, and parameters will be estimated, after which the degree of activation for different channels at different points in time will be assessed.
Data management
The research data will be collected by outcome assessors, then transcribed into an electronic database and stored in it with password protection.
Quality control
Subject quality control
Strict implementation of the diagnostic, inclusion, and exclusion criteria for this study will be used to ensure consistency in the demographic characteristics of recruited study participants.
Intervention quality control
Initially, the standard HTWPE stimulation approach will be demonstrated to research subjects, and then a video of this approach will be provided to the subjects. After completing the exercise every day, subjects will provide feedback to the research investigators in the form of a WeChat punch-in. Research investigators will check daily whether the standard HTWPE movements are being used by subjects.
Quality Control of fNIRS Data Acquisition
1. All fNIRS testing will be performed at the Tianjin University of Traditional Chinese Medicine using LABNIRS equipment (Shimadzu, Japan).
2. Qualified graduate students that have received strict training from the Tianjin University of Traditional Chinese Medicine will perform all fNIRS data collection.
3. When fNIRS data have been collected, the quality of the data will be assessed to ensure that the entirety of the process has been accurately recorded. When the experiment is complete, the collected data will be analyzed by researchers who have received training in professional data processing and analysis.