Protocol for a feasibility trial of digital mindfulness and cognitive-motor exercise for subclinical depression in older adults

Abstract

Objective

Subclinical depression in older adults, though below the diagnostic threshold for major depressive disorder (MDD), is associated with an increased risk of progression and functional decline. This study aims to assess the feasibility, safety, and preliminary efficacy of a combined mindfulness-based and cognitive-motor intervention, with a view to future optimization and broader application.

Methods

This single-arm design study will involve older adults with subclinical depression aged 60 years and above. Participants will undergo an 8-week intervention combining mindfulness practices and cognitive-motor exercises. The primary outcomes will be feasibility and adherence to the intervention, and the secondary outcomes will be depressive and anxiety symptoms, cognitive function, activities of daily living, and safety. Additional secondary outcomes will be brain magnetic resonance imaging (MRI) findings and serum cortisol levels.

Results

We anticipate high feasibility and adherence, with minimal adverse events. Improvements are expected in depressive and anxiety symptoms, cognition, and function, along with reduced cortisol levels. MRI may reveal structural and functional changes in brain regions associated with emotional regulation and cognition. Findings will inform the development of scalable digital interventions.

Conclusion

This study will provide initial evidence on the utility of integrating mindfulness and cognitive-motor approaches for older adults with subclinical depression. The results will support the design of accessible, non-pharmacological strategies that can be digitally delivered to enhance mental health in aging populations.

Trial status

The study is currently ongoing (identifier: ChiCTR2400087251).

Keywords

Subclinical depression older adults mindfulness-based intervention (MBI)cognitive-motor exercise feasibility study,digital health

Introduction

Subclinical depression, also known as subthreshold depression, is characterized by depressive symptoms that do not fully meet the criteria for major depressive disorder (MDD).¹ Although subclinical depression is less severe than MDD, it is common, particularly in older adults, with a prevalence of 18.6%.² Research has shown that individuals with subthreshold depression are more likely to transition to MDD, with a conversion rate of 17.62% compared with 6.08% in non-depressed individuals.³ Additionally, 8% to 10% of older adults with subclinical depression progress to MDD each year.⁴ Moreover, subclinical depression is associated with various negative outcomes, such as reduced health-related quality of life, higher healthcare use, increased economic burden, and elevated mortality rate.^4,5

Early intervention for subclinical depression has gained recognition as a critical strategy in preventing the development of MDD, especially among older adults.⁶ Given the growing aging population worldwide, effective and accessible interventions are paramount. Non-pharmacological therapies, which include mindfulness-based interventions (MBIs) and cognitive-motor exercise, have emerged as promising approaches for mitigating depressive symptoms and improving psychological resilience.

MBIs are grounded in the concept of mindfulness, which is defined as the intentional and non-judgmental awareness of present thoughts and emotions.⁷ Rooted in contemplative traditions, mindfulness has become widely applied in both clinical and community-based mental health practices.^8,9 MBIs include techniques such as meditation, body scanning, and controlled breathing exercises, all of which are aimed at enhancing emotional regulation and managing stress.¹⁰ Clinical guidelines (e.g. the National Institute for Health and Care Excellence guidelines) encourage the use of mindfulness practices to alleviate depressive symptoms and prevent relapse in individuals with depressive tendencies.¹¹

Although numerous studies have demonstrated the efficacy of MBIs in alleviating depressive symptoms, most have been focused on younger adult populations.¹² However, recent research has shifted attention to the potential benefits of these interventions in older adults. A meta-analysis of 19 studies examining the effect of MBIs on older adult populations found significant improvement in depressive symptoms, with a pooled effect size of g = 0.65.¹³ Interestingly, the analysis revealed greater improvements in Asian populations (g = 1.28) than in European (g = 0.59) and North American (g = 0.32) populations, which suggests that cultural factors influence the effectiveness of mindfulness training among older adults.

Recent neuroimaging research has suggested that mindfulness-based cognitive therapy modifies brain connectivity during ruminative states, with improvements in the ability to maintain attention on bodily sensations. Such enhancement may help reduce the tendency for individuals to become fixated on ruminative thought patterns.¹⁴ These findings suggest that mindfulness may hold promise for improving subclinical depression in older adults.

Cognitive-motor exercises have been widely recognized for their role in improving both mental and physical health.¹⁵ Traditionally, these exercises combine physical activity with cognitive tasks to enhance overall well-being. Recent studies have indicated that digital cognitive-motor exercises, delivered via digital platforms, may help reduce depressive symptoms in older adults in general, suggesting potential benefits for those with subclinical depression.¹⁶ For example, one type of digital cognitive-motor activity may involve following rhythmic audio cues on a tablet to tap alternating hands on a table in a specific sequence while simultaneously naming items from a category (e.g. animals or fruits), thus engaging coordination, attention, and executive function. Digital interventions offer several advantages: accessibility, scalability, and the potential for continuous monitoring and personalization. Cognitive-motor exercises may reduce symptoms via various mechanisms, such as lowering inflammation levels and improving cardiovascular health, both of which are linked to better mood regulation ability.¹⁷ Furthermore, cognitive-motor exercises have been shown to reduce cortisol levels, a key stress hormone, while promoting neuroplasticity and enhancing cognitive function.¹⁸

Given these findings, the combination of mindfulness and cognitive-motor exercises may offer a comprehensive strategy for managing subclinical depression. MBIs help individuals cultivate greater emotional awareness and resilience, while cognitive-motor exercises contribute to physical and cognitive health, potentially reducing stress-related physiological changes such as cortisol elevation. Delivering these interventions digitally addresses significant barriers associated with traditional mindfulness therapy, including limited accessibility due to a shortage of trained professionals and geographical constraints.^19–21 Yet, despite these promising possibilities, several critical questions regarding the integrated application of these interventions remain unanswered.

Specifically, existing digital interventions have predominantly been evaluated independently rather than as integrated strategies.^22,23 Recent studies have demonstrated the feasibility and acceptability of digital mindfulness interventions for older adults but have not explored the added value of combining them with cognitive-motor exercises.²⁴ Likewise, digital cognitive-motor programs have typically prioritized physical and cognitive outcomes, leaving the psychological benefits—particularly for subclinical depression—underexplored.²⁵ Moreover, qualitative evidence indicates that while older adults generally accept digital mental health interventions, important factors such as technology-related barriers, user engagement, and adherence patterns remain poorly understood.²⁶

To address these specific knowledge gaps, our study evaluates the feasibility, acceptability, and preliminary effectiveness of an integrated digital mindfulness and cognitive-motor intervention tailored explicitly to older adults experiencing subclinical depression. By directly investigating user engagement, adherence barriers, and initial psychological outcomes, this study aims to provide critical insights to support the development of accessible, scalable digital mental health interventions, ultimately contributing to early mental health intervention in older populations.

Methods

Study design and sample size

This protocol was developed in accordance with the SPIRIT 2013 reporting guidelines.²⁷ It describes a single-arm feasibility trial using a within-subjects pre-post design. The study has been registered with the Chinese Clinical Trial Registry (identifier: ChiCTR2400087251).

Recruitment began in September 2024 and will continue through December 2025. Each participant will complete an 8-week intervention, with baseline and post-intervention assessments conducted within 2 weeks before and after the intervention period.

The sample size calculation was based on a previous study that reported a Hedges’ g of 0.62 for the effect of exercise on depressive symptoms.¹⁷ We hypothesize that the effect size of our combined intervention will be at least as large as that observed for exercise alone, given the complementary nature of mindfulness and cognitive-motor exercises. For an α = 0.05 and a power of 1 − β = 0.8, with a one-sided significance level of p = 0.025, we calculated that 23 participants would be required. Considering a 20% attrition rate, the total number of participants needed would be 28. To account for potential dropouts and ensure that we retain an adequate sample size, we plan to recruit 30 participants with subclinical depression.

Participants

Subjects will be recruited through the following channels: roll-up banners, posters, lectures, WeChat Moments, and other digital promotional materials.

Eligible participants will be those aged 60 years and older, of either sex, who are right-handed, and with a minimum educational level of elementary school. Right-handedness was chosen to control for potential cognitive and motor differences linked to hemispheric lateralization, ensuring more consistent results across participants. Participants will be required to score 2 or higher (out of a possible 12 points) in the Geriatric Depression Inventory but not meet the diagnostic criteria for a depressive episode.²⁸

Exclusion criteria are any neurological or neuropsychiatric disorder affecting mood, current use of any psychiatric medication, and any physical conditions that might prevent regular attendance and full participation in the intervention program.

Participants will be withdrawn from the study if they experience exacerbation of depressive symptoms that require medication or meet the diagnostic criteria for MDD. Additionally, participants may be excluded if they voluntarily withdraw from the study, develop another illness unrelated to the study during the study period, or engage in other psychological therapies or training during the study. Participants will also be withdrawn if they show significant health deterioration, psychological distress related to the intervention, or other serious difficulties that prevent continued participation.

The work will be carried out according to the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. The ethics committee of the Peking University Institute of Mental Health has approved the study (Number: X2024-01-17-3-1). All subjects will be fully informed of the study protocol and provide written informed consent.

Setting

Patients with subclinical depression will be recruited from communities within Guangyuan City, Sichuan Province, which is a city located in western China with relatively scarce resources. Patients who meet the eligibility criteria will be invited by the research team to participate in the study. Referrals may come from primary care providers or other healthcare professionals involved in their care. After the initial screening, patients will be fully informed of the procedures of the trial and invited to provide written informed consent. Participants will complete the intervention and undergo pre- and post-treatment assessments. Interventions will be delivered on a tablet computer (Figure 1).

Figure 1.

Flowchart of the study design.

Randomization and blinding

Because there is only a single group in the study, randomization is not required, and blinding will not be implemented.

Intervention

Participants will wear a sports watch during the daily training session, and their heart rate, respiratory rate, and heart rate variability data during the training will be collected.

Participants will undergo an 8-week intervention combining mindfulness practice with cognitive-motor exercises. Each session will last 30 to 40 min, and participants will be guided by audio recordings during the mindfulness practice and by video recordings during the cognitive-motor exercises, on a tablet. Participants will be instructed to complete one training session per day, every day, throughout the 8-week intervention period. The mindfulness training will involve various activities aimed at increasing awareness and presence in the moment. Mindfulness exercises will include mindful eating, mindful breathing, body scans, and mindful stretching, each of which is designed to help participants connect more deeply with their body and surroundings. Although the intervention does not include a dedicated psychoeducational module, both the mindfulness audio and cognitive-motor video sessions feature brief introductions explaining the purpose of each practice. These exercises will be performed in a seated or lying position and include elements such as mindful breathing while seated and body scans while lying down (Table 1). The cognitive-motor exercises will focus on improving coordination, body awareness, and rhythm, and consist of seven sections, each with specific activities designed to engage both cognitive and motor skills. The exercises can be performed in either a seated or standing position, and participants will follow pre-recorded videos on a tablet. Each session will last approximately 13 min (Table 2). These exercises include fine motor activities of the fingers, upper limb spatial exploration, body part identification, and rhythm practice, all of which are designed to stimulate cognitive processing alongside physical movement. In contrast to conventional aerobic or strength-based exercise programs, our cognitive-motor intervention incorporates elements that target attention, visuospatial awareness, memory, and executive function through goal-directed, structured movement tasks. This integrated design is intended to maximize the cognitive engagement of participants while remaining accessible for older adults with varying levels of physical ability.

Table 1.

Mindfulness training schedule.

Week	Content	Notes
1	Mindful eating with raisins, mindful breathing, and body scan.	Requires raisins. Eat raisins mindfully while seated; perform the body scan lying on the bed.
2	Mindful breathing and body scan.	Practice mindful breathing seated on a sturdy chair; perform the body scan lying on the bed.
3	Mindful stretching, mindful sitting (focusing on breathing and the body), and breathing space.	Mindful stretching is done standing, while mindful breathing and breathing space are done seated.
4	Mindful stretching, mindful sitting (focusing on breathing and the body), and breathing space.	Same as Week 3.
5	Mindful breathing, mindful walking, breathing space.	Breathing exercises require sitting, while walking exercises can be done indoors or outdoors.
6	Mindful sitting (focusing on breathing and the body), mindful sitting (focusing on sounds and thoughts), and breathing space.	Practice seated on a sturdy chair with backrest.
7	Mindful sitting (focusing on breathing and the body), mindful sitting (focusing on sounds and thoughts), and breathing space.	Same as Week 6.
8	Self-selected practice.	Corresponds to the selected training requirements.

Table 2.

Cognitive-motor exercise schedule.

Chapter	Activity Timeline (Minutes)	Content
1	00:00-02:10	Warm-up exercises
2	02:11-03:27	Finger fine motor exercises
3	02:28-05:31	Bilateral hand coordination practice
4	05:32-07:43	Upper limb spatial exploration
5	07:44-09:15	Body part identification
6	09:16-10:32	Rhythm practice
7	10:33-12:52	Breathing relaxation

Note: Each training session includes all of the above activities and requires auxiliary tools, such as sand shakers and sand eggs.

The intervention will be delivered via a custom-developed digital platform installed on a 10.3-inch Android tablet with touchscreen functionality. Participants will be required to log in with a personal account before each session to ensure individual-level tracking. The tablet will be connected to the internet via mobile data, allowing real-time uploading of adherence and engagement data to a secure, cloud-based backend managed by the research team.

Research staff will monitor training progress through the system, and participants who miss scheduled sessions will receive follow-up reminders by phone. In addition, the system will automatically send a weekly reminder message every Monday to encourage continued participation. All data will be anonymized during transmission, and no personally identifiable information will be stored on the device. Data security and access will be managed by authorized personnel following institutional data protection protocols.

Outcome measurement

At baseline, participants will first complete a custom-designed demographic and background questionnaire to collect general personal information relevant to the feasibility and interpretation of the intervention. This includes age, sex, ethnicity, education level, marital status, living situation (e.g. living alone or with family), prior experience with digital devices (e.g. tablets or smartphones), and the presence of chronic physical health conditions.

Assessments will be conducted in person at the Guangyuan Institute of Mental Health by trained assessors using standardized electronic tools. Assessments will take place at baseline and within 2 weeks of completing the 8-week intervention, covering feasibility, safety, effectiveness, and secondary exploratory outcomes.

(1) Feasibility assessment

The primary outcome measures are (1) adherence to the study protocol (the number of intervention sessions attended by participants/total number of intervention sessions, which is 56); (2) and the completion rate (the number of participants who completed at least 70% of the intervention sessions/total number of individuals who received the intervention). All interventions will be conducted using a tablet, and participants’ progress will be automatically recorded in the backend of the system.

(2) Safety assessment

Adverse events and serious adverse events will be recorded using a structured electronic reporting form developed by the research team. The form includes fields such as event description, severity, onset and end time, relationship to the intervention, outcome, serious adverse status, and measures taken. These entries are completed via a secure digital interface and submitted directly to the study database.

(3) Effectiveness assessment

All participants will be subjected to a battery of neuropsychological assessments at baseline and after completing the 8-week intervention. These will comprise assessments of cognitive function, depressive and anxiety symptoms, and living function.

Cognitive function will be assessed for (1) general mental status (The Hong Kong Brief Cognitive Test)²⁹; (2) episodic memory (Hopkins Verbal Learning Test)³⁰; working memory (the Digit Span Test)³¹; (3) processing speed (the Trail Making Test A and Color Dots Test³²; (4) executive function (the Stroop Color and Word Test); ³³and (5) language (Verbal Fluency Test [Animals]).³⁴

Depressive and anxiety symptoms will be assessed using the Patient Health Questionnaire-9 (PHQ-9),³⁵ the 7-item Generalized Anxiety Disorder Questionnaire (GAD-7),³⁶ and the Geriatric Depression Scale (GDS).³⁷ The PHQ-9 is widely used in clinical research and enables comparisons across studies, while the GDS is specifically designed for older adults and reduces the influence of somatic symptoms. Including both tools allows for a more comprehensive assessment of depressive symptoms in this population.

Activities of daily living will be examined using the Activity of Daily Living Scale, which has a total of 14 items, each of which is rated between 1 and 4 points. A higher total score indicates poorer daily living ability.³⁸

(4) Secondary exploratory indicators

Magnetic resonance imaging acquisition

At baseline and trial completion, MRI data will be obtained following the behavioral assessment. MRI acquisition will be conducted using a 3.0 T GE Signa Architect scanner (Boston, Massachusetts, USA) with an eight-channel sensitivity-encoding head coil (SENSE factor = 2.4) at the Neuroimaging Center of Guangyuan Institute of Mental Health. Sequences for MRI data acquisition will include T1, T2, T1-weighted fluid-attenuated inversion recovery (FLAIR), T2-weighted FLAIR, diffusion-weighted imaging (DWI), and arterial spin labeling (ASL) to assess structural and functional brain changes.

Blood sample collection for cortisol measurement

Venous blood samples (6 ml) will be collected from participants to quantify cortisol levels, which serve as a biomarker for stress and physiological response to the intervention. To minimize the impact of circadian variation on cortisol secretion, blood samples will be collected during the time window of 6:00 to 8:00 AM when cortisol levels are typically highest. Samples will be collected at the Guangyuan Institute of Mental Health by a designated study nurse, ensuring consistency and reliability across participants. This timing ensures consistency across participants and increases the reliability of cortisol measurements as an outcome variable. Samples will be collected in ethylenediaminetetraacetic acid-treated vacutainers, stored at 4°C, processed (centrifuged and plasma separated) within 30 min, and frozen at −80°C until batch analysis.

Statistical analysis

Descriptive statistics will be used to summarize the primary outcomes. Adherence and completion rates will be reported as percentages.

Effectiveness will be assessed by comparing pre- and post-intervention scores using paired t-tests (or the Mann–Whitney U test for non-normally distributed data) at a significance level of p < 0.05.

Safety issues related to this intervention will be carefully considered. All adverse events and negative consequences will be recorded using an adverse event reporting form to ensure thorough tracking. Descriptive statistics will be used to summarize the occurrence, frequency, and nature of adverse events. The results of the safety analysis will be presented as counts and percentages for all participants.

For the secondary exploratory indicators, MRI data will be preprocessed before conducting analyses. Preprocessing steps will include motion correction, skull stripping, spatial normalization to a standard brain template, tissue segmentation, registration of functional and structural images, smoothing (if necessary), artifact detection and removal, and extraction of cerebral blood flow and diffusion metrics for ASL and DWI data. MRI data will be analyzed using paired t-tests in Statistical Parametric Mapping (SPM 12), with a statistical significance level set at p < 0.001. Specific brain regions involved in cognitive and emotional processing, such as the prefrontal cortex, hippocampus, and amygdala, as well as key networks, such as the default mode network and salience network, will be explored to identify neural changes associated with the intervention.¹⁴ Structural analysis will include volumetric analysis of gray and white matter in these regions, whereas functional analysis will assess connectivity between these regions and functional connectivity within the associated brain networks. Cortisol levels measured in venous blood samples will be analyzed via descriptive statistics at baseline and post-intervention. Paired t-tests will be used to compare cortisol levels before and after the intervention, with a significance level set at p < 0.05.

In addition, baseline characteristics will be compared between intervention completers and non-completers using independent-samples t-tests or Mann–Whitney U tests for continuous variables and chi-square tests for categorical variables, to explore potential factors associated with adherence.

Discussion

This study aims to explore the feasibility, safety, and effectiveness of combining MBIs with cognitive-motor exercise as a non-pharmacological treatment for subclinical depression in older adults. Given the rising prevalence of subclinical depression in older populations and the associated risks of progression to MDD, early intervention is crucial. The integration of mindfulness practices with cognitive-motor exercise holds promise for providing a holistic approach to both mental and physical health in this vulnerable population.

Previous studies with high adherence rates suggest that our intervention is feasible. For instance, a study reported median attendance rates of 90% (80.0%–100.0%) for mindfulness classes and 83.3% (71.7%–91.7%) for exercise classes, which underscores the feasibility of combined interventions.³⁹ Unlike previously implemented group-based interventions, our program is designed for delivery via tablet computers, which offers participants greater flexibility and convenience. Our findings will provide a valuable reference point for our home-based approach, which may further enhance adherence, particularly among older adults who may face barriers such as mobility issues or geographical limitations. However, we also acknowledge that variability in digital literacy among older adults may present a barrier to engagement, particularly for participants less familiar with tablet-based technology. These factors should be considered when interpreting adherence rates and planning future implementation strategies.

Our study will employ a home-based cognitive-motor exercise program specifically designed to maximize accessibility for older adults. The exercises will be performed either while standing or sitting, which will accommodate individuals with varying levels of physical ability. This approach will address common barriers to exercise participation in older populations, such as mobility limitations, transportation difficulties, and comorbid physical conditions. By reducing physical demands and enabling participation from the comfort of home, our intervention aims to enhance the feasibility, inclusivity, and adherence of interventions among older adults.⁴⁰

We expect that the intervention will yield several beneficial outcomes. First, improvements in mood are anticipated because MBIs have been shown to enhance emotional regulation and reduce depressive symptoms.¹³ Additionally, the inclusion of cognitive-motor exercises will likely contribute to improvements in overall cognitive function. Indeed, previous research has shown that physical activity enhances neuroplasticity and promotes cognitive resilience, particularly in older adults.¹⁷ Therefore, we hypothesize that the combined intervention will have positive effects on both mood and cognitive function.

Furthermore, our intervention is expected to positively impact activities of daily living, which is a critical aspect of quality of life. By enhancing both psychological well-being and physical capabilities, participants may experience improved independence and functionality in routine tasks. Moreover, regular cognitive-motor activity, combined with mindfulness, could reduce anxiety and improve sleep quality,⁴¹ which would further contribute to participants’ ability to carry out daily activities with greater ease.

From a biological perspective, previous studies have demonstrated that depressive symptoms, even at a subthreshold level, are associated with volume reductions in the prefrontal cortex and hippocampus, particularly with advancing age.⁴² These regions are known to play critical roles in emotional regulation and memory function, and structural alterations in these regions may contribute to the psychological and cognitive symptoms exhibited by those with depression. To build on these findings, we plan to incorporate brain MRI scans to explore whether mindfulness and cognitive-motor exercises mitigate the neurobiological changes associated with subclinical depression. Specifically, we aim to assess potential improvements in structural and functional brain adaptations, such as enhanced functional connectivity within regions critical for emotional regulation (i.e. the prefrontal cortex, amygdala, and other subcortical structures), as well as increases in gray and white matter volume in regions implicated in memory and mood regulation (e.g. the hippocampus and anterior cingulate cortex). These analyses will help elucidate the mechanisms through which these interventions improve mood regulation and cognitive performance in older adults with subclinical depression.

Although this study is primarily exploratory, the results will provide valuable insights into the feasibility of combining mindfulness-based and exercise therapies for older adults with subclinical depression. If the anticipated benefits are confirmed, our intervention could offer a cost-effective and accessible approach to addressing mental health issues in aging populations, which could reduce the need for pharmacological treatments and prevent the escalation of subclinical depression to more severe depressive disorders.

However, it is important to note several potential limitations. The lack of a control group limits our ability to attribute changes solely to the intervention because other factors, such as social interaction or placebo effects, may influence outcomes. Future research should consider including a control group to strengthen the validity of the findings. If the results are positive, we plan to proceed with a randomized controlled trial to further validate the outcomes. Additionally, the generalizability of the results may be constrained by the sample size and demographic characteristics of the participants. Large-scale studies across diverse populations will be necessary to broaden the applicability of the intervention. Additionally, as our sample size estimation was based on studies of exercise effects in MDD, the actual effect size in a subclinical population may be smaller. This raises the possibility that the current sample size may be underpowered to detect more modest effects. Moreover, certain potentially influential variables, such as previous physical activity levels, were not formally assessed, which may further limit the interpretation of our findings. Finally, as this is a feasibility study that includes multiple exploratory cognitive outcome measures, we acknowledge an increased risk of Type I error due to multiple comparisons, and the findings should be interpreted with caution.

Despite these limitations, the current study may serve as a foundation for future trials examining integrated, home-based interventions for subclinical depression. Further research with larger, more diverse samples and randomized controlled designs will be essential to confirm efficacy and explore long-term outcomes.

Conclusion

This study proposes a novel, non-pharmacological intervention that integrates mindfulness-based practices with cognitive-motor training to address subclinical depression in older adults. The approach is designed to be accessible, inclusive, and home-based, with the potential to improve emotional regulation, cognitive performance, and daily functioning. Its flexible delivery format enables future integration into digital platforms, promoting self-guided mental health support and reducing barriers to access. By targeting individuals at an early stage of depressive symptoms, this intervention may help prevent progression to major depressive disorder and reduce reliance on pharmacological treatments. If proven effective, the model may offer a scalable and sustainable solution aligned with global digital health priorities, supporting mental health in aging populations while alleviating pressure on traditional healthcare systems.

Footnotes

Acknowledgments

We thank Sarina Iwabuchi, PhD, from Liwen Bianji (Edanz) () for editing the language of a draft of this manuscript.

ORCID iD

Haifeng Zhang

Author contributions

All authors contributed to the design and drafting of the report. HW, TL, and XY formulated the research question. HZ, CX, MZ, XZ, and TL wrote the first draft of the paper. TL was the Principal Investigator for this study and submitted the report for publication. The publication has been approved by all authors.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Key Research and Development Program of China (grant numbers 2022YFC3602600, 2022YFC3602603).

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors have completed the ICMJE uniform disclosure form at and declare no financial relationships with any organizations that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work.

Data availability statement

The data that support the findings of this study are available upon request. Please contact the corresponding author for access to the research data.

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