Synergistic effect of Tai Chi and transcranial direct current stimulation on memory function in patients with mild cognitive impairment: study protocol for a 2×2 factorial randomised controlled trial


The World Alzheimer’s Disease Report 2021, published by Alzheimer’s Disease International, shows that worldwide approximately 55 million people have dementia, which is further predicted to reach 78 million by 2030. Mild cognitive impairment (MCI) is a prodromal symptom of Alzheimer’s disease (AD), with memory impairment as the primary clinical manifestation and a dementia conversion rate of 5–15%.1 Research suggests that MCI can be considered as a critical time window for the early intervention and rehabilitation of dementia.2 Non-pharmacological interventions are essential for preventing or delaying cognitive decline.3 Recent systematic reviews have supported the efficacy of non-invasive brain stimulation4 and physical exercise5 6 on cognitive function in patients with MCI. Furthermore, many reviews have highlighted the possibility of combining physical exercise with non-invasive brain stimulation, suggesting that combining the two would synergistically promote neuroplasticity and improve cognitive function.7 8

The frequent practice of Tai Chi (TC), a traditional exercise therapy used in China, can alter the plasticity of the entire functional brain network and promote cognitive flexibility.9 The meta-analysis of 12 studies suggested that TC training for 30–60 min three times a week for 12 weeks significantly positively affected memory function in patients with MCI.10 On the other hand, transcranial direct current stimulation (tDCS) can selectively excite and inhibit cortical neural activity, alter local haemodynamics, modulate neurotransmitter release, strengthen synaptic connections and rapidly initiate neurofunctional activity.7 Several clinical studies have shown that anodal tDCS of the right dorsolateral prefrontal cortex (DLPFC) significantly improves executive function and memory performance, including spatial working and visual memory.11 12 A previous study has suggested that combining tDCS with aerobic exercise produces synergistic effects that improve cognitive function.13 Moreover, previous research has indicated that aerobic exercise induces changes in neuroplasticity throughout the brain, intensifying the local targeting of tDCS to the brain and exerting a more powerful cognitive improvement effect.7 14 Thus, the combination of TC and tDCS may provide a new therapeutic option for treating memory dysfunction in patients with MCI.

Therefore, we hypothesised that TC combined with tDCS may improve memory function in patients with MCI. Thus, we designed a 2×2 factorial randomised controlled trial to (1) evaluate the clinical efficacy of TC combined with tDCS to improve the memory function of patients with MCI and (2) to investigate whether the efficacy of the combination treatment is superior to that of the treatment methods individually and whether there are synergies between the combination treatments.

Methods and analysis

Trial design

A randomised controlled trial with a 2×2 factorial design will be used to evaluate the clinical effectiveness of TC combined with tDCS for improving memory function in patients with MCI. A total of 128 eligible participants will be randomly divided into the following four groups: (1) TC, (2) tDCS, (3) TC combined with tDCS and (4) health education. A flow diagram of this trial is presented in figure 1, and the enrollment, intervention and assessment schedules for this study are shown in table 1. This protocol is guided by the Standard Protocol Items15: Recommendations for Interventional Trials 2013 checklist (online supplemental additional file 1). The Ethics Committee of the Affiliated Rehabilitation Hospital of the Fujian University of Traditional Chinese Medicine (FJTCM) (2022KY-002–01) approved the trial. The trial is registered at Chinese Clinical (ChiCTR2200059316).

Supplemental material

Table 1

Schedule of enrolment, interventions and assessments

Figure 1
Figure 1

Study flow diagram. AVLT, Auditory Verbal Learning Test; ROCF, Rey-Osterrieth Complex Figure Test; TC, Tai Chi; tDCS, transcranial direct current stimulation; WMS-RC, the Chinese Wechsler Memory Scale-Revised.

Sample size

The sample size calculation for this study is based on the Chinese Wechsler Memory Scale-Revised (WMS-RC) memory quotient (MQ). Based on our previous pilot experiment and using sample size calculation software PASS 15, it was estimated that a total sample size of 27 patients would be required to detect an effect size of 0.275 at 80% power (1 − β error probability) with an alpha level of 0.05. Assuming an attrition rate of 15%, a total of 128 patients (n=32 per group) would be needed for this study.


Diagnostic criteria

MCI will be determined using Petersen’s criteria16: (1) the presence of cognitive impairment is confirmed by the patient, an informed person or by an experienced clinician; (2) the presence of impairment in one or more cognitive domains (memory, language, visuospatial or executive function); (3) the individual can perform essentially normal functional activities and (4) the patient has no dementia.

Inclusion criteria

Eligible patients must satisfy the following criteria: (1) meet the diagnostic criteria of MCI; (2) Montreal Cognitive Assessment score≤26; (3) Activity of Daily Living Scale score<22; (4) meet the level of global deterioration scale 2–3; (5) should be aged 50–75 years; (6) should not be engaged in regular exercise in the last 6 months (regular exercise was defined as exercise three times per week, with at least 20 min of exercise each time); (7) have no contraindications to tDCS and (8) provide informed consent (voluntary participation).

Exclusion criteria

Criteria for exclusion are as follows: (1) Geriatric Depression Scale (GDS-15) score≥9; (2) patients with uncontrollable blood pressure (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg after medication); (3) cannot cooperate to complete the exercise programme, due to motor dysfunction caused by nervous system diseases (stroke, Parkinson’s disease), musculoskeletal system diseases (lower limb arthritis, history of hip and knee replacement, etc.), serious organ diseases or other exercise contraindications; (4) cannot complete the index evaluation, due to having severe aphasia, audio-visual impairment, illiteracy, etc.; (5) participating in other research trials that may influence the results of this study and (6) taking any medications in the past 6 months which may impair or improve cognitive performance.

Recruitment and screening

Participants will be recruited from the community in Fuzhou City by posting posters, sending leaflets and brochures, and setting up a recruiting station at the community centre. Potential participants will first complete a screening questionnaire and assess their cognitive function to determine their eligibility for the study. Eligible participants will be provided with specific information about the trial. Patients who participate in this study will provide written informed consent and will be informed that they can withdraw anytime during the trial.

Randomisation and allocation concealment, and blinding

This study will use simple randomisation; the random grouping sequence of participants will be generated by specialised statistical staff using SPSS Statistics (version 24.0; IBM, Chicago, IL, USA), and the opaque, airtight envelope method will be applied to conceal the random grouping sequence. Eligible participants will be randomly assigned to the TC, tDCS, TC combined with tDCS or health education groups according to the sequential numbering of inclusion. The randomisation sequence will be administered by a dedicated person in the participant group who will not be involved in participant recruitment, outcome assessment or statistical analysis.

Only the outcome evaluators and statistical analysts will be blinded to the treatment group during the single-blind trial. Letters A, B, C and D will be used instead of groups; the SPSS 24.0 software will set the blinding protocol, and the blinded files will be password-protected and kept secure by a random sequence custodian. After the final statistical analysis of the data is completed, random sequence custodians will be unblinded.

Reasons of dropout and withdrawals

The reasons for dropouts and withdrawals could be as follows: (1) serious safety issues such as syncope, falls and hypoglycaemia requiring immediate discontinuation during the study and (2) participants who may withdraw from the trial by themselves.


All participants will receive health education on the aetiology and prevention of cognitive impairment, including MCI, prevention and treatment of AD, and a healthy lifestyle. After the participants’ baseline data collection is completed, the 3 month intervention will start uniformly.

TC combined with tDCS group

The 24-form TC will be adopted in this study. Two instructors with extensive experience of 5 years or more will lead the TC intervention sessions. The TC training process will include a 10 min warm-up, 40 min of TC training and a 10 min cool down, three times a week for 12 weeks.

The Brain Stimulator v3.0 Deluxe tDCS Kit will be used as the tDCS device. The anode will be placed on the participant’s right DLPFC, and the cathode will be placed on the left superior orbit (in accordance with the international 10–20 system). After initiation, the stimulation intensity will be adjusted to 2 mA until the participant experiences numbness and itching at the stimulation site, each time for 20 min, which will be performed three times a week for 12 weeks.17 tDCS will be performed during the first 20 min of TC training.

TC group

The TC group will undergo training similar to the TC combined with tDCS group three times a week for 12 weeks.

tDCS group

The tDCS group will undergo training similar to the TC combined with tDCS group three times a week for 12 weeks.

Health education group

The participants will receive health education, with one session every 4 weeks for 12 weeks.

Outcome assessment

This study will evaluate indicators, including basic information, primary and secondary outcomes. Basic information will include participants’ age, sex, occupation, education level and medical history. The study period is 12 weeks, and the outcomes will be assessed at baseline and after 12 weeks of intervention. The outcome measurements will include WMS-RC, Auditory Verbal Learning Test (AVLT) and Rey-Osterrieth Complex Figure Test (ROCF). All outcomes will be measured by several experienced evaluators who will be blinded to the randomised group.

Primary outcomes

The WMS-RC is widely used for memory function assessment and can reflect global memory function levels.18 WMS-RC includes 10 items on personal and current information, orientation, digital sequence relationships, picture recall, visual recognition, visual reproduction, associated learning, tactile performance test, logical memory and digit span, mainly testing the functions of immediate memory, working memory and long-term memory. The WMS-RC score is finally calculated as the MQ, with higher MQ scores indicating better memory.

Secondary outcomes

AVLT is used to assess immediate, short-term delayed and long-term delayed recall.19 The test includes 12 words, which are recalled immediately after the first reading of the 12 words, and the number of correct words recalled is recorded. The same operation will be repeated thrice, and the participants will be asked to recall the words after 5 and 20 min, respectively. The higher the number of correctly recalled words, the better the memory function.

The ROCF is the most commonly used test to assess visuospatial structure and visual memory ability. It consists of two sections, copying and recall, with each drawing lasting no more than 10 min and a delayed recall interval of 20–25 min. Each section of the test consists of 18 scoring parts, and each part is assigned a score of 0–2 points. Higher scores indicate better visuospatial structure and visual memory abilities.20

Patient safety

During the study, accidental injuries and sudden illnesses will be recorded as adverse events (AE), and will be classified as mild, moderate or severe. A serious AE (SAE) is an event that results in life-threatening death, requires hospitalisation or persistent significant disability. SAE and AE will be reported to the ethics committee. The researcher will record the degree of symptoms, time of occurrence, duration and treatment measures in the case report form (CRF) and evaluate their correlation with intervention training.

Data management and monitoring

During the evaluation period, the evaluators will complete the CRF as per the workbook. All CRFs will be dated and signed by the responsible investigator or one of the authorised staff members responsible for the quality and accuracy of the data collection process. The two research assistants will then enter the raw data into an Excel spreadsheet in double entry. During double data entry, a third person can be consulted to ensure data accuracy if there are inconsistent results.

In addition, an independent data and safety monitoring committee (DSMC) will be established to monitor trial safety. An independent DSMC comprises members who specialise in clinical physicians, statistics and ethics. The DSMC monitors the entire trial process, including participant recruitment, intervention safety, AE reporting, trial results, and data accuracy and completeness. The project manager will have access to the data, and all data will be treated with the utmost confidentiality and anonymity to anyone outside the study.

The Affiliated Rehabilitation Hospital of FJTCM and its ethics committee will make protocol decisions and communicate important protocol modifications. In addition, the project manager will coordinate the work of all departments (eg, trial registration, researcher training, informed consent from participants and data management). The project manager will notify the relevant parties at the coordination meeting if significant protocol modifications occur.

Statistical analysis

Outcome analysis of all allocated participants will be performed on an intention-to-treat basis or per-protocol analysis, and missing data will be imputed using multiple imputation methods. SPSS 24.0 software was used to conduct all statistical tests. Continuous variables will be described as mean and SD or median and IQR, and categorical variables will be described as frequencies and percentages (%), as appropriate. A significance level of 95% (two-sided alpha, p<0.05) will be used.

The normality of the data will be checked using the Kolmogorov-Smirnov test. The data will be analysed using analysis of variance (assuming a normal distribution) or the Kruskal-Wallis test (non-parametric). Intragroup comparisons (changes in the WMS-RC, AVLT and ROCF scores at baseline and after treatment) will be performed using paired t-tests. We will use a 2×2 factorial analysis of variance to evaluate the statistical significance of the differences observed between the groups. This test will examine the main and interaction effects of the two interventions (TC and tDCS).

Patient and public involvement

No patients or public were involved in this study.


Currently, most tDCS combination treatments for MCI patients focus on cognitive training.21 Only a small-sample study of tDCS combined with TC has been previously performed17; this study observed the combined effects of TC combined with tDCS technique on dual-task gait performance and cognitive function in patients with MCI and found that 12 weeks of TC combined with tDCS technique was superior to TC combined with sham tDCS technique in improving dual-task gait; however, the results of cognitive functions such as situational memory and working memory were not significant after correction. Therefore, in our study, we will use a 2×2 factorial design randomised controlled trial to explore whether TC combined with tDCS improves memory function in patients with MCI better than treatment alone (TC or tDCS), and whether there is a synergistic effect between the combined treatments.

In clinical practice, in addition to exploring the therapeutic effects of exercise combined with non-invasive brain stimulation technology, studies have investigated the feasibility and potential therapeutic effects of the combination from the perspective of mechanistic research. One study on walking rehabilitation combined with tDCS therapy in older adults suggested that the combination may improve executive functioning in older adults and potentially benefit in inducing adaptive neuroplasticity.22 Studies have shown that long-term TC practice modulates the functional connectivity of cognitive control networks,23 optimises local functional organisation24 and alters brain structure.25 Anodal tDCS of the DLPFC significantly improves memory performance in patients with MCI, possibly by enhancing synaptic plasticity within the prefrontal cortex to improve prefrontal cortical function, enabling memory compensation.12 26 27 tDCS is a targeted intervention that effectively stimulates memory-related DLPFC regions, reinforcing a wide range of TC-induced brain plasticity changes.

Thus, this trial will evaluate the effects of TC combined with tDCS on memory function in patients with MCI. These results should help improve the memory function of patients with MCI and may delay the transition from MCI to AD. Moreover, both non-pharmacological interventions are easy to implement, time- and cost-effective, safe, have no known severe side effects14 and can be easily implemented in a clinical setting.

The major limitation of this protocol is its non-double-blind design, which may increase the risk of detection bias. However, outcome assessors and statistical analysts will be blinded to the intervention to reduce bias and ensure trial quality. This study also lacks long-term follow-up observations and assessments, and the intervention measures’ long-term effects are unknown. However, the 12 week intervention period reflects its application in actual clinical practice and is sufficient to test whether the intervention is effective in the short term.

In conclusion, the results of this study are expected to elucidate the synergistic effect of TC treatment and tDCS on memory function in patients with MCI using an analytic design, and whether the efficacy of the combination treatment is better than that (TC or tDCS). Moreover, this study provides a theoretical basis for promoting the clinical application of this protocol.

Trial status

The trial is ongoing and recruiting participants. This study protocol is version 1 made on February 28, 2022. Recruitment commenced in May 2022 at the Affiliated Rehabilitation Hospital of FJTCM and is expected to be completed in December 2024.

This post was originally published on