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. 2024 Apr 10;14(4):e082764. doi: 10.1136/bmjopen-2023-082764

Effect of transcranial direct current stimulation combined with transcutaneous auricular vagus nerve stimulation on poststroke cognitive impairment: a study protocol for a randomised controlled trial

Wulong Liu 1,2, Xianglin Cheng 2, Yao Zhang 3, Weijing Liao 1,✉
PMCID: PMC11015246  PMID: 38604630

Abstract

Introduction

Poststroke cognitive impairment is a common complication in stroke survivors, seriously affecting their quality of life. Therefore, it is crucial to improve cognitive function of patients who had a stroke. Transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS) are non-invasive, safe treatments with great potential to improve cognitive function in poststroke patients. However, further improvements are needed in the effectiveness of a single non-invasive brain stimulation technique for cognitive rehabilitation. This study protocol aims to investigate the effect and neural mechanism of the combination of tDCS and taVNS on cognitive function in patients who had a stroke.

Methods and analysis

In this single-centre, prospective, parallel, randomised controlled trial, a total of 66 patients with poststroke cognitive impairment will be recruited and randomly assigned (1:1:1) to the tDCS group, the taVNS group and the combination of tDCS and taVNS group. Each group will receive 30 min of treatment daily, five times weekly for 3 weeks. Primary clinical outcome is the Montreal Cognitive Assessment. Secondary clinical outcomes include the Mini-Mental State Examination, Stroop Colour Word Test, Trail Marking Test, Symbol Digit Modalities Test and Modified Barthel Index. All clinical outcomes, functional MRI and diffusion tensor imaging will be measured at preintervention and postintervention.

Ethics and dissemination

The trial has been approved by the Ethics Committee of the First Affiliated Hospital of Yangtze University (approval no: KY202390). The results will be submitted for publication in peer-reviewed journals or at scientific conferences.

Trial registration number

ChiCTR2300076632.

Keywords: Magnetic Resonance Imaging, Rehabilitation medicine, Stroke medicine, Clinical Trial, Cognition, Neuroradiology

STRENGTHS AND LIMITATIONS OF THIS STUDY.

  • This is the first prospective, parallel, patient and outcome assessor blinded randomised controlled trial to assess the effect of transcranial direct current stimulation combined with transcutaneous auricular vagus nerve stimulation in poststroke cognitive impairment.

  • In order to investigate the neuroimaging mechanism, MRI scans will be performed before and after the intervention in this study.

  • As a single-centre study design, there may be limitations to the generalisability of the study.

  • The sample size may be a limitation to the power of the study.

  • The lack of a factorial design may be a limitation of this study.

Introduction

Stroke is the leading cause of death and the most common cause of disability in the world,1 affecting 15 million people each year.2 Poststroke cognitive impairment (PSCI) is one of the most common complications after stroke, affecting up to one-third of all survivors.3 4 The disability rate of cognitive impairment after stroke is high, with a serious impact on the physical and mental health of patients and a heavy burden on families and society.5 China has become the country with the highest lifetime risk of stroke and the heaviest disease burden.6 7 As the enormous burden of stroke continues to rise, PSCI has become a growing challenge for public health that needs to be addressed as a matter of urgency.8 9 Stroke survivors with cognitive impairment are more likely to have a transition to dementia. Nearly 90% of stroke are preventable, and about a quarter to a third of dementia cases can potentially be prevented by optimal treatment.10 11 Treatments that slow progression from cognitive impairment to dementia and improve quality of life in PSCI patients are urgently needed. Therefore, promoting the recovery of cognitive function has important clinical significance and social effects.

Significant efforts have been made to discover new drugs or therapeutic techniques. However, a breakthrough therapy for cognitive impairment and dementia is still a long way off. Current pharmaceutical therapies for PSCI include acetylcholinesterase inhibitors, memantine, sodium oligomannate drugs.12–14 Theoretically, medication can improve cognitive function and has short-term benefits.15 However, there is no convincing clinical evidence that it prevents further cognitive decline or restores cognitive function in stroke survivors, and long-term medication carries a risk of adverse effects.16 Therefore, there is increasing interest in non-drug therapies. Non-invasive brain stimulation (NIBS) is an effective treatment for PSCI that can gradually improve cognitive function.17 18

Transcranial direct current stimulation (tDCS) is an NIBS technology widely used in clinical practice to modulate cognitive function. It alters neuronal excitability by using a low-intensity direct current to depolarise or hyperpolarise the resting membrane potential of neurons.19 When brain excitability is changed, facilitating local neuronal activity and connectivity with other brain tissues can help improve the ability to relearn, thereby improving cognitive function. It may be related to long-term potentiation in the neural circuit, which is a top-down mechanism for brain plasticity, especially in terms of learning and memory.20 These characteristics make tDCS a promising intervention for the treatment of cognitive impairment after stroke. The left dorsolateral prefrontal cortex (DLPFC) by anodal tDCS, a common target for neuromodulation therapy and cognitive enhancement, has been shown in several studies to have a positive effect on cognitive function in patients who had a stroke.21–23 Compared with anodal tDCS targeting the right DLPFC or sham stimulation, anodal tDCS targeting the left DLPFC can improve accuracy and reduce reaction time, thereby improving cognitive effects and executive function.24 The left DLPFC may be an attractive target for anodal tDCS stimulation to improve cognitive function after stroke. Many studies have shown that tDCS has a positive effect on cognitive function in PSCI patients.21–23 25 26 The effects of tDCS may be mediated simultaneously by a number of different transcranial and possibly transcutaneous mechanisms that are difficult to distinguish. Thus, tDCS may produce effects through both transcranial (top-down) and transcutaneous (bottom-up) mechanisms. To some extent, tDCS can be considered a simultaneous dual-path mechanism.

As an important component of the peripheral nervous system, the vagus nerve activates the complex neuroendocrine network and plays an important role in regulating the brain’s recovery process after stroke.27 Vagus nerve stimulation (VNS) has recently been recognised as having the potential to improve cognitive impairment.28–30 Stimulation of the vagus nerve can activate the solitary tract nucleus of the brainstem, further activating the basal nucleus and locus coeruleus neurons.31 This causes norepinephrine to get released into the memory-forming areas such as the hippocampus and medial prefrontal cortex.32 The release of norepinephrine has been hypothesised to contribute to the effects of VNS on learning and memory, mood and recovery of function after brain damage.31 32 An animal research has shown that VNS can promote cognitive recovery from middle cerebral artery occlusion injury, which can be reversed by reducing norepinephrine, suggesting that norepinephrine may contribute to the influence of VNS on cognitive function.33 Because of the invasive nature and risk of complications of invasive VNS (iVNS), there is growing interest in the use of transcutaneous auricular VNS (taVNS). It is a novel, non-invasive treatment for stroke that works by directly stimulating the peripheral auricular branch of the vagus nerve. As taVNS is increasingly used in a variety of cognitive modulations, it has shown tremendous potential as an emerging NIBS method.34 A recent study has found that taVNS can improve cognitive function in vascular cognitive impairment, suggesting that it may increase the circulation of cerebrospinal fluid in the brain.35 Functional MRI (fMRI) has confirmed that taVNS therapy, which stimulates the external ear, is efficient and effective.36 37

Because of the complexity of neurophysiological changes in stroke, combined treatments may be more effective. Several studies have investigated the simultaneous effects of combined central and peripheral nerve stimulation on recovery after stroke.

For example, anodal tDCS combined with repetitive peripheral nerve stimulation can help patients who had a stroke recover hand motor function.38 Synchronous intermittent theta burst stimulation and iVNS have been shown to be safe and potentially effective in treating depression.39 Nowadays, simultaneous joint stimulation methods have already been used to promote brain activation and thus improve cognitive functions. Combined tDCS and taVNS produce a greater facilitation of working memory than either tDCS or taVNS alone, with a greater tendency to increase the consistency of improvement than the numerical sum of tDCS and taVNS, making this a clinically important finding.40 However, it is unclear whether tDCS and taVNS have the same effect in people with PSCI.

With the development of neuroimaging technology, the imaging biomarkers of disease associated with brain damage have increased the potential for clinical impact. The MRI studies, such as resting-state fMRI and diffusion tensor imaging (DTI), have shown an association between cognitive impairment and either morphometric or functional changes in brain connectivity. A brain imaging study found that the combination of tDCS and taVNS produced significantly greater activation in a number of cortical and subcortical brain regions, including the bilateral thalamus, parahippocampal gyrus, dorsal raphe nucleus, pallidum, substantia nigra and periaqueductal grey matter.41 However, it remains to be investigated whether combining tDCS and taVNS will produce the same effects and be effective in PSCI.

As tDCS and taVNS may modulate multiple cognitive functions in both healthy and diseased populations, we plan to conduct a prospective randomised controlled trial to investigate the immediate physiological effects of simultaneous tDCS and taVNS on PSCI using fMRI and DTI.

Method

Study design

This is a single-centre, patient-assessor blind, randomised controlled trial. A total of 66 patients will be randomised 1:1:1 to the tDCS group, the taVNS group and the combination group. The tDCS group will receive tDCS and sham taVNS intervention. The taVNS group will receive sham tDCS and taVNS intervention. The combination group will receive tDCS and taVNS intervention. The intervention will be given for 30 min a day, 5 days a week for 3 weeks. The outcomes of cognitive function will be assessed at baseline and 3 weeks at the end of the intervention, while the structure and function of brain regions associated with cognitive function will be measured using fMRI and DTI at baseline and 3 weeks. The procedure of this study is presented in figures 1 and 2.

Figure 1.

Figure 1

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Schedule of enrolment, interventions and assessments. DTI, diffusion tensor imaging; fMRI, functional MRI; MBI, Modified Barthel Index; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; SCWT, Stroop Colour Word Test; SDMT, Symbol Digit Modalities Test; taVNS, transcutaneous auricular vagus nerve stimulation; tDCS, Transcranial direct current stimulation; TMT, Trail Making Test.

Figure 2.

Figure 2

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Flow chart of the trial. taVNS, transcutaneous auricular vagus nerve stimulation; tDCS, Transcranial direct current stimulation.

Patient and public involvement

There was no involvement of patients or public in the design, conduct or dissemination of this study.

Participants

Patients who have a stroke with cognitive impairment will be recruited from the First Affiliated Hospital of Yangtze University from October 2023 to December 2024. All patients will sign an informed consent before the start of the baseline assessment.

Inclusion criteria

  1. Clinical diagnosis of stroke according to the diagnostic criteria of cerebrovascular disease in China (version 2019) and confirmed by CT or MRI.

  2. First stroke with unilateral lesion, ≤6 months from the accident.

  3. Montreal Cognitive Assessment (MoCA) score <26.

  4. Age range from 30 to 80 years old, gender not limited.

  5. Stable vital signs.

  6. Volunteer to sign the informed consent form.

Exclusion criteria

  1. Unstable vital signs.

  2. Craniectomy or intracranial metal implants.

  3. Presence of metallic implants such as pacemakers and cochlear implants.

  4. Severe heart and lung diseases, multiple organ failure, malignant tumours, history of epilepsy.

  5. Pre-stroke cognitive impairment, such as Alzheimer’s disease, Parkinson’s disease, dementia and mild cognitive impairment.

  6. Cognitive impairment caused by other reasons, such as alcohol and drug abuse.

  7. Poststroke delirium.

  8. Unable to cooperate.

Sample size calculation

The sample size was calculated on the basis of the MoCA score from a previous meta-analysis study, and the effect size of tDCS intervention on the cognitive function of PSCI patients is approximately 0.27–1.45.18 Then, we imported the result into the Gpower software. If the same effect size is guaranteed, assuming a type I error of 5% and 80% power, the sample size estimated by the software is 51. Considering a drop-out rate of 20% in the study, the total sample size required for this study is 66 cases, with 22 participants assigned to each group.

Randomisation and blinding

After baseline assessment, enrolled patients will be randomly assigned to the tDCS group, the taVNS group and the combination group. The randomisation method is as follows: a random number sequence is generated using SPSS v.20.0 software, and eligible cases are numbered in the order of enrolment. They will randomly be assigned to three groups in a 1:1:1 ratio. The generated digital serial number will be placed in a sealed envelope. The distribution and registration of random serial numbers will be managed by a dedicated person.

In this study, patients, outcome assessors, data managers and statistical analysts are blinded, using the numbers A, B and C instead of the groups. SPSS software will be used to set the blind base and it is kept under the custody of the research administrator. After all statistical analyses have been completed, the blinded base will be revealed.

Intervention

All patients will receive routine medical or rehabilitative treatment. Routine medical and rehabilitation are carried out in accordance with the Chinese Stroke Association Guidelines for cerebrovascular disease42 and the Chinese Stroke Association Guidelines for stroke rehabilitation.43

Intervention procedure

Two standard wet sponge electrodes (5×7 cm) are connected to the tDCS channel through the tDCS device (Sichuan Intelligent Electronic Industry, Sichuan, China). The electrodes are placed in accordance with the International 10–20 System for the placement of EEG electrodes. The electrodes are covered with saline soaked sponges for impedance reduction. The intervention procedures for tDCS and sham tDCS are as follows: (1) tDCS: The anode electrode is placed over F3 to stimulate the left DLPFC. The cathode is placed over the right supraorbital area. Patients will receive stimulation (2 mA) for 30 min daily for 3 weeks, 5 sessions per week. (2) sham tDCS: The anode electrode is placed over F3 to stimulate left DLPFC and the cathode over right supraorbital area. Patients will receive stimulation (2 mA) for 10 s and then the stimulation is turned off for 29 min and 50 s. It will last for 3 weeks, with five sessions per week.

The taVNS treatment is delivered using a device manufactured by Wuxi Jiajian Medical Equipment Factory. The skin around the left ear will be wiped with alcohol to remove any excess oil and to ensure the best possible conductivity. Stimulation parameters will be adjusted for (1) wave density: 25 Hz; (2) wave width: 300 μs; (3) Intensity: adjusted to the strongest sensation that can be tolerated without pain; (4) duration: 30 min/session, daily, 5 days/week, for 3 weeks. The taVNS stimulation location is the left cymba concha and the sham taVNS stimulation location is the left earlobe. Other than stimulation location, the stimulation parameters of taVNS and sham taVNS will be consistent.

Outcome assessment

The variables in this study include basic information, primary outcomes and secondary outcomes. The basic information will be measured before the intervention. The primary and secondary outcomes will be measured before and after the intervention. All primary and secondary outcomes will be assessed by an experienced staff member of the First Affiliated Hospital of Yangtze University, who will be blinded to the results of the participant group.

Basic information

Basic information includes name, gender, age, years of education, medical history, smoking history, drinking history, enrolment date and intervention end date.

Primary outcome

MoCA, a cognitive screening tool to detect cognitive impairment, will be used as the primary outcome in this study to evaluate global cognitive function in poststroke patients. It covers eight aspects, including visuospatial, executive function, naming, memory, attention, language, abstract thinking and orientation. The total score of the MoCA ranges from 0 to 30, with a higher score indicating better function. The Chinese version of the MoCA has been revised and is now widely used in China with a good level of validity and reliability.44

Secondary outcomes

Mini-Mental State Examination

The Mini-Mental State Examination is a widely used cognitive screening tool,45 which is scored on six aspects: orientation, immediate memory, attention and arithmetic, verbal ability (naming, retelling, understanding instructions), structural imitation and visual spatial ability. Each correct answer is worth 1 point and each incorrect answer is worth 0 point, with a total score of 30 points.

Stroop Colour Word Test

The Stroop Colour Word Test (SCWT) consists of three parts: a neutral test, a consistency test and a reverse test. It is widely used to measure the ability to suppress cognitive interference.46 It has good sensitivity and specificity in diagnosing PSCI using the SCWT, which is helpful in identifying PSCI at an early and rapid stage. Only instruction and pretest practice is required for the SCWT assessment process. The procedure is simple and easy to implement, only a single cognitive domain is tested, and the time required is short. The limitation of the SCWT is that it is not suitable for the assessment of patients who are colour blind, colour deficient or illiterate.

Trail Making Test

Executive function is measured using a Trail Making Test (TMT), which is usually divided into two parts: TMT-A and TMT-B. The TMT-B/TMT-A ratio is a valid measure of executive function.

Symbol Digit Modalities Test

In the test, nine different symbols are used to represent nine numbers. The participant has 90 s to write down the symbol corresponding to each number in the table as quickly as possible and to fill in the correct number of digits as the final result.47

Activities of daily living

The Modified Barthel Index (MBI), a widely used standard scale, is used to measure activities of daily living. The MBI consists of 10 items scored out of 100, with higher scores indicating better daily self-care.48

MRI assessments

The fMRI and DTI data will be collected at baseline and postintervention.The MRI scan will be performed at the Radiology Department of the First Affiliated Hospital of Yangtze University. A Philips Achieva 3.0T MRI system with a 16-channel head and neck coil will be used to acquire the MRI data. The scan parameters are listed below: The fMRI is acquired using an EPI sequence with the following parameters: repetition time (TR)=2000 ms, echo time (TE)=30 ms, fractional anisotropy (FA)=90°, number of slices=40, slice thickness=3 mm, field of view (FOV)=240×240 mm, imaging matrix=64×64, gap=0.75 mm. The BOLD scanning will last for 8 min 6 s. A three-dimensional T1-weighted image is acquired using a sequence with the following parameters: TR=shortest, TE=4 ms, FA=7°, number of slices=188, slice thickness=1 mm, FOV=256×256 mm, imaging matrix=256×256, gap=0 mm. The scanning time will last for 5 min 28 s. The DTI scan is acquired using a sequence with the following parameters: TR=shortest, TE=85 ms, FA=90°, number of slices=75, slice thickness=2 mm, FOV=256×256 mm, imaging matrix=128×128, gap=0 mm. The scanning time will last for 6 min 52 s.

Safety measurements

Any adverse events that participants experience during the intervention, including dizziness, pain, redness and itching of the skin, will be reported by the research assistant. We will evaluate the causal relationship of the adverse event to the treatment and the severity of the adverse event. The ethics committee will be notified of serious adverse events.

Statistical analysis

Statistical analysis will be performed by an independent person, and the p value for statistical significance is <0.05 for both sides. Statistical analysis of all clinical data will be performed using the SPSS v.20.0 software. All the data will be represented by means±SD. One-way analysis of variance analysis and Kruskal-Wallis rank sum test will be used for the evaluation of the clinical efficacy of the treatments in the three groups.

Neuroimaging data processing and analysis

fMRI data analysis

The fMRI data will be preprocessed and analysed by using the SPM V.12 software (https://www.fil.ion.ucl.ac.uk/spm/software) and the CONN toolbox (https://www.nitrc.org/projects/conn) in a Matlab R2020a (Mathworks, Natick, Massachusetts, USA) environment. After preprocessing is finished in this study, functional connectivity will be calculated. In accordance with the anatomical automatic labelling template, the hippocampus will be chosen to be the seed point. By analysing the Pearson correlation coefficients between the region of interest and the time series of various voxels in the whole brain, the brain function related images of each subject will be obtained, and then Fisher Z transformed will be performed. The correlation between changes in cognitive function and changes in functional connectivity will be analysed using partial correlation analysis.

DTI data analysis

The DTI data will be preprocessed and analysed by using the FSL tools (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/) and SPM V.12 software (https://www.fil.ion.ucl.ac.uk/spm/software). In this study, the FA will be calculated and analysed by means of tract-based spatial statistics.

Data collection and management

Trained outcome assessors will use paper-based case report forms to collect data. The information contained in the case report forms will be input in an electronic data system to record the data. The data stored in the system is kept in a separate, secure location. All documents are kept securely after the study is completed. All investigators will receive regular training, and all data will be monitored and reviewed by the investigators on a regular basis throughout the trial.

Ethics and dissemination

This protocol conforms to the Declaration of Helsinki. The ethical approval of this study protocol and the informed consent forms were obtained from the Ethics Committee of the First Affiliated Hospital of Yangtze University (approval no: KY202390). The study protocol has been registered on the Chinese registry website with the identifier number (ChiCTR2300076632).

Supplementary Material

Reviewer comments
bmjopen-2023-082764.reviewer_comments.pdf (154.7KB, pdf)
Author's manuscript
bmjopen-2023-082764.draft_revisions.pdf (854.6KB, pdf)

Footnotes

Contributors: WLiu conceived the study, initiated the study protocol and drafted the manuscript. WLiao assisted WLiu in the study design and reviewed the manuscript. XC performed the sample size calculation and defined the statistical strategy. YZ and XC collected the relevant materials and sorted them out. All authors participated in the review and writing of the manuscript.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: None declared.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review: Not commissioned; externally peer reviewed.

Ethics statements

Patient consent for publication

Not applicable.

References

  • 1. GBD 2016 Neurology Collaborators . Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol 2019;18:459–80. 10.1016/S1474-4422(18)30499-X [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional burden of stroke during 1990-2010: findings from the global burden of disease study 2010. Lancet 2014;383:245–54. 10.1016/s0140-6736(13)61953-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Portegies MLP, Wolters FJ, Hofman A, et al. Prestroke vascular pathology and the risk of recurrent stroke and poststroke dementia. Stroke 2016;47:2119–22. 10.1161/STROKEAHA.116.014094 [DOI] [PubMed] [Google Scholar]
  • 4. Mijajlović MD, Pavlović A, Brainin M, et al. Post-stroke dementia - a comprehensive review. BMC Med 2017;15:11. 10.1186/s12916-017-0779-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Rohde D, Gaynor E, Large M, et al. The impact of cognitive impairment on Poststroke outcomes: a 5-year follow-up. J Geriatr Psychiatry Neurol 2019;32:275–81. 10.1177/0891988719853044 [DOI] [PubMed] [Google Scholar]
  • 6. GBD 2016 Causes of Death Collaborators . Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the global burden of disease study 2016. Lancet 2017;390:1151–210. 10.1016/S0140-6736(17)32152-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Wang Y-J, Li Z-X, Gu H-Q, et al. China stroke statistics 2019: a report from the national center for healthcare quality management in neurological diseases, China national clinical research center for neurological diseases, the Chinese stroke association, national center for chronic and non-communicable disease control and prevention, Chinese center for disease control and prevention and institute for global neuroscience and stroke collaborations. Stroke Vasc Neurol 2020;5:211–39. 10.1136/svn-2020-000457 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Feigin VL, Brainin M, Norrving B, et al. World stroke organization (WSO): global stroke fact sheet 2022. Int J Stroke 2022;17:18–29. 10.1177/17474930211065917 [DOI] [PubMed] [Google Scholar]
  • 9. Rochmah TN, Rahmawati IT, Dahlui M, et al. Economic burden of stroke disease: a systematic review. Int J Environ Res Public Health 2021;18:14. 10.3390/ijerph18147552 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. de Bruijn RFAG, Bos MJ, Portegies MLP, et al. The potential for prevention of dementia across two decades: the prospective, population-based Rotterdam study. BMC Med 2015;13:132. 10.1186/s12916-015-0377-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet 2017;390:2673–734. 10.1016/S0140-6736(17)31363-6 [DOI] [PubMed] [Google Scholar]
  • 12. Wang K, Dong Q, Yu JT, et al. Expert consensus on the management of post-stroke cognitive impairment 2021. Chinese Journal of Stroke 2021;16:376–89. [Google Scholar]
  • 13. Quinn TJ, Richard E, Teuschl Y, et al. European stroke organisation and European academy of neurology joint guidelines on post-stroke cognitive impairment. Eur J Neurol 2021;28:3883–920. 10.1111/ene.15068 [DOI] [PubMed] [Google Scholar]
  • 14. Huang Y-Y, Chen S-D, Leng X-Y, et al. Post-stroke cognitive impairment: epidemiology, risk factors, and management. J Alzheimers Dis 2022;86:983–99. 10.3233/JAD-215644 [DOI] [PubMed] [Google Scholar]
  • 15. Tomassoni D, Lanari A, Silvestrelli G, et al. Nimodipine and its use in cerebrovascular disease: evidence from recent preclinical and controlled clinical studies. Clin Exp Hypertens 2008;30:744–66. 10.1080/10641960802580232 [DOI] [PubMed] [Google Scholar]
  • 16. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol 2007;6:782–92. 10.1016/S1474-4422(07)70195-3 [DOI] [PubMed] [Google Scholar]
  • 17. Draaisma LR, Wessel MJ, Hummel FC. Non-invasive brain stimulation to enhance cognitive rehabilitation after stroke. Neurosci Lett 2020;719:133678. 10.1016/j.neulet.2018.06.047 [DOI] [PubMed] [Google Scholar]
  • 18. Wang Y, Xu N, Wang R, et al. Systematic review and network meta-analysis of effects of noninvasive brain stimulation on post-stroke cognitive impairment. Front Neurosci 2022;16:1082383. 10.3389/fnins.2022.1082383 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Fregni F, El-Hagrassy MM, Pacheco-Barrios K, et al. Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders. Int J Neuropsychopharmacol 2021;24:256–313. 10.1093/ijnp/pyaa051 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Stagg CJ, Antal A, Nitsche MA. Physiology of transcranial direct current stimulation. J ECT 2018;34:144–52. 10.1097/YCT.0000000000000510 [DOI] [PubMed] [Google Scholar]
  • 21. Ko M-H, Yoon J-Y, Jo Y-J, et al. Home-based transcranial direct current stimulation to enhance cognition in stroke: randomized controlled trial. Stroke 2022;53:2992–3001. 10.1161/STROKEAHA.121.037629 [DOI] [PubMed] [Google Scholar]
  • 22. Jo JM, Kim Y-H, Ko M-H, et al. Enhancing the working memory of stroke patients using tDCS. Am J Phys Med Rehabil 2009;88:404–9. 10.1097/PHM.0b013e3181a0e4cb [DOI] [PubMed] [Google Scholar]
  • 23. Liu Y-W, Chen Z-H, Luo J, et al. Explore combined use of transcranial direct current stimulation and cognitive training on executive function after stroke. J Rehabil Med 2021;53:2766. 10.2340/16501977-2807 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Dubreuil-Vall L, Chau P, Ruffini G, et al. tDCS to the left DLPFC modulates cognitive and physiological correlates of executive function in a state-dependent manner. Brain Stimul 2019;12:1456–63. 10.1016/j.brs.2019.06.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Shaker HA, Sawan SAE, Fahmy EM, et al. Effect of transcranial direct current stimulation on cognitive function in stroke patients. Egypt J Neurol Psychiatr Neurosurg 2018;54:32. 10.1186/s41983-018-0037-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Lyu Z, Liu F, Xiu H, et al. Transcranial direct current stimulation for global cognitive functioning and ability in daily life activities in poststroke cognitive impairment: a systematic review and meta-analysis. Am J Phys Med Rehabil 2023;102:965–74. 10.1097/PHM.0000000000002263 [DOI] [PubMed] [Google Scholar]
  • 27. Mravec B. The role of the vagus nerve in stroke. Auton Neurosci 2010;158:8–12. 10.1016/j.autneu.2010.08.009 [DOI] [PubMed] [Google Scholar]
  • 28. Cheng K, Wang Z, Bai J, et al. Research advances in the application of vagus nerve electrical stimulation in ischemic stroke. Front Neurosci 2022;16:1043446. 10.3389/fnins.2022.1043446 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Aniwattanapong D, List JJ, Ramakrishnan N, et al. Effect of vagus nerve stimulation on attention and working memory in neuropsychiatric disorders: a systematic review. Neuromodulation 2022;25:343–55. 10.1016/j.neurom.2021.11.009 [DOI] [PubMed] [Google Scholar]
  • 30. Li Z-D, Qiu H-J, Wang X-Q, et al. Transcutaneous auricular vagus nerve stimulation in poststroke cognitive impairment: protocol for a randomised controlled trial. BMJ Open 2022;12:e063803. 10.1136/bmjopen-2022-063803 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Hassert DL, Miyashita T, Williams CL. The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala. Behav Neurosci 2004;118:79–88. 10.1037/0735-7044.118.1.79 [DOI] [PubMed] [Google Scholar]
  • 32. Roosevelt RW, Smith DC, Clough RW, et al. Increased extracellular concentrations of norepinephrine in cortex and hippocampus following Vagus nerve stimulation in the rat. Brain Res 2006;1119:124–32. 10.1016/j.brainres.2006.08.048 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Liu A, Zhao F, Wang J, et al. Effects of vagus nerve stimulation on cognitive functioning in rats with cerebral ischemia reperfusion. J Transl Med 2016;14:101. 10.1186/s12967-016-0858-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Wang L, Wang Y, Wang Y, et al. Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. Expert Rev Med Devices 2022;19:43–61. 10.1080/17434440.2022.2020095 [DOI] [PubMed] [Google Scholar]
  • 35. Choi S, Jang DC, Chung G, et al. Transcutaneous auricular vagus nerve stimulation enhances cerebrospinal fluid circulation and restores cognitive function in the rodent model of vascular cognitive impairment. Cells 2022;11:19. 10.3390/cells11193019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Yakunina N, Kim SS, Nam EC. Optimization of transcutaneous vagus nerve stimulation using functional MRI. Neuromodulation 2017;20:290–300. 10.1111/ner.12541 [DOI] [PubMed] [Google Scholar]
  • 37. Kraus T, Kiess O, Hösl K, et al. CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - a pilot study. Brain Stimul 2013;6:798–804. 10.1016/j.brs.2013.01.011 [DOI] [PubMed] [Google Scholar]
  • 38. Sattler V, Acket B, Raposo N, et al. Anodal tDCS combined with radial nerve stimulation promotes hand motor recovery in the acute phase after ischemic stroke. Neurorehabil Neural Repair 2015;29:743–54. 10.1177/1545968314565465 [DOI] [PubMed] [Google Scholar]
  • 39. George MS, Caulfield KA, O’Leary K, et al. Synchronized cervical VNS with accelerated theta burst TMS for treatment resistant depression. Brain Stimul 2020;13:1449–50. 10.1016/j.brs.2020.08.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Zhao R, He Z-Y, Cheng C, et al. Assessing the effect of simultaneous combining of transcranial direct current stimulation and transcutaneous auricular vagus nerve stimulation on the improvement of working memory performance in healthy individuals. Front Neurosci 2022;16:947236. 10.3389/fnins.2022.947236 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Sun J-B, Tian Q-Q, Yang X-J, et al. Synergistic effects of simultaneous transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS) on the brain responses. Brain Stimul 2021;14:417–9. 10.1016/j.brs.2021.02.010 [DOI] [PubMed] [Google Scholar]
  • 42. Lou M, Ding J, Hu B, et al. Chinese stroke association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update on organizational stroke management. Stroke Vasc Neurol 2020;5:260–9. 10.1136/svn-2020-000355 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Zhang T, Zhao J, Li X, et al. Chinese stroke association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of stroke rehabilitation. Stroke Vasc Neurol 2020;5:250–9. 10.1136/svn-2019-000321 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Feng Y, Zhang J, Zhou Y, et al. Concurrent validity of the short version of montreal cognitive assessment (MoCA) for patients with stroke. Sci Rep 2021;11. 10.1038/s41598-021-86615-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Yuan X-F, Zhang Y, Zhang Y, et al. Reliability and validity of the brief assessment of impaired cognition (Chinese version) for stroke patients. Appl Neuropsychol Adult 2023;30:27–33. 10.1080/23279095.2021.1908287 [DOI] [PubMed] [Google Scholar]
  • 46. Scarpina F, Tagini S. The stroop color and word test. Front Psychol 2017;8:557. 10.3389/fpsyg.2017.00557 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Hsiao P-C, Yu W-H, Lee S-C, et al. Responsiveness and predictive validity of the tablet-based symbol digit modalities test in patients with stroke. Eur J Phys Rehabil Med 2019;55:29–34. 10.23736/S1973-9087.18.05210-3 [DOI] [PubMed] [Google Scholar]
  • 48. Ohura T, Hase K, Nakajima Y, et al. Validity and reliability of a performance evaluation tool based on the modified barthel index for stroke patients. BMC Med Res Methodol 2017;17:131. 10.1186/s12874-017-0409-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

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