High-dose intermittent theta burst stimulation targeting the individualised frontoparietal cognitive network for post-stroke cognitive impairment: protocol for a randomised sham-controlled trial in China

Abstract

Introduction

Cognitive impairment is a common consequence after stroke. Intermittent theta burst stimulation (iTBS) has emerged as a promising cognitive therapy. However, traditional iTBS typically employs lower doses and one-size-fits-all stimulation targets, which may not fully capitalise on the potential of this therapy and warrants further evaluation for both efficacy and safety. This study aims to evaluate the efficacy and safety of high-dose iTBS targeting the individualised frontoparietal cognitive network (FCN) identified by precision functional neuroimaging for post-stroke cognitive impairment (PSCI).

Methods and analysis

This is a prospective, double-blind, sham-controlled, parallel-group randomised controlled trial. 60 eligible participants with PSCI will be randomly assigned (1:1) to an active iTBS or a sham-controlled group. The active group will receive high-dose iTBS (3600 pulses/day) at 80% resting motor threshold targeting the left individualised FCN, guided by a real-time neuronavigation system. The sham group will follow identical procedures using a sham coil. Both groups will also undergo conventional computerised cognitive training. The intervention will be administered on workdays over a period of 3 weeks, totalling 15 workdays. The primary outcome is the change in Montreal Cognitive Assessment scores from baseline to immediately post-treatment. Secondary outcomes include long-term change in global cognition, activities of daily living and specific cognitive domains (assessed by a comprehensive neuropsychological battery covering memory, attention, executive function and language), as well as mood. Assessments occur at baseline, post-treatment and 3-month follow-up. Safety outcomes, specifically the number of adverse events related to iTBS, will be monitored and recorded throughout the trial.

Ethics and dissemination

This study has been approved by the Medical Ethics Committee of the China Rehabilitation Research Center. The results of this study will be published in peer-reviewed scientific journals and disseminated at academic conferences.

Trial registration number

NCT05953415.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This study employs a high-dose intermittent theta burst stimulation protocol (3600 pulses/day), exceeding conventional stimulation doses.

• Stimulation targets are individualised using resting-state functional MRI-based functional parcellation of the frontoparietal cognitive network.

• The design is a double-blind, randomised controlled trial with an assessment of blinding integrity.

• A 3-month follow-up period is included to evaluate long-term effects.

• As a single-centre study, the results may be influenced by site-specific practices and patient demographics, which may limit the external validity.

Introduction and rationale

Post-stroke cognitive impairment (PSCI) has become a common and severe complication worldwide, significantly reducing patients’ quality of life and hindering their functional recovery.^{1 2} PSCI refers to a range of cognitive deficits that meet the diagnostic criteria for cognitive impairment and persist for three to 6 months following a stroke.³ It is primarily characterised by memory decline, inattention and executive dysfunction. Among various therapies for improving PSCI, computerised cognitive training (CCT) remains one of the most commonly used cognitive rehabilitation approaches. However, its therapeutic effects remain unsatisfactory,⁴ highlighting the urgent need for more effective treatment methods. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive neuromodulation technique, can modulate cortical neural activity to promote neuroplasticity. Recently, the intermittent theta burst stimulation (iTBS), a rapid form of rTMS, has gained increasing attention. iTBS mimics endogenous theta rhythms to induce long-term potentiation in a shorter time,^{5 6} potentially offering a more efficient approach to improving cognitive impairment.

Recent studies employing conventional iTBS doses (typically 600–1600 pulses/day) for PSCI have shown only modest efficacy.7,10 Evidence suggests that such lower-dose stimulation may fail to sufficiently engage critical brain networks, thereby limiting its therapeutic potential.¹¹ To address this limitation, high-dose, accelerated protocols are being explored.12,14 In this study, we adopt a high-dose regimen of 3600 pulses/day. This dose was selected based on our pilot data indicating superior effects of 3600 pulses over 1200 pulses¹⁵ and aligns with other evidence of a dose-response relationship for cortical excitability changes.¹⁶ As a pragmatic escalation, this dose is substantially higher than conventional regimens yet remains conservative compared with extreme paradigms (eg, the 18000-pulse Stanford Neuromodulation Therapy protocol,¹⁷ whose safety in stroke populations is unestablished).

Furthermore, the delivery schedule is critical. Substantial evidence indicates that distributing the total daily dose across spaced, multiple sessions is more effective for inducing neuroplasticity than a single, continuous session.18,21 We therefore deliver the 3600 pulses in two separate sessions with at least 50 min interval. This design is grounded in the spaced-stimulation principle: clinical studies suggest that intervals of approximately 50 min can enhance synaptic potentiation,^{17 22 23} and animal models show that intervals of 60 min or longer are effective for inducing additive long-term potentiation, thereby promoting cumulative and potentially non-linear improvements in clinical outcomes.^{18 24}

The selection of stimulation targets is another key factor affecting iTBS efficacy. Most studies on PSCI patients have targeted the left dorsolateral prefrontal cortex (DLPFC).⁷ However, the left DLPFC shows great variability in the topography of functional networks among individuals.^{25 26} Traditional anatomical localisation methods are not ideally suited to account for these differences. In contrast, functional localisation enables more precise targeting based on each individual’s unique functional topography, potentially enhancing therapeutic efficacy. Our study will employ a personalised brain functional sector (pBFS) approach,²⁶ based on precision resting-state functional MRI (rs-fMRI), to facilitate functional network mapping and enable individualised targeting of the frontoparietal cognitive network (FCN) in the DLPFC. Additionally, we will integrate this personalised targeting with a real-time neuronavigation system to guide the stimulation coil precisely, aiming to guarantee precision pulse delivery to the target.

Prior to this study, we completed a three-arm trial (high-dose, standard low-dose and sham groups), which demonstrated the dose-dependent effects and safety of high-dose iTBS targeting individualised FCN for short-term PSCI rehabilitation despite several limitations.¹⁵ To strengthen the validity and robustness of key findings, this randomised controlled trial (RCT) will implement five key methodological improvements: (1) implementing blinding assessment of participants, iTBS operators and assessor to minimise potential biases and ensure objective outcome evaluation; (2) extending the follow-up period to 3 months to assess the long-term sustainability of cognitive improvements and the safety of high-dose iTBS, which is crucial for clinical decision-making; (3) adopting stricter inclusion/exclusion criteria to reduce participant heterogeneity and selection biases, thereby improving internal validity; (4) expanding the sample size to increase statistical power; (5) incorporating a broader range of neuropsychological assessments to provide a more comprehensive evaluation of iTBS effects across cognitive domains.

In summary, this study aims to evaluate the efficacy and safety of high-dose iTBS targeting the individualised FCN for PSCI, using a more rigorous RCT design.

Methods

Study design

This study is a prospective, double-blind, sham-controlled, parallel-group RCT conducted at the China Rehabilitation Research Center (CRRC), Beijing, China. Participants will be randomly assigned to the active or sham iTBS group at a 1:1 ratio. The study comprises five phases: (1) enrolment, including baseline assessment, (2) randomisation, (3) intervention period using iTBS, paired with CCT (4) post-treatment and follow-up assessments and (5) data analysis. The intervention will be administered on workdays over 3 weeks, totalling 15 treatment days (week 3) and the follow-up will be conducted 3 months after the completion of the 3-week intervention (week 15). This trial is reported in accordance with the Standard Protocol Items: Recommendations for Intervention Trials Statement.²⁷ The study has been approved by the Medical Ethics Committee of the CRRC (approval number: 2023-060-01) and has been registered on ClinicalTrials.gov (NCT05953415) before recruitment. The study was initiated on 18 August 2023, with the enrolment of the first participant. Collection of data for the primary outcome is planned to conclude in November 2025, and the study will conclude in February 2026. The study flowchart is shown in figure 1, and the detailed study timeline is presented in table 1.

Figure 1. The study flowchart. CCT, computerised cognitive training; iTBS, intermittent theta burst stimulation.

Table 1. The detailed study timeline.

	Enrolment and randomisation	Post-randomisation			Follow-up
Procedure	Days −5~0	Week 1	Week 2	Week 3	Week 15
Enrolment
Eligibility screening	×
Informed consent	×
Data collection	×
MRI scanning	×
Randomisation
Randomisation	×
Intervention
Active group
Sham group
Assessment
MoCA	×			×	×
MMSE	×			×	×
MBI	×			×	×
RBMT-III	×			×
DST	×			×
SDMT	×			×
TMT	×			×
SCWT	×			×
CDT	×			×
BNT	×			×
HAMD-17	×			×
HAMA	×			×
Blinding assessment				×
AEs/SAEs		×	×	×	×

Week 3 and week 15 refer to the post-treatment and 3-month follow-up assessments, respectively.

AEs, adverse events; BNT, Boston Naming Test; CDT, Clock Drawing Test; DST, Digit Span Test; HAMA, Hamilton Anxiety Scale; HAMD-17, 17-item Hamilton Depression Scale; MBI, Modified Barthel Index; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; RBMT-III, Rivermead Behavioral Memory Test-Third Edition; SAEs, serious adverse events; SCWT, Stroop Color and Word Test; SDMT, Symbol Digit Modalities Test; TMT, Trail Making Test.

Participants

Participants will be recruited and screened based on the following inclusion and exclusion criteria.

Inclusion criteria

1. Age between 35 years and 75 years.

2. Meet the diagnosis of ischaemic or haemorrhagic stroke.28,31

3. Meet the PSCI diagnostic criteria of ‘2021 Experts Consensus on Post-stroke Cognitive Impairment Management’.³

4. First stroke.

5. Have a stroke duration of 3–12 month.

6. Have the stroke located in the unilateral supratentorial region.

7. Meet at least one of the following conditions: (1) dysfunction in at least one of the five domains: executive function, attention, memory, language ability and visuospatial ability; (2) mild to moderate cognitive impairment: Mini-Mental State Examination (MMSE) ≥10 and the Montreal Cognitive Assessment (MoCA) <26 or MMSE <27.

8. Understand the trial and be willing to sign the informed consent form.

Exclusion criteria

1. Have been diagnosed with cognitive impairment resulting from other disorders including mild cognitive impairment, Alzheimer’s disease, vascular dementia, acquired traumatic brain injury.

2. Have a history of drug or alcohol abuse.

3. Have a history of other psychiatric disorders or currently experiencing severe depression or anxiety (17-item Hamilton Depression Scale (HAMD-17) >24 points), anxiety (Hamilton Anxiety Scale (HAMA) ≥29 points).

4. Be with severe primary diseases in the circulatory, respiratory, digestive, urinary, endocrine or haematopoietic systems that cannot be controlled by conventional medications.

5. Be with malignant hypertension or malignant tumours.

6. Be with severe infections, water and electrolyte imbalances or acid-base disturbances.

7. Be with severe aphasia (National Institutes of Health Stroke Scale (NIHSS)_language ≥2 points), dysarthria (NIHSS_dysarthria ≥2 points), disorder of consciousness (NIHSS_level of consciousness ≥1 score), audiovisual impairments or those unable to cooperate with the assessment or treatment.

8. Be with a history of seizures.

9. Have any contraindications to TMS treatment, including the presence of implanted electronic devices (eg, cardiac pacemaker, cochlear implant).

10. Have any contraindications to MRI scanning, such as the presence of ferromagnetic metallic implants or claustrophobia.

11. Have received neuromodulation therapy such as TMS, transcranial electrical stimulation or transcranial focused ultrasound within the past 3 months prior to enrolment.

12. Be concurrently participating in other clinical trials.

13. Be pregnant women or those planning to become pregnant.

14. Be with other abnormalities as determined by the investigator that do not meet the trial criteria.

Sample size calculation

Based on the results of our preliminary study,¹⁵ we estimate that after the 3-week treatment, the average change in MoCA scores between the high-dose active and sham groups will differ by 4.4 points. The SD of the changes in MoCA scores is 5.61 for the active group and 4.81 for the sham group. Assuming a two-tailed alpha of 0.05 and a power of 80%, the required sample size for each group, calculated using the two-sample T-tests allowing unequal variances in PASS V.21.0 software (NCSS, Kaysville, Utah, USA), is 24 participants. To account for an estimated 20% dropout rate, the target sample size for each group is 30, resulting in a total sample size of 60 participants.

Randomisation

This study will employ variable block randomisation to ensure balanced allocation of participants to treatment groups while maintaining unpredictability in the assignment process. An independent researcher, not involved in the study, will use a computer programme to generate the randomisation code. The code will then be provided to an independent organisation to generate sealed, opaque envelopes to maintain concealment for participant assignment. These envelopes will be securely stored in a centrally locked filing cabinet by this independent researcher and will be opened only when randomising participants.

Blinding

This study uses a double-blind design, ensuring that participants and their caregivers, clinical staff, rehabilitation therapists, recruiter, iTBS operators, assessor, data collectors, data managers and data analysts are blinded to group assignment.

To maintain blinding throughout the trial, a blinding procedure has been included in the informed consent. Similarly, all blinded researchers in this trial have been instructed not to discuss any information related to the group assignment. In this trial, we will use the MT20A System (Neural Galaxy, Hunan, China) equipped with a double-sided CBF-02 figure-of-eight coil, which provides active iTBS on one side while sham iTBS on the other. Importantly, the appearances and the stimulation sounds are identical on both sides of the coil.

A blinded imaging data analyst will determine each participant’s personalised stimulation target. An independent, non-blinded researcher will then assign participants to groups written in the randomisation envelope. To ensure iTBS operators remain blinded, this non-blinded researcher will specify the correct stimulation side based on the assigned group for each participant prior to treatment. The resting motor threshold (RMT) required for TMS intervention will also be measured by this non-blinded researcher using the coil on the correct side. Importantly, we will perform the blinding assessment for participants, iTBS operators and assessor at week 3. Participants whose blinding is compromised will be excluded from further participation. The study will remain blinded until the completion of data analysis, except in the event of serious adverse events (SAEs), where emergency unblinding will be performed if necessary.

MRI data acquisition

All participants will undergo MRI scanning to acquire both structural and functional images before and at the end of the 3-week treatment. Scans will be conducted using a Philips Ingenia 3T MRI equipped with a 32-channel head coil at the CRRC, Beijing, China. During MRI scanning, participants will be instructed to close their eyes and remain at rest. If significant head movement is detected during the scan that affects data quality, a rescan will be performed. The scanning parameters are as follows. The structural MRI will use a magnetisation-prepared rapid gradient echo sequence. For three-dimensional (3D) T1-weighted: repetition time (TR)=7 ms, echo time (TE)=3.17 ms, field of view (FOV)=256, flip angle (FA)=7°, 256×256×192 matrix, 192 slices, voxel size=1×1×1 mm³. For 3D T2-weighted: TR=2500 ms, TE=250 ms; FOV=256, FA=90°, 256×256×192 matrix, 192 slices, voxel size=1×1×1 mm³. The rs-fMRI will use a gradient echo planar imaging sequence (TR=3000 ms, TE=30 ms, FOV=240×240 mm², FA=90°, 80×80×45 matrix, voxel size=3.0×3.0×3.5 mm³). Each participant will undergo four 6 min runs of rs-fMRI scans, yielding 24 min in total.

MRI data preprocessing and functional parcellation

The data preprocessing and individual functional parcellation will be conducted using pBFS Cloud V.1.0.7 (Neural Galaxy, Beijing, China). The detailed procedures are described in our previous studies.2632,34

Personalised stimulation target localisation

Following parcellation, each participant’s individualised FCN will be delineated (figure 2), with a confidence value assigned to each vertex to indicate the certainty of its assignment to a specific functional network. Higher confidence values will be prioritised to refine the search area for optimised targeting. Moreover, considering TMS accessibility, only gyral regions will be targeted, thus vertices with a FreeSurfer sulcal depth >0 will be excluded. From this refined area, the centre of the largest contiguous cluster will be selected as the personalised target site, in accordance with similar procedures described in our previous reports.^{13 15 35}

Figure 2. Illustration of the personalised stimulation targeting within the FCN. The brain images shown are the left hemisphere from a representative participant. (A) The individualised 213 brain functional parcellation. (B) Individualised FCN identified from the parcellation. (C) Personalised target site selection within the FCN, based on both TMS accessibility and confidence values (yellow indicates higher confidence, red indicates lower confidence). FCN, frontoparietal cognitive network.

Interventions

RMT will be determined as the minimum stimulation intensity that evokes muscle contractions of the contralesional first dorsal interosseous muscle in more than five of 10 consecutive trials. The stimulation intensity will be set at 80% RMT. Participants in the active group will receive 3-week active iTBS on the left individualised FCN, with two sessions of 600 s stimulations per day (triplet 50 Hz bursts, repeated at 5 Hz; 2 s on and 8 s off; 1800 pulses), and an intersession interval of at least 50 min (a total of 3600 pulses per day). The sham group will be stimulated with the same parameters as the active group, but using the sham iTBS stimulation side of the coil. Both groups will undergo stimulation guided by a real-time neuronavigation system for online monitoring and precise localisation of the target.

During this trial, each participant will also receive a 30 min daily session of CCT between the two iTBS sessions. The CCT, delivered via a commercial platform based on the International Group of Cognitive Researchers and Clinicians (INCOG) guidelines,³⁶ will consistently target core cognitive domains (memory, attention, executive function, orientation). While specific exercises are adaptively selected based on individual cognitive profiles to maintain ecological validity and engagement, the dosage, timing, core domains and performance-driven difficulty progression are held constant for all participants. This design ensures CCT is a uniform active background therapy, isolating iTBS as the experimental variable.

Outcome measurements

To capture the multifaceted nature of cognitive recovery of PSCI, we plan to implement a comprehensive battery of tests spanning global cognition, specific cognitive domains, activities of daily living and mood. To mitigate practice and fatigue effects, this extended battery is administered over 2 days by a single, blinded assessor, with the test sequence randomised for each participant. A detailed description of each test is provided in table 2. All outcome assessments will be conducted at baseline, week 3 and week 15.

Table 2. Summary of tests and descriptions by domains.

Functional domains	Tests	Description
Global cognition	MoCA, MMSE	The MoCA is a brief multidomain screen with superior sensitivity to mild impairment, including post stroke, compared with MMSE.37 38 The MMSE remains the most widely used benchmark for global cognition, facilitating comparability with prior studies.39 Therefore, we will include both to provide a more comprehensive evaluation.
ADL function	MBI	The MBI is a widely used measure of functional independence; its modified scoring improves sensitivity and reliability over the original Barthel Index without increasing administration burden.40
Memory	RBMT-III, DST	The RBMT-III is a comprehensive assessment tool designed specifically to evaluate everyday memory abilities in individuals with brain injury41 and the DST indexes working memory capacity, which is crucial for daily life.42
Attention	SDMT, TMT-A	The SDMT captures sustained attention and is sensitive to change with minimal burden43; and the TMT-A measures attention function and motor speed.44 45 They are commonly used tools for assessing attention functions.
Executive function	TMT-B, SCWT CDT	The TMT-B is commonly used to assess executive function, particularly combined with the SCWT,46 together providing a brief assessment on executive functions.44 45 The CDT is a validated screen of visuospatial and constructional abilities, is sensitive to mild impairment and is widely used clinically as a cognitive screening instrument.47 48
Language	BNT	The BNT is a widely used neuropsychological measure assessing visual confrontation naming and is sensitive to lexical retrieval impairments and aphasia. The 30-item abbreviated form, used in our study, suits the time constraints of clinical and research settings while preserving diagnostic utility.49
Mood	HAMD-17, HAMA	The HAMD-1750 and HAMA,51 both interviewer-administered scales, are widely validated, sensitive to short-term change and minimise literacy demands in poststroke cohorts.

ADL, activities of daily living; BNT, Boston Naming Test; CDT, Clock Drawing Test; DST, Digit Span Test; HAMA, Hamilton Anxiety Scale; HAMD-17, 17-item Hamilton Depression Scale; MBI, Modified Barthel Index; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; RBMT-III, Rivermead Behavioral Memory Test-Third Edition; SCWT, Stroop Color and Word Test; SDMT, Symbol Digit Modalities Test; TMT-A, Trail Making Test part A; TMT-B, Trail Making Test part B.

Primary outcome

The primary outcome in this study is the change in MoCA scores from baseline to week 3. The MoCA is a widely used, rapid and validated tool for detecting cognitive impairment, and it was chosen as the primary outcome due to its well-documented superior sensitivity to mild impairment, including post-stroke. It assesses seven cognitive domains, including visuospatial and executive functions, naming, memory, attention, language, abstraction and delayed recall.^{37 38} Scores range from 0 to 30, with higher scores indicating better cognitive function.

Secondary outcomes

Secondary outcomes are changes in MoCA scores from baseline to week 15, as well as changes in MMSE and Modified Barthel Index (MBI) scores from baseline to week 3 and week 15. The MMSE is another widely used neuropsychological test for assessing global cognitive decline,³⁹ and the MBI assesses an individual’s ability to perform activities of daily living.⁴⁰ Furthermore, we will also measure changes in Rivermead Behavioral Memory Test-Third Edition,⁴¹ Digit Span Test,⁴² Symbol Digit Modalities Test,⁴³ Trail Making Test,^{44 45} Stroop Color and Word Test,⁴⁶ Clock Drawing Test,^{47 48} Boston Naming Test,⁴⁹ HAMD-17⁵⁰ and HAMA⁵¹ scores from baseline to week 3, which will be used to assess participants’ memory, attention, executive function, language and mood, respectively.

Safety

The safety outcome will include the number of adverse events (AEs) and SAEs observed throughout this trial. This study will strictly adhere to the safety guidelines for TMS as outlined in current recommendations.⁵² In the event of AEs or SAEs such as dizziness, headache, nausea, facial muscle spasms, fatigue, drowsiness, epilepsy, tinnitus or other unforeseen complications, researchers and clinicians will make prompt clinical judgments and take necessary medical actions to ensure patient safety. All AEs and SAEs will be documented in detail on the Case Report Forms (CRFs). In the case of SAEs, they will be reported to the ethics committee immediately. Professional clinicians will assess the relationship between AE/SAE and TMS treatment. Furthermore, the management of AEs and SAEs will strictly comply with Good Clinical Practice (GCP) guidelines, ensuring the ethical standards and regulatory compliance of the clinical study.

Data collection and management

Study data, including demographic information, clinical data, laboratory test results, MRI images, assessment outcomes, treatment details and AEs/SAEs, will be collected by uniformly trained and qualified researchers. The collected information will be documented in CRFs and other study-related records using unique participant identification codes. Throughout the study, a clinical research assistant will oversee data verification and perform quality control measures to maintain the integrity and reliability of the data. All study-related documents will be securely preserved and managed by professional data managers, with access strictly limited to authorised individuals to ensure data integrity and confidentiality.

Statistical analysis

Statistical analysis will be performed using SAS V.9.4 (SAS Institute, North Carolina, USA). The primary analysis will use a modified intent-to-treat approach, excluding participants who: (1) do not receive any treatment or (2) are deemed ineligible. Additionally, a per-protocol analysis will be conducted as a sensitivity analysis to assess treatment efficacy, further excluding participants classified as non-compliance, specifically those with treatment interruptions lasting more than three consecutive days or those who are unable to complete the treatment within 20 workdays. A significance level of p<0.05 (two-tailed) will be used, and the CIs will be set at 95%.

Participants’ baseline demographic and clinical characteristics will be summarised using descriptive statistics. For intergroup comparisons, continuous variables will be assessed using independent t tests or Wilcoxon rank-sum tests, while categorical variables will be analysed using χ² tests or Fisher’s exact tests as appropriate. The treatment efficacy will be analysed using a linear mixed model, which includes both fixed and random effects. The fixed effects will include group (active group, sham group), time (baseline, week 3 and week 15) and their interaction term (group × time), while the random effect will be the participant. The model will be adjusted for covariates such as age, gender, education level and time since stroke. AEs and SAEs will be presented as frequencies (percentages) since they are categorical variables. The occurrence of AEs and SAEs between groups will be compared using a χ² test or Fisher’s exact test to determine statistical significance.

Study organisation

This single-centre RCT will be led by the principal investigator, supported by subinvestigators, research coordinators and data managers, who are responsible for ensuring protocol adherence, quality data collection and participant safety. The Medical Ethics Committee of the CRRC will supervise the study process and ensure compliance with ethical standards. All team members are trained in GCP to uphold data integrity, accuracy and ethical conduct.

Patient and public involvement

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

Trial status

The first participant was recruited on 18 August 2023.

Ethics and dissemination

This study adheres to the Declaration of Helsinki and GCP guidelines. This study has been approved by the Medical Ethics Committee of the CRRC (2023-060-01) and has been registered on ClinicalTrials.gov (NCT05953415). Informed consent forms will be signed and collected from all participants (online supplemental material (informed consent form)). All procedures will adhere to established guidelines for maintaining the confidentiality of medical data, including applicable legal and regulatory requirements. The findings of this study will be published in peer-reviewed scientific journals and disseminated at academic conferences.

Discussion

This study is a prospective, double-blind, sham-controlled, parallel-group RCT, designed to evaluate the efficacy and safety of high-dose iTBS targeting the individualised FCN, employing a rigorous methodology to provide a novel therapeutic approach for PSCI.

Compared with our previous trial,¹⁵ this study incorporates two key improvements. First, the efficacy of iTBS may be influenced by the expectations of both participants and researchers, particularly due to the placebo effect and observer bias.⁵³ While our previous trial employed a double-blind design, this study will additionally assess the effectiveness of the blinding process by incorporating blinding assessment for both participants and researchers (iTBS operators and assessor). This enhancement aims to minimise potential biases and improve the objectivity and reliability of the results.

Second, while iTBS has demonstrated promising short-term efficacy and safety in PSCI,^{9 10} its long-term effects, including the sustainability of benefits and potential rebound or deterioration, remain underexplored. Previous trials only assessed outcomes immediately after treatment, whereas this study will extend the follow-up to 3 months to assess the sustainability of cognitive improvements and the long-term safety of iTBS. The extended follow-up will reduce time-related biases, enable a more accurate assessment of time-dependent effects on outcomes, further supporting clinical treatment decisions.⁵⁴

Compared with our preliminary trial, the current protocol incorporates several key methodological refinements. First, to enhance internal validity, this study employs stricter inclusion criteria than our prior pilot work,¹⁵ enrolling only patients with chronic-phase (>3 months), unilateral supratentorial stroke and excluding those with severe mood disorders. This focuses the study on a more homogeneous population, reducing variance from these known confounders. Other baseline variables, including sex and age, will be balanced through randomisation. These measures improve the ability to attribute treatment effects to the iTBS protocol. Second, small sample sizes may lead to greater data variability, reducing the reliability of the results, and are vulnerable to attrition in long-term follow-up.⁵⁵ To improve statistical power and mitigate attrition effects, this study will increase the sample size to 30 participants per group. Finally, cognitive function involves multiple domains—memory, attention, executive function, language, calculation and visuospatial abilities—often interacting with each other. To comprehensively assess iTBS effects, multidimensional neuropsychological tests will be used, enabling a more complete evaluation and reducing the potential for failing to detect any specific cognitive domains of cognitive impairments in PSCI patients.

Data availability statement

Deidentified participant data that support the findings of this study are available upon reasonable request.