Cerebellar iTBS Combined With Emotional Stroop Task for Post-Stroke Depression: Randomized Controlled Trial Protocol From Kunming, China

Cerebellar iTBS Combined With Emotional Stroop Task for Post-Stroke Depression: Randomized Controlled Trial Protocol From Kunming, China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cerebellar iTBS Combined With Emotional Stroop Task for Post-Stroke Depression: Randomized Controlled Trial Protocol From Kunming, China Zihan Chen, Xue Yang, Yao Zhou, Qian Liu, Hongmei Zhang, Haotian Wu, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5170397/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Patients with stroke often experience both balance issues and poststroke depression (PSD), which can potentially influence each other. Despite incomplete knowledge of the specific mechanisms, the cerebellum plays a role in emotions and balance, which could be linked via the cerebellar-thalamus-cortical (CTC) pathway. Therefore, the cerebellum may serve as a common target for regulating emotional and balance functions post-stroke. Therefore, the aim of this study is to evaluate the efficacy of utilizing a combination of Stroop visual task and iTBS stimulation of the cerebellar vermis in enhancing emotions and balance function in stroke patients. Method 160 patients diagnosed with middle cerebral artery (MCA) infarction and post-stroke depression (PSD) will be randomly assigned to one of four groups: Group A (active iTBS of the cerebellar vermis with active Stroop training), Group B (sham iTBS with active Stroop training), Group C (active iTBS and sham Stroop training), and Group D (sham iTBS with sham Stroop training). The total intervention period will be two weeks. The primary outcome measures were evaluated using the Hamilton Depression Rating Scale (HAMD) and Berg Balance Scale at four different time points: baseline (T0), after five treatment sessions (T1), after ten treatment sessions (T2), and 4 weeks post-treatment (T3) during the follow-up period. The secondary outcomes will include EEG spectral analysis and MRI connectivity. Adverse effects will also be monitored to assess the safety of the intervention. Discussion By combining cerebellar iTBS with the emotional Stroop task, stroke patients may experience a simultaneous improvement in emotions and balance, with the enhancement being mediated through the same pathway as cerebellar TMS, specifically CTC. Trial registration: NCT direct link: https://www.chictr.org.cn/ ChiCTR2200058553. Registered in April 2022. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences (Protocol version 1.0–20240709). iTBS cerebellum emotion-word Stroop poststroke depression Figures Figure 1 Figure 2 Figure 3 Introduction Background and rationale {6a} According to Global Burden of Disease studies, stroke ranks as the second leading cause of disability worldwide [1]. After a stroke, patients often struggle with both balance and emotional issues. 83% of stroke patients will experience balance dysfunction[2]. According to Mitchell et al., the incidence of post-stroke depression is also as high as 33.5%[3]. The large percentage of two stroke complications indicates that both disorders are very likely to be present together in stroke patients. Additionally, Khan et al.'s study directly observed a significant correlation between balance impairment and depression after a stroke[4]. A compromised trunk balance can result in falls, which may worsen feelings of despair or anxiety, thus creating a harmful cycle that impacts patients' daily activities[5]. Following a 6-week acupuncture treatment on Shenmen (HT7), Neiguan (PC6), Sanyinjiao (SP6), and Taichong (LR3) acupoints, symptoms of depression in patients showed improvement, which may be associated with increased functional connectivity between the striatum and frontal lobe, as well as the striatum and cerebellum[6]. Despite being typically associated with balance, the cerebellum is shown in the research above to also play a role in emotional regulation. Further research has shown that both emotion and balance functions are related to the cerebellum-thalamus-cortex pathway (CTC)[7, 8]. The projection from the cerebellum to the thalamus covers almost all subnuclei, including nuclei involved in cognition and sensory integration. This extensive connectivity allows the cerebellum to influence multiple cortical areas through the thalamus, coordinating the motor and sensory integration required for balance[9]. In terms of emotional regulation, the pathway connecting the thalamus, basal ganglia, and cerebellum to the widespread regions of the cerebral cortex provides a structural basis for their comprehensive influence on the limbic system function. The way in which the cerebellum guides learning by modulating cortical oscillations through the CTC circuitry influences an individual's processing of emotional stimuli[10]. The evidence above clearly indicates that both the regulation of balance movement and emotional regulation are closely related to the CTC circuit. However, there is currently no research evidence on the co-circuit effects of these two functions. Focusing on the cortical level of the CTC loop is also a point worth exploring. In terms of motor balance, CTC's cortical level refers to the motor sensory cortex. The cerebellum can integrate proprioceptive information from various parts of the body through its connection with the parietal lobe, allowing for better perception of body position and movement status, thus maintaining balance[11]. The cerebellum is also functionally connected to the pre-motor cortex of the frontal lobe, which is crucial for the planning and execution of movements, helping to maintain balance in the body during motion[12]. However, recent research suggests that the cerebellum mainly regulates emotions through its connections with the cortical limbic system. Connections exist between the X area of the cerebellum and the orbitofrontal, anterior cingulate cortex (ACC), and amygdala cortex, contributing to the regulation of emotions. The ACC is closely related to processes like emotion regulation, conflict monitoring, and decision-making. The connection between the cerebellum and this area may help regulate emotional responses, especially when processing conflicting information and making decisions[10]. The functional connection between the left dorsolateral prefrontal cortex (DLPFC) and the ACC plays a crucial role in depression. Research indicates that prior to treatment, there is typically impaired functional connectivity between the DLPFC and ACC in patients with depression, particularly in treatment responders[13, 14]. The reason why the DLPFC can serve as a target for Transcranial Magnetic Stimulation (TMS) in modulating depression may be due to its ability to regulate ACC activity. Some studies suggest that the vermis plays a crucial role in regulating emotions in the cerebellum, and it has similarities with the DLPFC[15]. In general, the cerebellum may play a role in motor balance and emotional disorders in stroke survivors, offering potential for a combined intervention target for these two impairments. TMS has gained widespread recognition for its efficacy in treating depression among all non-invasive brain stimulation methods. The focus of TMS protocol for treating depression primarily includes repetitive transcranial magnetic stimulation (rTMS), microelectric stimulation, and intermittent theta burst stimulation (iTBS)[16]. Currently, both rTMS and iTBS stimulation are considered effective in treating depression[17, 18]. Therapeutically, comparative studies targeting the DLPFC in patients with treatment-resistant depression have shown that the effectiveness of iTBS is comparable to that of 10 Hz rTMS [19]. However, iTBS offers a shorter treatment time compared to rTMS, making it more cost-effective. Additionally, applying iTBS to the cerebellum has been shown to improve gait and balance[20]. Combining TMS stimulation with certain visual cognitive tasks can further enhance the efficacy of TMS. Research indicates that abnormal theta band activity (4–8 Hz) is strongly linked to the pathological mechanism of depression. Baseline and treatment first-week midline theta power show promising potential for predicting response to TMS therapy for depression[21]. Research has indicated that during the Stroop task, an increase in gamma and theta power is observed in the DLPFC and dorsal ACC[22]. However, there is limited research on whether performing Stroop visual tasks before TMS therapy might enhance the effectiveness of TMS for depression. Study objectives{7} In conclusion, the cerebellum plays a crucial role in regulating emotions, movement, and balance. The implementation of the above functions is related to the CTC circuit. However, research on the co-circuit problem of the cerebellum in regulating emotional and balance functions is still insufficient. Therefore, we hypothesize that the cerebellum has a common pathway effect on balance and emotion regulation through the CTC circuit, and cerebellar iTBS stimulation can promote the recovery of both functions simultaneously. We will evaluate the effectiveness of this therapy on improving post-stroke depression and balance disorders, as well as the relationship between these two functions in stroke patients using the Hamilton Depression Rating Scale (HAMD) and Berg Balance Scale (BBS) as primary outcome measures. Secondary outcome measures will include Magnetic Resonance Imaging (MRI) and Electroencephalography (EEG). MRI will be used to evaluate changes in connectivity within and between components of the CTC circuit, while high temporal resolution EEG will be used to monitor real-time effects of this intervention. Finally, establish the correlation between changes in MRI and EEG indicators and functional improvement through relevant analysis. Trial design {8} This study will be a prospective, single-blinded, parallel armed, randomized controlled trial (RCT) with factorial design. Participants will be allocated to one of the four groups: (A) the active iTBS of the cerebellar vermis with active Stroop training group, (B) the sham iTBS with active Stroop training group, (C) the active iTBS and sham Stroop training group, or (D) the sham iTBS with sham Stroop training group. Figure 1 shows the flow chart of the trial process. The checklist of Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) is provided in Appendix I[23]. Methods: participants, interventions, and outcomes Study setting {9} The experiment will be conducted at the Department of Rehabilitation Medicine, Second Affiliated Hospital of Kunming Medical University, Yunnan Province, China. The study is scheduled to take place between July 2024 and July 2027. Eligibility criteria {10} The inclusion criteria: (1) chronic phase of stroke; (2) age > = 18 years, 4 and = 15 [24]; and (7) All the participants were right-handed. The exclusion criteria: (1) history of epilepsy or psychiatric disorders (including depression, anxiety, or schizophrenia); (2) severe comorbidities; (3) history of medication use, such as benzodiazepines, baclofen, or antidepressants; (4) noncompliant individuals; (5) acute cerebral hemorrhage or acute infectious diseases; (6) patients with strong suicidal tendencies; (7) patients with severe headache, hypertension, malignancy, open wound vascular embolism, or leukopenia; (8) alcoholism; (9) patients with a history of cranial surgery and metal implants in the brain; (10) pacemaker implantation; (11) NIHSS score > 26, MMSE score < 15; (12) any disease that may prevent the patient from surviving more than one month; and (13) pregnancy. Who will take informed consent? {26a} Professional rehabilitation therapists will explain the trial to potential participants, and if they show willingness to participate, the therapist will obtain the participant's signature on the informed consent form. Additional consent provisions for collection and use of participant data and biological specimens {26b} N/A. Additional consent provisions are not needed for collection and use of participant data and biological specimens in trial. Interventions Explanation for the choice of comparators {6b} There is currently no study comparing the effects of iTBS stimulation in the cerebellar vermis, emotion Stroop task, and combined training on post-stroke balance and emotional function improvement. Through this factorial design, we can compare the effects of cerebellar iTBS stimulation and emotional Stroop task on improving emotional and balance functions (main effects), as well as the combined effects of both interventions on improving emotional and balance functions in stroke patients (interaction effects). Intervention description {11a} The differences lie in the task training and iTBS stimulation. Figure 2 and Table 1 outline the intervention details for each group. (1)Active iTBS and active Stroop task group (group A) The participants in this group will first complete the active Stroop task training, followed immediately by iTBS stimulation. The visual task training will last 15 minutes, followed by iTBS stimulation, which is expected to take 3–4 minutes. There will be 5 sessions per week, with a total of 10 interventions over a two-week period. (2)Sham iTBS and active Stroop task group (group B) This group will first complete the active Stroop task, followed by sham iTBS stimulation. The duration and number of trials for the active Stroop task will be identical to those of Group A. Sham iTBS stimulation will be administered according to the input code, producing only sound without a magnetic field, and will last the same duration as in Group A. This group will also receive one session per day, totaling 10 interventions. (3)Active iTBS and sham Stroop task groups (group C) This group will first undergo the sham Stroop task, followed by active iTBS stimulation. The sham Stroop task will have the same number of trials and duration as the active Stroop task, but participants will only view the stimuli on the screen without making any responses. The active iTBS stimulation will be identical to that used in Group A. (4)Sham iTBS and sham Stroop task groups (group D) This group will first complete the sham Stroop task, followed by sham iTBS stimulation. The sham Stroop task and sham iTBS stimulation will be consistent with the sham conditions used in Groups B and C. The duration and schedule of the intervention will match those of the previous three groups. Active and sham iTBS stimulation: Before starting TMS, all participants underwent T1-weighted structural MRI. The cerebellar vermis will be identified via anatomical landmarks within the Talairach coordinate system. rTMS will be administered in the form of iTBS, delivered via a TMS device (model NS5000, manufactured in Wuhan, China) equipped with a figure-8 coil (model B9076, coil diameter 92 mm)[25]. Using 100% of the active motor threshold (aMT), which is defined as the minimum stimulation intensity required to elicit MEPs with amplitudes of 200–300 µV in at least 50% of 10 consecutive trials, the target muscle maintains 20% of its maximum voluntary contraction[26]. The electromyographic signal is received by the TMS device through its recording electrodes. Each iTBS burst consists of 3 pulses at a frequency of 50 Hz. Bursts will be delivered at a frequency of 5 Hz, with each train comprising 10 bursts. Each stimulation session will includes 20 trains, with an 8-second interval between trains [27]. Sham iTBS will generate a sound similar to that of iTBS without delivering any magnetic stimulation. iTBS stimulation will be administered after the Stroop task training, with each TMS session lasting a total of 180 seconds. Each treatment will be administered once daily for a total of 10 days. To ensure patient safety, the intensity of iTBS stimulation will be limited to no more than 120% of the patient's motor threshold and adheres to all safety guidelines and recommendations endorsed by the International Federation of Clinical Neurophysiology[28]. Active Emotion-Word Stroop Task: The Emotional-Word Stroop Task will employ two types of stimuli: facial expressions and Chinese characters (Hanzi). It will incorporat four specific stimulus configurations: (1) "Happy Congruent": a happy facial expression + the Hanzi for "happiness" (高兴); (2) "Happy Incongruent": a happy facial expression + the Hanzi for "sadness" (悲伤); (3) "Sad Congruent": a sad facial expression + "sadness" (悲伤); and (4) "Sad Incongruent": a sad facial expression + "happiness" (高兴), as illustrated in Fig. 3. The stimuli will be derived from black-and-white portraits (50% female) sourced from an external database ( https://kdef.se/download-2/7Yri1UsotH.html ). Each selected image featured a face directed toward the viewer, devoid of any distinctive markings such as tattoos, glasses, scars, or beards. These images will be formatted into 200 × 300 pixel ellipses, which were set against a 237 × 160 pixel horizontal rectangular background. The brightness and contrast settings for the stimuli will be standardized at 42 cd/m² and 18 cd/m², respectively, ensuring uniformity in visual presentation across all facial and Hanzi stimuli. The participants will be positioned in a tranquil environment and seat approximately 100 cm from a monitor. They will be instructed to identify emotional facial expressions rapidly and accurately by pressing a button linked to the perceived emotion: sadness (left index finger) or happiness (right index finger). Consistent with previous research protocols[29, 30], the experimental sequence will be initiated with a 500 ms display of a fixation cross ("+"), followed by an interstimulus interval (ISI) with a blank screen lasting 600 ms. Subsequently, an emotion-word composite image will be presented centrally on the screen for 1,000 ms, followed by an intertrial interval (ITI) featuring a blank screen, again lasting 800 ms. Participant response times (RTs) will be carefully monitored. If a participant's RT is shorter than the set maximum of 1,000 ms, the stimulus presentation time will be adjusted to match the actual response latency. If the RT is greater than 1,000 ms, the stimulus will be visible for the full 1,000 ms and an extra 500 ms will be given for the participant to respond. Figure 3 provides details on the emotion‒word Stroop task. Sham Emotion-Word Stroop Task: The Sham Emotion-Word Stroop Task will also be conducted in a quiet ERP examination room, using the same images as those selected for the active Emotion-Word Stroop Task. The difference between the two tasks is that participants in the Sham Emotion-Word Stroop Task will only need to view the images displayed alternately on the screen. In each trial, the duration of each image and the ISI will be set the same as in the active emotion‒word Stroop task. Criteria for discontinuing or modifying allocated interventions {11b} If participants experience irreversible iTBS-related adverse events such as headaches, dizziness, fatigue, etc. during the trial, the trial will be stopped for the participant, even though the trial is very safe in itself. Strategies to improve adherence to interventions {11c} We will take the following measures to achieve the best training adherence: 1. Throughout the two-week intervention period, participants will need to be involved in the intervention on a daily basis, and the training schedule will be adapted to fit each participant's specific situation. 2.The feedback and fitness of the participants will be closely monitored during training. 3. The intervention effect on subjects during training will be evaluated weekly. 4. Patients will be supported in their decision to withdraw from the study. Relevant concomitant care permitted or prohibited during the trial {11d} All groups will receive standard rehabilitation treatment, including occupational therapy, physical therapy, and auditory and speech therapy. No psychological therapy or central nervous system invasive stimulation will be provided. Provisions for posttrial care {30} To ensure patient safety, blood pressure and oxygen levels will be measured immediately after each session, and detailed records of the experimental procedures and any abnormalities will be maintained. Any issues detected will be addressed by the attending physician. Outcomes {12} In this study, we will use the poststroke depression scale (PSDS) as a screening tool for poststroke depression. This scale has been confirmed to be an effective, reliable, and specific tool for screening poststroke depression in Chinese patients, and it is easy to use [31]. It also had acceptable psychometric properties and was used to assess different subtypes of PSD patients [32]. The PSDS will be assessed at four different time points during the study. The outcome measures will be evaluated at four time points during the experiment: baseline (T0), after five treatment sessions (T1), after ten treatment sessions (T2), and at 30 days posttreatment (T3) during the follow-up period. Primary outcomes Hamilton Depression Rating Scale (HAMD): The HDRS, developed by Max Hamilton in 1960, is a clinical rating scale used to assess the severity of depression. Originally used for studying the efficacy of antidepressant medications, the standard version consists of 17 items (HAMD-17), with each item scored from 0–4 or 0–2 points. A higher total score indicates more severe depression. Following a stroke diagnosis, HDRS shows a sensitivity of 0.92, specificity of 0.89, and a diagnostic odds ratio of 94 for depression[33]. Berg Balance Scale (BBS): The BBS is a widely used tool for assessing an individual's balance ability, especially in elderly individuals and patients with neurological injuries. The scale consists of 14 items covering sitting balance, standing balance, and dynamic balance, with each item scored from 0 to 4 points, and a total score ranging from 0 to 56 points. BBS has been widely used in the assessment of balance ability in stroke patients. A study evaluated the test-retest reliability of BBS in chronic stroke patients, and the results showed very high reliability, with an ICC value of 0.99[34]. Secondary outcomes The following neuroimaging and electrophysiological data will be collected: (1) resting fMRI: within-network integrity, between-network segregation, pairwise functional connectivity, global functional connectivity[35]; (2) EEG: spectral analysis, dynamic analysis of spectral activity, time domain analysis, resting-state and task-state functional connectivity; and (3) TMS-EEG: time-frequency analysis, time domain analysis, and resting-state and task-state functional connectivity analysis of EEG signals following single-pulse stimulation of the cerebellum vermis. Table 1 illustrates our measurement of the administration schedule for repeated measurements. MRI recording: T1-weighted brain images will be obtained via an MRI scanner to evaluate the resting-state brain structure of each patient before enrollment. Patients with severe damage to the cerebellum will be not included in the study to ensure the effectiveness of iTBS stimulation. EEG recording: Resting state EEG, Stroop task state ERP, and TMS-EEG will be recorded in this study. To minimize artifacts arising from blinking and ocular movements during EEG data collection, participants will be required to maintain a state of silence, wakefulness, and assume a comfortable seated posture. We will use a 24-channel (FP1, FP2, F3, F4, F7, F8, Fz, T3, T4, T5, T6, A1, A2, C3, C4, Cz, P3, P4, Pz, O1, Oz, O2) EEG device (model NSM2 by Biosemi, supplied by Technocon, Qingdao, China) arranged in conformity with the 10–20 system. TMS-compatible Ag/AgCl sintered C-ring electrodes are going to be used. The equipment parameters will be configured with a bandpass filter range spanning 0 to 100 Hz and a sampling frequency set at 5000 Hz. Electrodes situated on bilateral mastoids (A1, A2) will be employed as reference points. Throughout the data acquisition process, impedance levels of each electrode were consistently maintained below 5 KΩ. To explore the real-time effects of single-pulse TMS stimulation on the cerebellar vermis and the connectivity between the cerebellar vermis and the cortical regions, we will use TMS-EEG technology. Resting-state EEG data will be acquired via a TMS-EEG system that included a TMS device (model NS5000, manufactured in Wuhan, China) equipped with a figure-8 coil (model B9076, coil diameter 92 mm). A Biosemi EEG recorder will be used for EEG data acquisition and recording. During TMS-EEG detection, considering the cerebellar vermis is relatively deep, we will use pulse stimulation at 100% aMT intensity on the cerebellar vermis, with an inter-stimulus interval of 6.5-8 seconds [36]. Offline preprocessing of the raw EEG data will be conducted via MATLAB (Version 2020b, MathWorks Inc., Natick, USA). This preprocessing involved applying 2–50 Hz bandpass filters, 50 Hz notch filters, and downsampling the data to 200 Hz. EEG artifacts were identified and corrected via independent component analysis. All the channels will be subsequently rereferenced to the average reference. Additionally, TMS-related artifacts in the TMS-EEG datasets will be mitigated via the tms-eeg toolbox. Poststroke depression screening Table 1 Measurement schedule for repeated measurements Time point Study period Enrollment After 5 treatment sessions Termination of all treatments Follow-up 0 W 0 W 1 W 2 W 6 W Screening and enrollment Eligibility screen RPTs ✓ Informed consent ✓ Eligibility screen face to face to blinded evaluator ✓ Allocation principal investigator ✓ Interventions Group A: active(iTBS + Stroop) 5 times per week Group B: Active iTBS + sham Stroop 5 times per week Group C: sham iTBS + Active Stroop 5 times per week Group D: Sham(iTBS + Stroop) 5 times per week Assessments Demographic variables: ✓ Age, gender, education, occupational and marital status Clinical presentation of TrPs: ✓ Location Interrogation Worsens Improvement Clinical variables: ✓ ✓ ✓ ✓ PSDS HAMD NIHSS FIM Timed Up and Go test BBS ABS HMDS HAM-A, HAM-D HADS-A, HADS-D IDS-SR PGI MMSE MoCA Neuroimaging and electrophysiological assessments: ✓ ✓ ✓ rsfMRI EEG(rest/task) TEP Participant timeline {13} The timeline for participants' enrolment, interventions, and assessments can be seen in Table 1 . Sample size {14} The occurrence of poststroke depression within three weeks of the event exceeded 50% in some instances, with a reported range of 11–63%. Specifically, the prevalence of severe depression was estimated at 31%. For our study, on the basis of a 13.2% prevalence of mild depression (95% confidence interval: 10.9%-15.8%) and an error tolerance of 0.16, the calculated sample size was 80 patients. Considering a broader prevalence of depression at any severity of 33.5% (95% confidence interval: 30.3%-36.8%) [37], a sample size of 144 was believed to be appropriate with the same error tolerance [3]. Factoring a potential follow-up loss rate of 15–20%, we adjusted the total sample size to 160 patients to ensure robust statistical power and account for potential attrition. Recruitment {15} The participants will be recruited from the inpatients of the Department of Rehabilitation Medicine, Second Affiliated Hospital of Kunming Medical University. First, the study team will screen and assess the eligibility of the participants. All patients will receive updates on the research progress and their partial results during the follow-up period. Moreover, the researchers will ensure ongoing contact with the physicians overseeing each patient. A final report on the results will be given to physicians and patients at the end of the study. Assignment of interventions: allocation Sequence generation {16a} We'll utilize the RAND function in Excel (Version 2022, Microsoft) to create two random number tables each containing 80 random values. Two sets of random number tables will be used to collect patients with left and right MCA stroke, respectively. Participants will be given a number upon enrollment and then randomly allocated to one of four groups in a 1:1:1:1 ratio according to the random number table. Concealment mechanism {16b} The allocation sequence will be kept in a sealed, opaque envelope. Implementation {16c} The principal investigator will assign participants to the respective intervention groups. Assignment of interventions: blinding Who will be blinded {17a} The outcome assessors and research statisticians will be kept blinded throughout the entire process. They will solely focus on evaluating and presenting results, without any involvement in other aspects. The assessment results uploaded will not include any information that could identify patient groups. Blinding will be maintained throughout the entire experimental process. Procedure for unblinding if needed {17b} N/A. It is not possible to implement emergency unblinding in our trial since both the participants and rehabilitation trainers are not blinded. Data collection and management Plans for assessment and collection of outcomes {18a} Prior to the study's initiation, the recruiting doctors, physical therapists, and assessors will be trained to check the relevant equipment to ensure the research's quality, and will take the following steps: 1. The doctor responsible for recruiting will have a thorough understanding of the experimental process. 2. The therapists will receive training on conducting the program and handling potential adverse events during the training. 3. The assessors will receive training on how to standardize the use of EEG signal acquisition equipment and guide patients to undergo MRI scans at the hospital imaging department. 4. The data administrator will be trained on managing Case Report Form (CRF) and storing electronic data of EEG and MRI. Plans to promote participant retention and complete followup {18b} The follow-up assessment will be scheduled to take place 4 weeks after the training program ends. Participants will receive a phone call inviting them to the hospital for the assessment. Data management {19} In order to ensure the integrity and quality of the clinical data, the CRF documentation process will be utilized. Each patient will have their own CRF monitored by a third party and overseen by a skilled researcher. Confidentiality {27} Throughout all stages of the trial, personal information of potential and registered participants will be collected and maintained in accordance with the confidentiality agreement. Prior to commencing, informed consent will be obtained from each participant, outlining the purpose, procedures, and risks involved in the study. Throughout the experiment, all gathered data will be anonymized and stored securely, with only authorized individuals overseeing data analysis and trial supervision having access. After the experiment is completed, all personal information will be maintained according to strict protection protocols. All identifiable data, such as specific protocol codes, will be retained for the designated period in a secure archival manner as required by governing confidentiality and data protection agencies and regulatory directives. Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} N/A. Biological specimens are not relevant to our trial. Statistical methods Statistical methods for primary and secondary outcomes {20a} Display of baseline data: Quantitative data with a normal or approximately normal distribution will be presented as the means ± standard deviations. Data not normally distributed or showing heterogeneous variances will be expressed as medians (interquartile ranges or total ranges). Categorical data will be denoted as the number of cases (percentages). The scale and demographic data will be preprocessed and analyzed using Python 3.7.4 software. Data preprocessing will be done using NumPy and Pandas , while statistical analysis will be conducted using Statsmodels . Visualization of the results will be achieved through Matplotlib and Seaborn . For quantitative data with a normal or near-normal distribution, a repeated measures mixed ANOVA will be used to analyze between-group differences and temporal changes across two groups. The Mann‒Whitney U test will be used to compare two datasets of quantitative data that do not follow a normal distribution. Categorical data will be evaluated via Fisher’s exact test or the chi-square test, as appropriate. Continuous data will be analyzed using Pearson Correlation Coefficient, while ordinal data will be analyzed using Spearman's Rank Correlation Coefficient. Ordinal data will be analyzed using either Spearman's Rank Correlation Coefficient or Kendall's Tau. We will employ methods including connectivity analysis, time-frequency analysis, and time-domain analysis to analyze the TMS‒EEG data. EEG time-frequency analysis, time domain analysis, and functional connectivity metrics will be statistically analyzed using the EEGLAB and FieldTrip toolboxes in MATLAB . Statistical analysis of MRI data will be conducted using the SPM12 toolbox in MATLAB . In the analyses performed, a p value of less than 0.05 will be considered indicative of statistically significant differences. Bonferroni correction will be employed to control the inflation risk of Type I errors due to multiple subgroup comparisons. 95% confidence intervals will be presented for the estimates. Interim analyses {21b} The interim analysis will be performed after half of the sample size is reached, in order to monitor outcomes and verify the trial process. Methods for additional analyses (e.g., subgroup analyses) {20b} N/A. No additional analyses beyond the primary and secondary outcomes will be conducted for the study. Methods in analysis to handle protocol nonadherence and any statistical methods to handle missing data {20c} Data analysis will utilize the intention-to-treat analysis (ITT) approach. In case of missing data, the last observation carried forward method will be used. Plans to give access to the full protocol, participantlevel data, and statistical code {31c} The current study data and statistical code will be available upon reasonable request from the corresponding author, and the complete protocol can be obtained from the same correspondence. Oversight and monitoring Composition of the coordinating center and trial steering committee {5d} The Hospital Safety Supervision Committee has been tasked with monitoring the project. Its main responsibilities include evaluating the experimental design, scientific rigor, and procedural integrity throughout the research process, as well as ensuring participant safety, adherence to medical ethics, and proper management and handling of collected data. The Trial Steering Committee will hold meetings to assess the availability of suitable research subjects and oversee critical stages of the trial initiation. Additional meetings will be arranged at intervals corresponding to the data collection points. Each committee will offer comprehensive support for the trial, encompassing early, late, and follow-up assessments to promote robust data collection and analysis. Composition of the data monitoring committee, its role and reporting structure {21a} Data entry will be conducted by two separate researchers to allow for cross-checking the accuracy of the input data. Adverse event reporting and harms {22} Earlier studies have shown that active iTBS stimulation can cause manic or hypomanic symptoms in only a few patients, with no other adverse events reported[38]. Researchers will inform participants of potential adverse events with informed consent and will document any adverse events that occurred during the study. If such events are observed, their frequency will be analyzed between the two groups. If patients have any questions about symptoms or need further information, they will be able to contact the attending physician by phone or email. Frequency and plans for auditing trial conduct {23} The project management team will hold regular meetings to assess the progress of the trial and compliance with the trial protocol, with meetings scheduled monthly. In addition, the trial steering committee and ethics committee will play a crucial role in ongoing monitoring and review. These bodies will be responsible for overseeing the conduct of the trial, ensuring the well-being of participants, and maintaining data integrity throughout the trial. This structured approach will ensure active monitoring and adherence to established ethical and regulatory standards throughout the trial. Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25} We will communicate in a timely manner with funding agencies through structured notifications. Subsequently, the Principal Investigator (PI) will inform each coordinating center and ensure the revised protocol is distributed promptly. The PI will receive a copy of the updated protocol to include in the investigator site file. We will meticulously document any deviations from the established protocol by completing a violation report form. The clinical trial registry will be diligently updated to accurately reflect the modified procedures. This rigorous approach is crucial for maintaining transparency and accuracy in clinical trial management, complying with regulatory standards, and preserving the integrity of the research process. Dissemination plans {31a} The dissemination plan includes specific strategies to communicate the trial results to healthcare professionals and the public, with findings being disseminated through conference presentations, peer-reviewed journal publications, medical forums, and other channels. Ethics and trial registration {24} This study received ethical approval from the Ethics Committee of the Second Hospital of Kunming Medical University (Shen-PJ-Ke-2022-2) and was registered under the Chinese Clinical Trial Registry system with the registration number ChiCTR2200058553. Discussion Given the cerebellum's extensive connections with cortical regions involved in motor, associative, and emotional functions, the CTC pathway shows promising potential as a target for innovative noninvasive brain stimulation techniques. Hence, the cerebellar vermis will be selected as our intervention target, given its involvement in emotional regulation and postural control. The aim of this research is to confirm the effectiveness of combining Stroop visual task with iTBS stimulation of the cerebellar vermis in improving the emotions and balance function of stroke patients, as well as to validate the shared circuit effect of the cerebellum in regulating emotions and balance. Moreover, we hypothesize that combining cerebellar iTBS stimulation with emotion-related visual Stroop tasks may improve mood disorders in stroke patients and regulate balance impairments, thereby promoting overall functional recovery in stroke survivors. Timeline Patients will be recruited between May 2023 and August 2025. The study is expected to be completed in November 2025. Data analysis, writing of the scientific manuscript and submission to peer-reviewed scientific journals will take place from January 2026. A summary of the study outline is shown in Table 1 . Abbreviations PSD: Poststroke depression CTC: Cerebellar-thalamus-cortical ACC: Anterior cingulate cortex MCA: Middle cerebral artery DLPFC: Left dorsolateral prefrontal cortex rTMS: Repetitive transcranial magnetic stimulation iTBS: Intermittent theta burst stimulation CRF: Case Report Form HAMD: Hamilton Depression Rating Scale BBS: Berg Balance Scale Declarations Acknowledgments We thank all of the clinicians and clinical supervisors who provided and supervised the therapy and clinical care. Authors’ contributions {31b} Conceptualization: ZHC, LQY, XY, and YZ. Methodology: ZHC, XY, HTW, XCL. Formal analysis: ZHC, XY,YZ. Investigation: ZHC, LQY, XY, QL, HMZ, XCL, and HTW. Resources: ZHC, LQY, XY, YZ, HTW, XCL, and QL. Data curation: ZHC, XY. Writing—original draft preparation: ZHC, XY, QL, HMZ. Writing—review and editing: ZHC, XY, HMZ, and QL. Visualization; ZHC, XY. Supervision: LQY, XY. Project administration: LQY, XY, QL, HMZ. All the authors have read and agreed to the published version of the manuscript. Funding{4} Doctoral research project of the Second Affiliated Hospital of Kunming Medical University (Grant number 2023BS01). Consent for publication {32} All the authors read the manuscript and approved the publication. Competing interests {28} The authors declare that they have no competing interests. Roles and responsibilities: sponsor and funder {5c} This research will be funded by the Second Affiliated Hospital of Kunming Medical University. The sponsor and funder will participate in discussions at the design stage but will not intervene in core scientific or methodological issues. During data collection, management, and analysis, the research team will remain independent. The sponsors and funder will not participate in specific data processing or analysis. For data interpretation, the research team will communicate with them, but the final interpretation rights will belong to the research team. The research team will have full autonomy in report writing and publication, and the sponsors and funder will not influence the content or publication decisions. The research team will be fully responsible for the authenticity and scientific validity of the results, and the sponsors and funder will not assume any legal liability for any consequences arising from the research. References Wafa HA, Wolfe CDA, Emmett E, Roth GA, Johnson CO, Wang Y: Burden of Stroke in Europe: Thirty-Year Projections of Incidence, Prevalence, Deaths, and Disability-Adjusted Life Years . Stroke 2020, 51 (8):2418-2427. Ghrouz A, Guillen-Sola A, Morgado-Perez A, Muñoz-Redondo E, Ramírez-Fuentes C, Curbelo Peña Y, Duarte E: The effect of a motor relearning on balance and postural control in patients after stroke: An open-label randomized controlled trial . European stroke journal 2024, 9 (2):303-311. Mitchell AJ, Sheth B, Gill J, Yadegarfar M, Stubbs B, Yadegarfar M, Meader N: Prevalence and predictors of post-stroke mood disorders: A meta-analysis and meta-regression of depression, anxiety and adjustment disorder . General hospital psychiatry 2017, 47 :48-60. Khan F, Chevidikunnan MF: Prevalence of Balance Impairment and Factors Associated with Balance among Patients with Stroke. A Cross Sectional Retrospective Case Control Study . Healthcare (Basel, Switzerland) 2021, 9 (3). Mat S, Ng CT, Tan PJ, Ramli N, Fadzli F, Rozalli FI, Mazlan M, Hill KD, Tan MP: Effect of Modified Otago Exercises on Postural Balance, Fear of Falling, and Fall Risk in Older Fallers With Knee Osteoarthritis and Impaired Gait and Balance: A Secondary Analysis . PM & R : the journal of injury, function, and rehabilitation 2018, 10 (3):254-262. Wu X, Tu M, Yu Z, Cao Z, Qu S, Chen N, Jin J, Xiong S, Yang J, Pei S et al : The efficacy and cerebral mechanism of intradermal acupuncture for major depressive disorder: a multicenter randomized controlled trial . Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2025, 50 (7):1075-1083. Cao H, Wei X, Hu N, Zhang W, Xiao Y, Zeng J, Sweeney JA, Lencer R, Lui S, Gong Q: Cerebello-Thalamo-Cortical Hyperconnectivity Classifies Patients and Predicts Long-Term Treatment Outcome in First-Episode Schizophrenia . Schizophrenia bulletin 2022, 48 (2):505-513. Nicoletti V, Cecchi P, Pesaresi I, Frosini D, Cosottini M, Ceravolo R: Cerebello-thalamo-cortical network is intrinsically altered in essential tremor: evidence from a resting state functional MRI study . Scientific reports 2020, 10 (1):16661. Heck DH, Fox MB, Correia Chapman B, McAfee SS, Liu Y: Cerebellar control of thalamocortical circuits for cognitive function: A review of pathways and a proposed mechanism . 2023, Volume 17 - 2023 . Pierce JE, Péron J: The basal ganglia and the cerebellum in human emotion . Social cognitive and affective neuroscience 2020, 15 (5):599-613. Sansare A, Magalhaes TNC, Bernard JA: Relationships of functional connectivity of motor cortex, primary somatosensory cortex, and cerebellum to balance performance in middle-aged and older adults . Neurobiology of aging 2025, 147 :1-11. Alasmar Z, Chakravarty MM, Penhune VB, Steele CJ: Patterns of Cerebellar-Cortical Structural Covariance Mirror Anatomical Connectivity of Sensorimotor and Cognitive Networks . Human brain mapping 2025, 46 (1):e70079. Jamieson AJ, Harrison BJ, Razi A, Davey CG: Rostral anterior cingulate network effective connectivity in depressed adolescents and associations with treatment response in a randomized controlled trial . Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2022, 47 (6):1240-1248. Zhang Y, Shao J, Wang X, Chen Z, Liu H, Pei C, Zhang S, Yao Z, Lu Q: Functional impairment-based segmentation of anterior cingulate cortex in depression and its relationship with treatment effects . Human brain mapping 2021, 42 (12):4035-4047. Saleem A, Harmata G, Jain S, Voss MW, Fiedorowicz JG, Williams AJ, Shaffer JJ, Richards JG, Barsotti EJ, Sathyaputri L et al : Functional connectivity of the cerebellar vermis in bipolar disorder and associations with mood . Frontiers in psychiatry 2023, 14 :1147540. Yang J, Tang T, Gui Q, Zhang K, Zhang A, Wang T, Yang C, Liu X, Sun N: Status and trends of TMS research in depressive disorder: a bibliometric and visual analysis . Frontiers in psychiatry 2024, 15 :1432792. Noda Y, Osawa R, Takeda Y, Fujii K, Saijo Y, Kajiya T, Takeishi K, Moriyama S, Saeki T, Nakajima S et al : Left prefrontal intermittent theta-burst stimulation therapy for major depressive disorder: A real-world, multisite observational study in Japan . Journal of affective disorders 2025, 375 :316-323. Gao W, Xue F, Yu B, Yu S, Zhang W, Huang H: Repetitive transcranial magnetic stimulation for post-stroke depression: An overview of systematic reviews . Frontiers in neurology 2023, 14 :930558. Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ et al : Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial . Lancet (London, England) 2018, 391 (10131):1683-1692. Koch G, Bonnì S, Casula EP, Iosa M, Paolucci S, Pellicciari MC, Cinnera AM, Ponzo V, Maiella M, Picazio S et al : Effect of Cerebellar Stimulation on Gait and Balance Recovery in Patients With Hemiparetic Stroke: A Randomized Clinical Trial . JAMA neurology 2019, 76 (2):170-178. Bailey NW, Hoy KE, Rogasch NC, Thomson RH, McQueen S, Elliot D, Sullivan CM, Fulcher BD, Daskalakis ZJ, Fitzgerald PB: Responders to rTMS for depression show increased fronto-midline theta and theta connectivity compared to non-responders . Brain stimulation 2018, 11 (1):190-203. Smith EH, Horga G, Yates MJ, Mikell CB, Banks GP, Pathak YJ, Schevon CA, McKhann GM, 2nd, Hayden BY, Botvinick MM et al : Widespread temporal coding of cognitive control in the human prefrontal cortex . Nature neuroscience 2019, 22 (11):1883-1891. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krle AJK, Hrobjartsson A, Mann H, Dickersin K, Berlin JA et al : SPIRIT 2013 Statement: defining standard protocol items for clinical trials . Revista panamericana de salud publica = Pan American journal of public health 2015, 38 (6):506-514. Kim NY, Lee SC, Shin JC, Park JE, Kim YW: Voxel-based lesion symptom mapping analysis of depressive mood in patients with isolated cerebellar stroke: A pilot study . NeuroImage Clinical 2017, 13 :39-45. Basavaraju R, Ithal D, Thanki MV, Ramalingaiah AH, Thirthalli J, Reddy RP, Brady RO, Jr., Halko MA, Bolo NR, Keshavan MS et al : Intermittent theta burst stimulation of cerebellar vermis enhances fronto-cerebellar resting state functional connectivity in schizophrenia with predominant negative symptoms: A randomized controlled trial . Schizophrenia research 2021, 238 :108-120. Filipović SR, Rothwell JC, Bhatia K: Low-frequency repetitive transcranial magnetic stimulation and off-phase motor symptoms in Parkinson's disease . Journal of the neurological sciences 2010, 291 (1-2):1-4. Demirtas-Tatlidede A, Freitas C, Cromer JR, Safar L, Ongur D, Stone WS, Seidman LJ, Schmahmann JD, Pascual-Leone A: Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia . Schizophrenia research 2010, 124 (1-3):91-100. Rossi S, Hallett M, Rossini PM, Pascual-Leone A: Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research . Clin Neurophysiol 2009, 120 (12):2008-2039. Shen Y, Xue S, Wang K, Qiu J: Neural time course of emotional conflict control: an ERP study . Neuroscience letters 2013, 541 :34-38. Xue S, Ren G, Kong X, Liu J, Qiu J: Electrophysiological correlates related to the conflict adaptation effect in an emotional conflict task . Neuroscience letters 2015, 584 :219-223. Yue Y, Liu R, Lu J, Wang X, Zhang S, Wu A, Wang Q, Yuan Y: Reliability and validity of a new post-stroke depression scale in Chinese population . Journal of affective disorders 2015, 174 :317-323. Yue Y, Liu R, Chen J, Cao Y, Wu Y, Zhang S, Li H, Zhu J, Wu A, Yuan Y: The Reliability and Validity of Post Stroke Depression Scale in Different Type of Post Stroke Depression Patients . Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2022, 31 (2):106222. Liu F, Gong L, Zhao H, Li YL, Yan Z, Mu J: Validity of evaluation scales for post-stroke depression: a systematic review and meta-analysis . BMC neurology 2024, 24 (1):286. Alghadir AH, Al-Eisa ES, Anwer S, Sarkar B: Reliability, validity, and responsiveness of three scales for measuring balance in patients with chronic stroke . BMC neurology 2018, 18 (1):141. Timmermann C, Roseman L, Haridas S, Rosas FE, Luan L, Kettner H, Martell J, Erritzoe D, Tagliazucchi E, Pallavicini C et al : Human brain effects of DMT assessed via EEG-fMRI . Proceedings of the National Academy of Sciences of the United States of America 2023, 120 (13):e2218949120. Tscherpel C, Mustin M, Massimini M, Paul T, Ziemann U, Fink GR, Grefkes C: Local neuronal sleep after stroke: The role of cortical bistability in brain reorganization . Brain stimulation 2024, 17 (4):836-846. Ayerbe L, Ayis S, Rudd AG, Heuschmann PU, Wolfe CD: Natural history, predictors, and associations of depression 5 years after stroke: the South London Stroke Register . Stroke 2011, 42 (7):1907-1911. Basavaraju R, Ithal D, Ramalingaiah AH, Thirthalli J, Mehta UM, Kesavan M: "Apathetic to hypomanic/manic": A case series-illustration of emergent mood symptoms during intermittent theta burst stimulation (iTBS) of cerebellar vermis in schizophrenia with predominant negative symptoms . Schizophrenia research 2020, 222 :501-502. Supplementary Files Reportingchecklistforprotocolofaclinicaltrialv1.3.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5170397","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":482783960,"identity":"082b03f3-66cf-456c-8455-c6803c164135","order_by":0,"name":"Zihan 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diagram.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5170397/v1/87a7bddb7d71bce3e7e955cc.png"},{"id":86669827,"identity":"b3159098-143b-43db-8d5f-4034395f3460","added_by":"auto","created_at":"2025-07-14 11:25:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":126909,"visible":true,"origin":"","legend":"\u003cp\u003eOverall experimental process\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5170397/v1/ba490797d1e87ce55517786c.png"},{"id":86670931,"identity":"732351c7-e473-4376-8e57-63eb0d79da2c","added_by":"auto","created_at":"2025-07-14 11:33:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":317848,"visible":true,"origin":"","legend":"\u003cp\u003eEmotion-word Stroop task\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5170397/v1/8f1078bc03380fe55ce520d2.png"},{"id":94672554,"identity":"0adf6cc3-98df-4f62-adc5-cc43ee78f8f1","added_by":"auto","created_at":"2025-10-29 13:40:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3150809,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5170397/v1/b89f5cff-e72c-4b9e-9db4-977304c18c6c.pdf"},{"id":86669832,"identity":"c76e9542-1e0e-499e-90bb-23890789c071","added_by":"auto","created_at":"2025-07-14 11:25:00","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":134912,"visible":true,"origin":"","legend":"","description":"","filename":"Reportingchecklistforprotocolofaclinicaltrialv1.3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5170397/v1/8c8c600e0fd4c524b4d748e9.pdf"}],"financialInterests":"","formattedTitle":"Cerebellar iTBS Combined With Emotional Stroop Task for Post-Stroke Depression: Randomized Controlled Trial Protocol From Kunming, China","fulltext":[{"header":"Introduction","content":"\u003ch3\u003eBackground and rationale {6a}\u003c/h3\u003e\n\u003cp\u003eAccording to Global Burden of Disease studies, stroke ranks as the second leading cause of disability worldwide [1]. After a stroke, patients often struggle with both balance and emotional issues. 83% of stroke patients will experience balance dysfunction[2]. According to Mitchell et al., the incidence of post-stroke depression is also as high as 33.5%[3]. The large percentage of two stroke complications indicates that both disorders are very likely to be present together in stroke patients. Additionally, Khan et al.'s study directly observed a significant correlation between balance impairment and depression after a stroke[4]. A compromised trunk balance can result in falls, which may worsen feelings of despair or anxiety, thus creating a harmful cycle that impacts patients' daily activities[5].\u003c/p\u003e\u003cp\u003eFollowing a 6-week acupuncture treatment on Shenmen (HT7), Neiguan (PC6), Sanyinjiao (SP6), and Taichong (LR3) acupoints, symptoms of depression in patients showed improvement, which may be associated with increased functional connectivity between the striatum and frontal lobe, as well as the striatum and cerebellum[6]. Despite being typically associated with balance, the cerebellum is shown in the research above to also play a role in emotional regulation. Further research has shown that both emotion and balance functions are related to the cerebellum-thalamus-cortex pathway (CTC)[7, 8]. The projection from the cerebellum to the thalamus covers almost all subnuclei, including nuclei involved in cognition and sensory integration. This extensive connectivity allows the cerebellum to influence multiple cortical areas through the thalamus, coordinating the motor and sensory integration required for balance[9]. In terms of emotional regulation, the pathway connecting the thalamus, basal ganglia, and cerebellum to the widespread regions of the cerebral cortex provides a structural basis for their comprehensive influence on the limbic system function. The way in which the cerebellum guides learning by modulating cortical oscillations through the CTC circuitry influences an individual's processing of emotional stimuli[10]. The evidence above clearly indicates that both the regulation of balance movement and emotional regulation are closely related to the CTC circuit. However, there is currently no research evidence on the co-circuit effects of these two functions.\u003c/p\u003e\u003cp\u003eFocusing on the cortical level of the CTC loop is also a point worth exploring. In terms of motor balance, CTC's cortical level refers to the motor sensory cortex. The cerebellum can integrate proprioceptive information from various parts of the body through its connection with the parietal lobe, allowing for better perception of body position and movement status, thus maintaining balance[11]. The cerebellum is also functionally connected to the pre-motor cortex of the frontal lobe, which is crucial for the planning and execution of movements, helping to maintain balance in the body during motion[12]. However, recent research suggests that the cerebellum mainly regulates emotions through its connections with the cortical limbic system. Connections exist between the X area of the cerebellum and the orbitofrontal, anterior cingulate cortex (ACC), and amygdala cortex, contributing to the regulation of emotions. The ACC is closely related to processes like emotion regulation, conflict monitoring, and decision-making. The connection between the cerebellum and this area may help regulate emotional responses, especially when processing conflicting information and making decisions[10]. The functional connection between the left dorsolateral prefrontal cortex (DLPFC) and the ACC plays a crucial role in depression. Research indicates that prior to treatment, there is typically impaired functional connectivity between the DLPFC and ACC in patients with depression, particularly in treatment responders[13, 14]. The reason why the DLPFC can serve as a target for Transcranial Magnetic Stimulation (TMS) in modulating depression may be due to its ability to regulate ACC activity. Some studies suggest that the vermis plays a crucial role in regulating emotions in the cerebellum, and it has similarities with the DLPFC[15]. In general, the cerebellum may play a role in motor balance and emotional disorders in stroke survivors, offering potential for a combined intervention target for these two impairments.\u003c/p\u003e\u003cp\u003eTMS has gained widespread recognition for its efficacy in treating depression among all non-invasive brain stimulation methods. The focus of TMS protocol for treating depression primarily includes repetitive transcranial magnetic stimulation (rTMS), microelectric stimulation, and intermittent theta burst stimulation (iTBS)[16]. Currently, both rTMS and iTBS stimulation are considered effective in treating depression[17, 18]. Therapeutically, comparative studies targeting the DLPFC in patients with treatment-resistant depression have shown that the effectiveness of iTBS is comparable to that of 10 Hz rTMS [19]. However, iTBS offers a shorter treatment time compared to rTMS, making it more cost-effective. Additionally, applying iTBS to the cerebellum has been shown to improve gait and balance[20]. Combining TMS stimulation with certain visual cognitive tasks can further enhance the efficacy of TMS. Research indicates that abnormal theta band activity (4–8 Hz) is strongly linked to the pathological mechanism of depression. Baseline and treatment first-week midline theta power show promising potential for predicting response to TMS therapy for depression[21]. Research has indicated that during the Stroop task, an increase in gamma and theta power is observed in the DLPFC and dorsal ACC[22]. However, there is limited research on whether performing Stroop visual tasks before TMS therapy might enhance the effectiveness of TMS for depression.\u003c/p\u003e\u003cp\u003eStudy objectives{7}\u003c/p\u003e\u003cp\u003eIn conclusion, the cerebellum plays a crucial role in regulating emotions, movement, and balance. The implementation of the above functions is related to the CTC circuit. However, research on the co-circuit problem of the cerebellum in regulating emotional and balance functions is still insufficient. Therefore, we hypothesize that the cerebellum has a common pathway effect on balance and emotion regulation through the CTC circuit, and cerebellar iTBS stimulation can promote the recovery of both functions simultaneously. We will evaluate the effectiveness of this therapy on improving post-stroke depression and balance disorders, as well as the relationship between these two functions in stroke patients using the Hamilton Depression Rating Scale (HAMD) and Berg Balance Scale (BBS) as primary outcome measures. Secondary outcome measures will include Magnetic Resonance Imaging (MRI) and Electroencephalography (EEG). MRI will be used to evaluate changes in connectivity within and between components of the CTC circuit, while high temporal resolution EEG will be used to monitor real-time effects of this intervention. Finally, establish the correlation between changes in MRI and EEG indicators and functional improvement through relevant analysis.\u003c/p\u003e\u003cp\u003eTrial design {8}\u003c/p\u003e\u003cp\u003eThis study will be a prospective, single-blinded, parallel armed, randomized controlled trial (RCT) with factorial design. Participants will be allocated to one of the four groups: (A) the active iTBS of the cerebellar vermis with active Stroop training group, (B) the sham iTBS with active Stroop training group, (C) the active iTBS and sham Stroop training group, or (D) the sham iTBS with sham Stroop training group. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the flow chart of the trial process. The checklist of Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) is provided in Appendix I[23].\u003c/p\u003e"},{"header":"Methods: participants, interventions, and outcomes","content":"\u003cp\u003eStudy setting {9}\u003c/p\u003e\n\u003cp\u003eThe experiment will be conducted at the Department of Rehabilitation Medicine, Second Affiliated Hospital of Kunming Medical University, Yunnan Province, China. The study is scheduled to take place between July 2024 and July 2027.\u003c/p\u003e\n\u003cp\u003eEligibility criteria {10}\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria: (1) chronic phase of stroke; (2) age\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;18 years, \u0026lt; 85 years; (3) MCA injury; (4) National Institutes of Health Stroke Scale (NIHSS)\u0026thinsp;\u0026gt;\u0026thinsp;4 and \u0026lt;\u0026thinsp;26; (5) completed CT or MRI examination; (6) patients with sufficient cognitive and auditory comprehension abilities to cooperate with the treatment, Mini-Mental State Examination (MMSE)\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;15 [24]; and (7) All the participants were right-handed.\u003c/p\u003e\n\u003cp\u003eThe exclusion criteria: (1) history of epilepsy or psychiatric disorders (including depression, anxiety, or schizophrenia); (2) severe comorbidities; (3) history of medication use, such as benzodiazepines, baclofen, or antidepressants; (4) noncompliant individuals; (5) acute cerebral hemorrhage or acute infectious diseases; (6) patients with strong suicidal tendencies; (7) patients with severe headache, hypertension, malignancy, open wound vascular embolism, or leukopenia; (8) alcoholism; (9) patients with a history of cranial surgery and metal implants in the brain; (10) pacemaker implantation; (11) NIHSS score\u0026thinsp;\u0026gt;\u0026thinsp;26, MMSE score\u0026thinsp;\u0026lt;\u0026thinsp;15; (12) any disease that may prevent the patient from surviving more than one month; and (13) pregnancy.\u003c/p\u003e\n\u003cp\u003eWho will take informed consent? {26a}\u003c/p\u003e\n\u003cp\u003eProfessional rehabilitation therapists will explain the trial to potential participants, and if they show willingness to participate, the therapist will obtain the participant\u0026apos;s signature on the informed consent form.\u003c/p\u003e\n\u003cp\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/p\u003e\n\u003cp\u003eN/A. Additional consent provisions are not needed for collection and use of participant data and biological specimens in trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExplanation for the choice of comparators {6b}\u003c/p\u003e\n\u003cp\u003eThere is currently no study comparing the effects of iTBS stimulation in the cerebellar vermis, emotion Stroop task, and combined training on post-stroke balance and emotional function improvement. Through this factorial design, we can compare the effects of cerebellar iTBS stimulation and emotional Stroop task on improving emotional and balance functions (main effects), as well as the combined effects of both interventions on improving emotional and balance functions in stroke patients (interaction effects).\u003c/p\u003e\n\u003cp\u003eIntervention description {11a}\u003c/p\u003e\n\u003cp\u003eThe differences lie in the task training and iTBS stimulation. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e outline the intervention details for each group.\u003c/p\u003e\n\u003cp\u003e(1)Active iTBS and active Stroop task group (group A)\u003c/p\u003e\n\u003cp\u003eThe participants in this group will first complete the active Stroop task training, followed immediately by iTBS stimulation. The visual task training will last 15 minutes, followed by iTBS stimulation, which is expected to take 3\u0026ndash;4 minutes. There will be 5 sessions per week, with a total of 10 interventions over a two-week period.\u003c/p\u003e\n\u003cp\u003e(2)Sham iTBS and active Stroop task group (group B)\u003c/p\u003e\n\u003cp\u003eThis group will first complete the active Stroop task, followed by sham iTBS stimulation. The duration and number of trials for the active Stroop task will be identical to those of Group A. Sham iTBS stimulation will be administered according to the input code, producing only sound without a magnetic field, and will last the same duration as in Group A. This group will also receive one session per day, totaling 10 interventions.\u003c/p\u003e\n\u003cp\u003e(3)Active iTBS and sham Stroop task groups (group C)\u003c/p\u003e\n\u003cp\u003eThis group will first undergo the sham Stroop task, followed by active iTBS stimulation. The sham Stroop task will have the same number of trials and duration as the active Stroop task, but participants will only view the stimuli on the screen without making any responses. The active iTBS stimulation will be identical to that used in Group A.\u003c/p\u003e\n\u003cp\u003e(4)Sham iTBS and sham Stroop task groups (group D)\u003c/p\u003e\n\u003cp\u003eThis group will first complete the sham Stroop task, followed by sham iTBS stimulation. The sham Stroop task and sham iTBS stimulation will be consistent with the sham conditions used in Groups B and C. The duration and schedule of the intervention will match those of the previous three groups.\u003c/p\u003e\n\u003cp\u003eActive and sham iTBS stimulation: Before starting TMS, all participants underwent T1-weighted structural MRI. The cerebellar vermis will be identified via anatomical landmarks within the Talairach coordinate system. rTMS will be administered in the form of iTBS, delivered via a TMS device (model NS5000, manufactured in Wuhan, China) equipped with a figure-8 coil (model B9076, coil diameter 92 mm)[25]. Using 100% of the active motor threshold (aMT), which is defined as the minimum stimulation intensity required to elicit MEPs with amplitudes of 200\u0026ndash;300 \u0026micro;V in at least 50% of 10 consecutive trials, the target muscle maintains 20% of its maximum voluntary contraction[26]. The electromyographic signal is received by the TMS device through its recording electrodes. Each iTBS burst consists of 3 pulses at a frequency of 50 Hz. Bursts will be delivered at a frequency of 5 Hz, with each train comprising 10 bursts. Each stimulation session will includes 20 trains, with an 8-second interval between trains [27]. Sham iTBS will generate a sound similar to that of iTBS without delivering any magnetic stimulation. iTBS stimulation will be administered after the Stroop task training, with each TMS session lasting a total of 180 seconds. Each treatment will be administered once daily for a total of 10 days. To ensure patient safety, the intensity of iTBS stimulation will be limited to no more than 120% of the patient\u0026apos;s motor threshold and adheres to all safety guidelines and recommendations endorsed by the International Federation of Clinical Neurophysiology[28].\u003c/p\u003e\n\u003cp\u003eActive Emotion-Word Stroop Task: The Emotional-Word Stroop Task will employ two types of stimuli: facial expressions and Chinese characters (Hanzi). It will incorporat four specific stimulus configurations: (1) \u0026quot;Happy Congruent\u0026quot;: a happy facial expression\u0026thinsp;+\u0026thinsp;the Hanzi for \u0026quot;happiness\u0026quot; (高兴); (2) \u0026quot;Happy Incongruent\u0026quot;: a happy facial expression\u0026thinsp;+\u0026thinsp;the Hanzi for \u0026quot;sadness\u0026quot; (悲伤); (3) \u0026quot;Sad Congruent\u0026quot;: a sad facial expression + \u0026quot;sadness\u0026quot; (悲伤); and (4) \u0026quot;Sad Incongruent\u0026quot;: a sad facial expression + \u0026quot;happiness\u0026quot; (高兴), as illustrated in Fig.\u0026nbsp;3. The stimuli will be derived from black-and-white portraits (50% female) sourced from an external database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://kdef.se/download-2/7Yri1UsotH.html\u003c/span\u003e\u003c/span\u003e). Each selected image featured a face directed toward the viewer, devoid of any distinctive markings such as tattoos, glasses, scars, or beards. These images will be formatted into 200 \u0026times; 300 pixel ellipses, which were set against a 237 \u0026times; 160 pixel horizontal rectangular background. The brightness and contrast settings for the stimuli will be standardized at 42 cd/m\u0026sup2; and 18 cd/m\u0026sup2;, respectively, ensuring uniformity in visual presentation across all facial and Hanzi stimuli.\u003c/p\u003e\n\u003cp\u003eThe participants will be positioned in a tranquil environment and seat approximately 100 cm from a monitor. They will be instructed to identify emotional facial expressions rapidly and accurately by pressing a button linked to the perceived emotion: sadness (left index finger) or happiness (right index finger). Consistent with previous research protocols[29, 30], the experimental sequence will be initiated with a 500 ms display of a fixation cross (\u0026quot;+\u0026quot;), followed by an interstimulus interval (ISI) with a blank screen lasting 600 ms. Subsequently, an emotion-word composite image will be presented centrally on the screen for 1,000 ms, followed by an intertrial interval (ITI) featuring a blank screen, again lasting 800 ms. Participant response times (RTs) will be carefully monitored. If a participant\u0026apos;s RT is shorter than the set maximum of 1,000 ms, the stimulus presentation time will be adjusted to match the actual response latency. If the RT is greater than 1,000 ms, the stimulus will be visible for the full 1,000 ms and an extra 500 ms will be given for the participant to respond. Figure\u0026nbsp;3 provides details on the emotion‒word Stroop task.\u003c/p\u003e\n\u003cp\u003eSham Emotion-Word Stroop Task: The Sham Emotion-Word Stroop Task will also be conducted in a quiet ERP examination room, using the same images as those selected for the active Emotion-Word Stroop Task. The difference between the two tasks is that participants in the Sham Emotion-Word Stroop Task will only need to view the images displayed alternately on the screen. In each trial, the duration of each image and the ISI will be set the same as in the active emotion‒word Stroop task.\u003c/p\u003e\n\u003cp\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/p\u003e\n\u003cp\u003eIf participants experience irreversible iTBS-related adverse events such as headaches, dizziness, fatigue, etc. during the trial, the trial will be stopped for the participant, even though the trial is very safe in itself.\u003c/p\u003e\n\u003cp\u003eStrategies to improve adherence to interventions {11c}\u003c/p\u003e\n\u003cp\u003eWe will take the following measures to achieve the best training adherence:\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e1. Throughout the two-week intervention period, participants will need to be involved in the intervention on a daily basis, and the training schedule will be adapted to fit each participant\u0026apos;s specific situation.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e2.The feedback and fitness of the participants will be closely monitored during training.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e3. The intervention effect on subjects during training will be evaluated weekly.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e4. Patients will be supported in their decision to withdraw from the study.\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/p\u003e\n\u003cp\u003eAll groups will receive standard rehabilitation treatment, including occupational therapy, physical therapy, and auditory and speech therapy. No psychological therapy or central nervous system invasive stimulation will be provided.\u003c/p\u003e\n\u003cp\u003eProvisions for posttrial care {30}\u003c/p\u003e\n\u003cp\u003eTo ensure patient safety, blood pressure and oxygen levels will be measured immediately after each session, and detailed records of the experimental procedures and any abnormalities will be maintained. Any issues detected will be addressed by the attending physician.\u003c/p\u003e\n\u003cp\u003eOutcomes {12}\u003c/p\u003e\n\u003cp\u003eIn this study, we will use the poststroke depression scale (PSDS) as a screening tool for poststroke depression. This scale has been confirmed to be an effective, reliable, and specific tool for screening poststroke depression in Chinese patients, and it is easy to use [31]. It also had acceptable psychometric properties and was used to assess different subtypes of PSD patients [32]. The PSDS will be assessed at four different time points during the study. The outcome measures will be evaluated at four time points during the experiment: baseline (T0), after five treatment sessions (T1), after ten treatment sessions (T2), and at 30 days posttreatment (T3) during the follow-up period.\u003c/p\u003e\n\u003cp\u003ePrimary outcomes\u003c/p\u003e\n\u003cp\u003eHamilton Depression Rating Scale (HAMD): The HDRS, developed by Max Hamilton in 1960, is a clinical rating scale used to assess the severity of depression. Originally used for studying the efficacy of antidepressant medications, the standard version consists of 17 items (HAMD-17), with each item scored from 0\u0026ndash;4 or 0\u0026ndash;2 points. A higher total score indicates more severe depression. Following a stroke diagnosis, HDRS shows a sensitivity of 0.92, specificity of 0.89, and a diagnostic odds ratio of 94 for depression[33].\u003c/p\u003e\n\u003cp\u003eBerg Balance Scale (BBS): The BBS is a widely used tool for assessing an individual\u0026apos;s balance ability, especially in elderly individuals and patients with neurological injuries. The scale consists of 14 items covering sitting balance, standing balance, and dynamic balance, with each item scored from 0 to 4 points, and a total score ranging from 0 to 56 points. BBS has been widely used in the assessment of balance ability in stroke patients. A study evaluated the test-retest reliability of BBS in chronic stroke patients, and the results showed very high reliability, with an ICC value of 0.99[34].\u003c/p\u003e\n\u003cp\u003eSecondary outcomes\u003c/p\u003e\n\u003cp\u003eThe following neuroimaging and electrophysiological data will be collected: (1) resting fMRI: within-network integrity, between-network segregation, pairwise functional connectivity, global functional connectivity[35]; (2) EEG: spectral analysis, dynamic analysis of spectral activity, time domain analysis, resting-state and task-state functional connectivity; and (3) TMS-EEG: time-frequency analysis, time domain analysis, and resting-state and task-state functional connectivity analysis of EEG signals following single-pulse stimulation of the cerebellum vermis. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates our measurement of the administration schedule for repeated measurements.\u003c/p\u003e\n\u003cp\u003eMRI recording: T1-weighted brain images will be obtained via an MRI scanner to evaluate the resting-state brain structure of each patient before enrollment. Patients with severe damage to the cerebellum will be not included in the study to ensure the effectiveness of iTBS stimulation.\u003c/p\u003e\n\u003cp\u003eEEG recording: Resting state EEG, Stroop task state ERP, and TMS-EEG will be recorded in this study. To minimize artifacts arising from blinking and ocular movements during EEG data collection, participants will be required to maintain a state of silence, wakefulness, and assume a comfortable seated posture. We will use a 24-channel (FP1, FP2, F3, F4, F7, F8, Fz, T3, T4, T5, T6, A1, A2, C3, C4, Cz, P3, P4, Pz, O1, Oz, O2) EEG device (model NSM2 by Biosemi, supplied by Technocon, Qingdao, China) arranged in conformity with the 10\u0026ndash;20 system. TMS-compatible Ag/AgCl sintered C-ring electrodes are going to be used. The equipment parameters will be configured with a bandpass filter range spanning 0 to 100 Hz and a sampling frequency set at 5000 Hz. Electrodes situated on bilateral mastoids (A1, A2) will be employed as reference points. Throughout the data acquisition process, impedance levels of each electrode were consistently maintained below 5 KΩ.\u003c/p\u003e\n\u003cp\u003eTo explore the real-time effects of single-pulse TMS stimulation on the cerebellar vermis and the connectivity between the cerebellar vermis and the cortical regions, we will use TMS-EEG technology. Resting-state EEG data will be acquired via a TMS-EEG system that included a TMS device (model NS5000, manufactured in Wuhan, China) equipped with a figure-8 coil (model B9076, coil diameter 92 mm). A Biosemi EEG recorder will be used for EEG data acquisition and recording. During TMS-EEG detection, considering the cerebellar vermis is relatively deep, we will use pulse stimulation at 100% aMT intensity on the cerebellar vermis, with an inter-stimulus interval of 6.5-8 seconds [36].\u003c/p\u003e\n\u003cp\u003eOffline preprocessing of the raw EEG data will be conducted via MATLAB (Version 2020b, MathWorks Inc., Natick, USA). This preprocessing involved applying 2\u0026ndash;50 Hz bandpass filters, 50 Hz notch filters, and downsampling the data to 200 Hz. EEG artifacts were identified and corrected via independent component analysis. All the channels will be subsequently rereferenced to the average reference. Additionally, TMS-related artifacts in the TMS-EEG datasets will be mitigated via the \u003cem\u003etms-eeg\u003c/em\u003e toolbox.\u003c/p\u003e\n\u003cp\u003ePoststroke depression screening\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMeasurement schedule for repeated measurements\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTime point\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eStudy period\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEnrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter 5 treatment sessions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTermination of all treatments\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFollow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 W\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eScreening and enrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEligibility screen RPTs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEligibility screen face to face to blinded evaluator\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAllocation principal investigator\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInterventions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGroup A: active(iTBS\u0026thinsp;+\u0026thinsp;Stroop)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e5 times per week\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGroup B: Active iTBS\u0026thinsp;+\u0026thinsp;sham Stroop\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e5 times per week\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGroup C: sham iTBS\u0026thinsp;+\u0026thinsp;Active Stroop\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e5 times per week\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGroup D: Sham(iTBS\u0026thinsp;+\u0026thinsp;Stroop)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e5 times per week\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAssessments\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDemographic variables:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, gender, education, occupational and marital status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical presentation of TrPs:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInterrogation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWorsens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImprovement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical variables:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePSDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHAMD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNIHSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFIM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTimed Up and Go test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eABS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHMDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHAM-A, HAM-D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHADS-A, HADS-D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIDS-SR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePGI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMMSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMoCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeuroimaging and electrophysiological assessments:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e✓\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ersfMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEEG(rest/task)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTEP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eParticipant timeline {13}\u003c/p\u003e\n\u003cp\u003eThe timeline for participants\u0026apos; enrolment, interventions, and assessments can be seen in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eSample size {14}\u003c/p\u003e\n\u003cp\u003eThe occurrence of poststroke depression within three weeks of the event exceeded 50% in some instances, with a reported range of 11\u0026ndash;63%. Specifically, the prevalence of severe depression was estimated at 31%. For our study, on the basis of a 13.2% prevalence of mild depression (95% confidence interval: 10.9%-15.8%) and an error tolerance of 0.16, the calculated sample size was 80 patients. Considering a broader prevalence of depression at any severity of 33.5% (95% confidence interval: 30.3%-36.8%) [37], a sample size of 144 was believed to be appropriate with the same error tolerance [3]. Factoring a potential follow-up loss rate of 15\u0026ndash;20%, we adjusted the total sample size to 160 patients to ensure robust statistical power and account for potential attrition.\u003c/p\u003e\n\u003cp\u003eRecruitment {15}\u003c/p\u003e\n\u003cp\u003eThe participants will be recruited from the inpatients of the Department of Rehabilitation Medicine, Second Affiliated Hospital of Kunming Medical University. First, the study team will screen and assess the eligibility of the participants. All patients will receive updates on the research progress and their partial results during the follow-up period. Moreover, the researchers will ensure ongoing contact with the physicians overseeing each patient. A final report on the results will be given to physicians and patients at the end of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSequence generation {16a}\u003c/p\u003e\n\u003cp\u003eWe\u0026apos;ll utilize the \u003cem\u003eRAND\u003c/em\u003e function in \u003cem\u003eExcel\u003c/em\u003e (Version 2022, Microsoft) to create two random number tables each containing 80 random values. Two sets of random number tables will be used to collect patients with left and right MCA stroke, respectively. Participants will be given a number upon enrollment and then randomly allocated to one of four groups in a 1:1:1:1 ratio according to the random number table.\u003c/p\u003e\n\u003cp\u003eConcealment mechanism {16b}\u003c/p\u003e\n\u003cp\u003eThe allocation sequence will be kept in a sealed, opaque envelope.\u003c/p\u003e\n\u003cp\u003eImplementation {16c}\u003c/p\u003e\n\u003cp\u003eThe principal investigator will assign participants to the respective intervention groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWho will be blinded {17a}\u003c/p\u003e\n\u003cp\u003eThe outcome assessors and research statisticians will be kept blinded throughout the entire process. They will solely focus on evaluating and presenting results, without any involvement in other aspects. The assessment results uploaded will not include any information that could identify patient groups. Blinding will be maintained throughout the entire experimental process.\u003c/p\u003e\n\u003cp\u003eProcedure for unblinding if needed {17b}\u003c/p\u003e\n\u003cp\u003eN/A. It is not possible to implement emergency unblinding in our trial since both the participants and rehabilitation trainers are not blinded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlans for assessment and collection of outcomes {18a}\u003c/p\u003e\n\u003cp\u003ePrior to the study\u0026apos;s initiation, the recruiting doctors, physical therapists, and assessors will be trained to check the relevant equipment to ensure the research\u0026apos;s quality, and will take the following steps:\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e1. The doctor responsible for recruiting will have a thorough understanding of the experimental process.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e2. The therapists will receive training on conducting the program and handling potential adverse events during the training.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e3. The assessors will receive training on how to standardize the use of EEG signal acquisition equipment and guide patients to undergo MRI scans at the hospital imaging department.\u003cbr\u003e\u003c/span\u003e\u003cspan\u003e4. The data administrator will be trained on managing Case Report Form (CRF) and storing electronic data of EEG and MRI.\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003ePlans to promote participant retention and complete followup {18b}\u003c/p\u003e\n\u003cp\u003eThe follow-up assessment will be scheduled to take place 4 weeks after the training program ends. Participants will receive a phone call inviting them to the hospital for the assessment.\u003c/p\u003e\n\u003cp\u003eData management {19}\u003c/p\u003e\n\u003cp\u003eIn order to ensure the integrity and quality of the clinical data, the CRF documentation process will be utilized. Each patient will have their own CRF monitored by a third party and overseen by a skilled researcher.\u003c/p\u003e\n\u003cp\u003eConfidentiality {27}\u003c/p\u003e\n\u003cp\u003eThroughout all stages of the trial, personal information of potential and registered participants will be collected and maintained in accordance with the confidentiality agreement. Prior to commencing, informed consent will be obtained from each participant, outlining the purpose, procedures, and risks involved in the study. Throughout the experiment, all gathered data will be anonymized and stored securely, with only authorized individuals overseeing data analysis and trial supervision having access. After the experiment is completed, all personal information will be maintained according to strict protection protocols. All identifiable data, such as specific protocol codes, will be retained for the designated period in a secure archival manner as required by governing confidentiality and data protection agencies and regulatory directives.\u003c/p\u003e\n\u003cp\u003ePlans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/p\u003e\n\u003cp\u003eN/A. Biological specimens are not relevant to our trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/p\u003e\n\u003cp\u003eDisplay of baseline data: Quantitative data with a normal or approximately normal distribution will be presented as the means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations. Data not normally distributed or showing heterogeneous variances will be expressed as medians (interquartile ranges or total ranges). Categorical data will be denoted as the number of cases (percentages).\u003c/p\u003e\n\u003cp\u003eThe scale and demographic data will be preprocessed and analyzed using \u003cem\u003ePython 3.7.4\u003c/em\u003e software. Data preprocessing will be done using \u003cem\u003eNumPy\u003c/em\u003e and \u003cem\u003ePandas\u003c/em\u003e, while statistical analysis will be conducted using \u003cem\u003eStatsmodels\u003c/em\u003e. Visualization of the results will be achieved through \u003cem\u003eMatplotlib\u003c/em\u003e and \u003cem\u003eSeaborn\u003c/em\u003e. For quantitative data with a normal or near-normal distribution, a repeated measures mixed ANOVA will be used to analyze between-group differences and temporal changes across two groups. The Mann‒Whitney U test will be used to compare two datasets of quantitative data that do not follow a normal distribution. Categorical data will be evaluated via Fisher\u0026rsquo;s exact test or the chi-square test, as appropriate. Continuous data will be analyzed using Pearson Correlation Coefficient, while ordinal data will be analyzed using Spearman\u0026apos;s Rank Correlation Coefficient. Ordinal data will be analyzed using either Spearman\u0026apos;s Rank Correlation Coefficient or Kendall\u0026apos;s Tau.\u003c/p\u003e\n\u003cp\u003eWe will employ methods including connectivity analysis, time-frequency analysis, and time-domain analysis to analyze the TMS‒EEG data. EEG time-frequency analysis, time domain analysis, and functional connectivity metrics will be statistically analyzed using the \u003cem\u003eEEGLAB\u003c/em\u003e and \u003cem\u003eFieldTrip\u003c/em\u003e toolboxes in \u003cem\u003eMATLAB\u003c/em\u003e. Statistical analysis of MRI data will be conducted using the SPM12 toolbox in \u003cem\u003eMATLAB\u003c/em\u003e. In the analyses performed, a p value of less than 0.05 will be considered indicative of statistically significant differences. Bonferroni correction will be employed to control the inflation risk of Type I errors due to multiple subgroup comparisons. 95% confidence intervals will be presented for the estimates.\u003c/p\u003e\n\u003cp\u003eInterim analyses {21b}\u003c/p\u003e\n\u003cp\u003eThe interim analysis will be performed after half of the sample size is reached, in order to monitor outcomes and verify the trial process.\u003c/p\u003e\n\u003cp\u003eMethods for additional analyses (e.g., subgroup analyses) {20b}\u003c/p\u003e\n\u003cp\u003eN/A. No additional analyses beyond the primary and secondary outcomes will be conducted for the study.\u003c/p\u003e\n\u003cp\u003eMethods in analysis to handle protocol nonadherence and any statistical methods to handle missing data {20c}\u003c/p\u003e\n\u003cp\u003eData analysis will utilize the intention-to-treat analysis (ITT) approach. In case of missing data, the last observation carried forward method will be used.\u003c/p\u003e\n\u003cp\u003ePlans to give access to the full protocol, participantlevel data, and statistical code {31c}\u003c/p\u003e\n\u003cp\u003eThe current study data and statistical code will be available upon reasonable request from the corresponding author, and the complete protocol can be obtained from the same correspondence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComposition of the coordinating center and trial steering committee {5d}\u003c/p\u003e\n\u003cp\u003eThe Hospital Safety Supervision Committee has been tasked with monitoring the project. Its main responsibilities include evaluating the experimental design, scientific rigor, and procedural integrity throughout the research process, as well as ensuring participant safety, adherence to medical ethics, and proper management and handling of collected data. The Trial Steering Committee will hold meetings to assess the availability of suitable research subjects and oversee critical stages of the trial initiation. Additional meetings will be arranged at intervals corresponding to the data collection points. Each committee will offer comprehensive support for the trial, encompassing early, late, and follow-up assessments to promote robust data collection and analysis.\u003c/p\u003e\n\u003cp\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/p\u003e\n\u003cp\u003eData entry will be conducted by two separate researchers to allow for cross-checking the accuracy of the input data.\u003c/p\u003e\n\u003cp\u003eAdverse event reporting and harms {22}\u003c/p\u003e\n\u003cp\u003eEarlier studies have shown that active iTBS stimulation can cause manic or hypomanic symptoms in only a few patients, with no other adverse events reported[38]. Researchers will inform participants of potential adverse events with informed consent and will document any adverse events that occurred during the study. If such events are observed, their frequency will be analyzed between the two groups. If patients have any questions about symptoms or need further information, they will be able to contact the attending physician by phone or email.\u003c/p\u003e\n\u003cp\u003eFrequency and plans for auditing trial conduct {23}\u003c/p\u003e\n\u003cp\u003eThe project management team will hold regular meetings to assess the progress of the trial and compliance with the trial protocol, with meetings scheduled monthly. In addition, the trial steering committee and ethics committee will play a crucial role in ongoing monitoring and review. These bodies will be responsible for overseeing the conduct of the trial, ensuring the well-being of participants, and maintaining data integrity throughout the trial. This structured approach will ensure active monitoring and adherence to established ethical and regulatory standards throughout the trial.\u003c/p\u003e\n\u003cp\u003ePlans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}\u003c/p\u003e\n\u003cp\u003eWe will communicate in a timely manner with funding agencies through structured notifications. Subsequently, the Principal Investigator (PI) will inform each coordinating center and ensure the revised protocol is distributed promptly. The PI will receive a copy of the updated protocol to include in the investigator site file. We will meticulously document any deviations from the established protocol by completing a violation report form. The clinical trial registry will be diligently updated to accurately reflect the modified procedures. This rigorous approach is crucial for maintaining transparency and accuracy in clinical trial management, complying with regulatory standards, and preserving the integrity of the research process.\u003c/p\u003e\n\u003cp\u003eDissemination plans {31a}\u003c/p\u003e\n\u003cp\u003eThe dissemination plan includes specific strategies to communicate the trial results to healthcare professionals and the public, with findings being disseminated through conference presentations, peer-reviewed journal publications, medical forums, and other channels.\u003c/p\u003e\n\u003cp\u003eEthics and trial registration {24}\u003c/p\u003e\n\u003cp\u003eThis study received ethical approval from the Ethics Committee of the Second Hospital of Kunming Medical University (Shen-PJ-Ke-2022-2) and was registered under the Chinese Clinical Trial Registry system with the registration number ChiCTR2200058553.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eGiven the cerebellum's extensive connections with cortical regions involved in motor, associative, and emotional functions, the CTC pathway shows promising potential as a target for innovative noninvasive brain stimulation techniques. Hence, the cerebellar vermis will be selected as our intervention target, given its involvement in emotional regulation and postural control. The aim of this research is to confirm the effectiveness of combining Stroop visual task with iTBS stimulation of the cerebellar vermis in improving the emotions and balance function of stroke patients, as well as to validate the shared circuit effect of the cerebellum in regulating emotions and balance. Moreover, we hypothesize that combining cerebellar iTBS stimulation with emotion-related visual Stroop tasks may improve mood disorders in stroke patients and regulate balance impairments, thereby promoting overall functional recovery in stroke survivors.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTimeline\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePatients will be recruited between May 2023 and August 2025. The study is expected to be completed in November 2025. Data analysis, writing of the scientific manuscript and submission to peer-reviewed scientific journals will take place from January 2026. A summary of the study outline is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePSD: Poststroke depression\u003c/p\u003e\n\u003cp\u003eCTC: Cerebellar-thalamus-cortical\u003c/p\u003e\n\u003cp\u003eACC: Anterior cingulate cortex\u003c/p\u003e\n\u003cp\u003eMCA: Middle cerebral artery\u003c/p\u003e\n\u003cp\u003eDLPFC: Left dorsolateral prefrontal cortex\u003c/p\u003e\n\u003cp\u003erTMS: Repetitive transcranial magnetic stimulation\u003c/p\u003e\n\u003cp\u003eiTBS: Intermittent theta burst stimulation\u003c/p\u003e\n\u003cp\u003eCRF: Case Report Form\u003c/p\u003e\n\u003cp\u003eHAMD: Hamilton Depression Rating Scale\u003c/p\u003e\n\u003cp\u003eBBS: Berg Balance Scale\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eWe thank all of the clinicians and clinical supervisors who provided and supervised the therapy and clinical care.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Authors\u0026rsquo; contributions {31b}\u003c/p\u003e\n\u003cp\u003eConceptualization: ZHC, LQY, XY, and YZ. Methodology: ZHC, XY, HTW, XCL. Formal analysis: ZHC, XY,YZ. Investigation: ZHC, LQY, XY, QL, HMZ, XCL, and HTW. Resources: ZHC, LQY, XY, YZ, HTW, XCL, and QL. Data curation: ZHC, XY. Writing\u0026mdash;original draft preparation: ZHC, XY, QL, HMZ. Writing\u0026mdash;review and editing: ZHC, XY, HMZ, and QL. Visualization; ZHC, XY. Supervision: LQY, XY. Project administration: LQY, XY, QL, HMZ. All the authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Funding{4}\u003c/p\u003e\n\u003cp\u003eDoctoral research project of the Second Affiliated Hospital of Kunming Medical University (Grant number 2023BS01).\u003c/p\u003e\n\u003cp\u003eConsent for publication {32}\u003c/p\u003e\n\u003cp\u003eAll the authors read the manuscript and approved the publication.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Competing interests {28}\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Roles and responsibilities: sponsor and funder {5c}\u003c/p\u003e\n\u003cp\u003eThis research will be funded by the Second Affiliated Hospital of Kunming Medical University. The sponsor and funder will participate in discussions at the design stage but will not intervene in core scientific or methodological issues. During data collection, management, and analysis, the research team will remain independent. The sponsors and funder will not participate in specific data processing or analysis. For data interpretation, the research team will communicate with them, but the final interpretation rights will belong to the research team. The research team will have full autonomy in report writing and publication, and the sponsors and funder will not influence the content or publication decisions. The research team will be fully responsible for the authenticity and scientific validity of the results, and the sponsors and funder will not assume any legal liability for any consequences arising from the research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWafa HA, Wolfe CDA, Emmett E, Roth GA, Johnson CO, Wang Y: \u003cstrong\u003eBurden of Stroke in Europe: Thirty-Year Projections of Incidence, Prevalence, Deaths, and Disability-Adjusted Life Years\u003c/strong\u003e. \u003cem\u003eStroke \u003c/em\u003e2020, \u003cstrong\u003e51\u003c/strong\u003e(8):2418-2427.\u003c/li\u003e\n\u003cli\u003eGhrouz A, Guillen-Sola A, Morgado-Perez A, Mu\u0026ntilde;oz-Redondo E, Ram\u0026iacute;rez-Fuentes C, Curbelo Pe\u0026ntilde;a Y, Duarte E: \u003cstrong\u003eThe effect of a motor relearning on balance and postural control in patients after stroke: An open-label randomized controlled trial\u003c/strong\u003e. \u003cem\u003eEuropean stroke journal \u003c/em\u003e2024, \u003cstrong\u003e9\u003c/strong\u003e(2):303-311.\u003c/li\u003e\n\u003cli\u003eMitchell AJ, Sheth B, Gill J, Yadegarfar M, Stubbs B, Yadegarfar M, Meader N: \u003cstrong\u003ePrevalence and predictors of post-stroke mood disorders: A meta-analysis and meta-regression of depression, anxiety and adjustment disorder\u003c/strong\u003e. \u003cem\u003eGeneral hospital psychiatry \u003c/em\u003e2017, \u003cstrong\u003e47\u003c/strong\u003e:48-60.\u003c/li\u003e\n\u003cli\u003eKhan F, Chevidikunnan MF: \u003cstrong\u003ePrevalence of Balance Impairment and Factors Associated with Balance among Patients with Stroke. 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FE, Luan L, Kettner H, Martell J, Erritzoe D, Tagliazucchi E, Pallavicini C\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eHuman brain effects of DMT assessed via EEG-fMRI\u003c/strong\u003e. \u003cem\u003eProceedings of the National Academy of Sciences of the United States of America \u003c/em\u003e2023, \u003cstrong\u003e120\u003c/strong\u003e(13):e2218949120.\u003c/li\u003e\n\u003cli\u003eTscherpel C, Mustin M, Massimini M, Paul T, Ziemann U, Fink GR, Grefkes C: \u003cstrong\u003eLocal neuronal sleep after stroke: The role of cortical bistability in brain reorganization\u003c/strong\u003e. \u003cem\u003eBrain stimulation \u003c/em\u003e2024, \u003cstrong\u003e17\u003c/strong\u003e(4):836-846.\u003c/li\u003e\n\u003cli\u003eAyerbe L, Ayis S, Rudd AG, Heuschmann PU, Wolfe CD: \u003cstrong\u003eNatural history, predictors, and associations of depression 5 years after stroke: the South London Stroke Register\u003c/strong\u003e. \u003cem\u003eStroke \u003c/em\u003e2011, \u003cstrong\u003e42\u003c/strong\u003e(7):1907-1911.\u003c/li\u003e\n\u003cli\u003eBasavaraju R, Ithal D, Ramalingaiah AH, Thirthalli J, Mehta UM, Kesavan M: \u003cstrong\u003e\u0026quot;Apathetic to hypomanic/manic\u0026quot;: A case series-illustration of emergent mood symptoms during intermittent theta burst stimulation (iTBS) of cerebellar vermis in schizophrenia with predominant negative symptoms\u003c/strong\u003e. \u003cem\u003eSchizophrenia research \u003c/em\u003e2020, \u003cstrong\u003e222\u003c/strong\u003e:501-502.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"iTBS, cerebellum, emotion-word Stroop, poststroke depression","lastPublishedDoi":"10.21203/rs.3.rs-5170397/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5170397/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePatients with stroke often experience both balance issues and poststroke depression (PSD), which can potentially influence each other. Despite incomplete knowledge of the specific mechanisms, the cerebellum plays a role in emotions and balance, which could be linked via the cerebellar-thalamus-cortical (CTC) pathway. Therefore, the cerebellum may serve as a common target for regulating emotional and balance functions post-stroke. Therefore, the aim of this study is to evaluate the efficacy of utilizing a combination of Stroop visual task and iTBS stimulation of the cerebellar vermis in enhancing emotions and balance function in stroke patients.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e\u003cp\u003e160 patients diagnosed with middle cerebral artery (MCA) infarction and post-stroke depression (PSD) will be randomly assigned to one of four groups: Group A (active iTBS of the cerebellar vermis with active Stroop training), Group B (sham iTBS with active Stroop training), Group C (active iTBS and sham Stroop training), and Group D (sham iTBS with sham Stroop training). The total intervention period will be two weeks. The primary outcome measures were evaluated using the Hamilton Depression Rating Scale (HAMD) and Berg Balance Scale at four different time points: baseline (T0), after five treatment sessions (T1), after ten treatment sessions (T2), and 4 weeks post-treatment (T3) during the follow-up period. The secondary outcomes will include EEG spectral analysis and MRI connectivity. Adverse effects will also be monitored to assess the safety of the intervention.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e\u003cp\u003eBy combining cerebellar iTBS with the emotional Stroop task, stroke patients may experience a simultaneous improvement in emotions and balance, with the enhancement being mediated through the same pathway as cerebellar TMS, specifically CTC.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e\u003cp\u003eNCT direct link: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.chictr.org.cn/\u003c/span\u003e\u003cspan address=\"https://www.chictr.org.cn/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e ChiCTR2200058553. Registered in April 2022. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences (Protocol version 1.0\u0026ndash;20240709).\u003c/p\u003e","manuscriptTitle":"Cerebellar iTBS Combined With Emotional Stroop Task for Post-Stroke Depression: Randomized Controlled Trial Protocol From Kunming, China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-14 11:24:56","doi":"10.21203/rs.3.rs-5170397/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4c8525a-26aa-4a7a-9941-ff0f5f0807b3","owner":[],"postedDate":"July 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-29T11:33:37+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-14 11:24:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5170397","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5170397","identity":"rs-5170397","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}