The Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) on Perioperative Neurocognitive Disorders in Patients after Cardiac Surgery: Study Protocol for a Randomized Controlled Trial

The Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) on Perioperative Neurocognitive Disorders in Patients after Cardiac Surgery: Study Protocol for a Randomized Controlled Trial | 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 The Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) on Perioperative Neurocognitive Disorders in Patients after Cardiac Surgery: Study Protocol for a Randomized Controlled Trial Jing Wang, Xuyang Wang, Sijie Li, Jinrong Yang, Xiang Yan, Jie Gao, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3298051/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Jul, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Introduction : Perioperative neurocognitive disorders(PND)is one of the most common postoperative complications among elderly patients (above 65 years old) undergoing cardiac surgery. However, thus far, there have not been any effective therapies for managing PND. Recent research has shown that repetitive transcranial magnetic stimulation (rTMS) alters brain plasticity and improves cognitive function in several neurodegenerative disorders and psychiatric disorders. However, the potential benefits of rTMS in reducing PND in patients undergoing cardiac surgery have not been investigated. Therefore, the current protocol is designed to determine whether rTMS can reduce the incidence of PND in patients undergoing cardiac surgery. Methods and analysis : The study will be a single-blinded, randomized controlled trial. Participants undergoing elective cardiac surgery will be randomized to receive either rTMS or sham stimulation with a focal figure of eight coils over the right dorsolateral prefrontal cortex. A series of neuropsychological tests will be completed to evaluate cognitive function in surgery patients before, on day 7, and on day 30 after cardiac surgery. The primary outcome is the prevalence of PND in cardiac surgery patients. The secondary outcomes will be the incidence of postoperative delirium, pain, sleep quality, depressive symptoms, activities of daily living, length of hospital stay and ICU length of stay, and rate of complication and mortality during the hospital stay. Ethics and dissemination : Beijing Chaoyang Hospital Ethics Committee approved this study and has number 2022-ke-487. It is registered with Clinical Trials (trial number NCT 05668559). Informed consent must be provided by all participants. The study result will be published in a peer-reviewed journal. Trial registration number : NCT05668559 clinical trials Perioperative neurocognitive disorders(PND) transcranial magnetic stimulation (TMS) psychiatry protocol Figures Figure 1 Figure 2 Figure 3 Introduction There is a relatively high incidence of perioperative neurocognitive disorders(PND) after surgeries, which are characterized by impairments in memory, learning, and attention( 1 – 3 ). The incidence of PND in elderly patients (above 65 years old) has been reported as 9 ~ 46% and increases with age( 4 , 5 ). Compounding this, the incidence is even higher in the geriatric population undergoing cardiac surgery( 6 ). As a result of PND, patients are more likely to die from the condition, suffer from long-term cognitive decline and dementia, and end up requiring multiple hospital stays( 4 ). In addition, it is one of the fastest-growing public health problems with huge financial burdens( 7 ). There is confusion as to what causes PND, but the etiology is widely believed to be multiple. Several predisposing factors have been identified, including old age, concomitant medical conditions like diabetes mellitus, and neurological disorders( 8 – 10 ). Etiology can also be categorized based on potential pathophysiologic processes, including inflammation( 11 – 13 ), neuronal damage( 14 ), vascular damage/embolism( 15 , 16 ), cerebral autoregulation and oxygen delivery( 17 , 18 ), neurodegenerative disease pathology, and brain network dysfunction( 19 , 20 ). However, inflammatory responses triggered by surgery and anesthesia contribute significantly to PND. Also, A significant impairment in executive function was observed following cardiac surgery, which may be caused by decreased functional connectivity of executive control networks and their anticorrelation with default mode networks( 20 ). This appears to indicate that inflammation may be responsible for these transient changes in FC and executive function impairments. However, there are currently few effective treatments for PND. Therefore, it is essential to identify effective interventions to treat or prevent PND. It has been shown that brain stimulation can improve cognitive function in mild cognitively impaired patients( 21 ). The repetitive transcranial magnetic stimulation (rTMS) technique is a noninvasive method of modulating the excitability of the cortex that has been widely used to study brain activity( 22 ). Researchers can investigate the properties and organization of neural function using rTMS, which has the ability to alter brain plasticity( 23 – 25 ). A significant increase in connectivity has been observed with low-frequency rTMS applied to the right dorsolateral prefrontal cortex (DLPFC) in previous studies. Furthermore, it appeared to steer functional brain network reconfiguration which was associated with an increase in cognitive abilities( 26 , 27 ). Previous research has confirmed that the rTMS can improve cognitive function in multiple diseases or dysfunctions, including anxiety disorders, major depressive disorder, sleep disorders, and so on. In light of the fact that rTMS may improve cognitive abilities, rTMS might be an effective intervening technique to prevent or treat PND in patients. Therefore, the current protocol is designed to conduct a randomized controlled single-blind study in participants undergoing elective cardiac surgeries to determine whether rTMS can reduce the incidence of PND in this patient population. Secondarily, we aim to explore the underlying mechanisms behind the efficacy. We hypothesize that postoperative rTMS intervention will reduce the incidence of PND. Methods/design Study Design A randomized, controlled single-center study was conducted at Beijing Chaoyang Hospital affiliated with Capital Medical University. 174 patients undergoing elective cardiac surgery will be recruited and randomly (1:1) assigned to either the rTMS group or the control group (sham rTMS). Studies included in this review selected the right DLPFC (RDLPFC) as the target for stimulation almost universally. A series of evaluations will be conducted before the intervention, within 7 days after surgery, and 30 days after surgery. SPIRIT recommendations were followed for the protocol study. See the additional file for the SPIRIT checklist. The overall study design is illustrated in Fig. 1 , and the study schedule is presented in Fig. 2 . Ethical Considerations/Guidelines Beijing Chaoyang Hospital Ethics Committee approved this study and has number 2022-ke-487. It is registered with Clinical Trials (trial number NCT05668559). Informed consent must be provided by all participants. The study result will be published in a peer-reviewed journal. Study population Inclusion and Exclusion Criteria Inclusion criteria are: Age 18 years or older. ASA class I – III, patients undergoing elective cardiac surgery (coronary artery bypass grafting, aortic or mitral valve surgery). Having a normal cognitive function at the time of enrolment with a Mini-Mental State Examination (MMSE) score equal to or above 24, and a Montreal Cognitive Assessment (MOCA)score equal to or above 26. Using Mandarin as their native language. Sign the informed consent. Able to complete follow-up visits. Exclusion criteria are: A history of psychopathology and/or taking medication. Previous history of neurological disease. Having severe organic diseases. Having rTMS contraindications( 28 ) (such as a history of epileptic seizures, and metal implants near the head). Having delirium, assessed by CAM, before surgery. Participating in other clinical studies at the time of screening. Having a severe hearing or visual impairment. Having a cardiopulmonary arrest and cardiopulmonary resuscitation. Having a short-term second operation. Randomization and allocation concealment Randomization and allocation will be carried out by an independent researcher at the beginning of the study. An independent statistician from the Center of Evidence-Based Medicine will generate the randomized number and sequence using SPSS Version 25, and they will not participate in assessments or execution in this trial. Blinding As soon as consent was obtained, eligibility was established, and baseline assessments completed, the technician received the corresponding envelope of the participant's ID before the first rTMS session. The clinical research coordinator who administers the rTMS will open the sealed envelope containing the allocation and randomization number 1 day before the intervention. Another research assistant who is blinded to the randomization and allocations will perform the assessments on the participants. Next, statistical analysis was completed by an independent research statistician following the completion of the trial. Study Process Study Intervention Description Each participant is required to receive all five sets of stimulations from postoperative day 1 to postoperative day 5. Data from participants who fail to accept the minimum stimulations for any reason will be used for intention-to-treat analysis. rTMS will be applied using a commercially available magnetic stimulator (YRD CCY-I, Wuhan Yiruide Medical Equipment, Wuhan, China) equipped with 70-mm figure-of-eight coils. Before joining the experiment, all subjects should undergo a diagnosis from a neuro-rehabilitation or neurology department to ensure that they are suitable. Stimulation schedule: According to previous studies, intermittent theta burst continuous TBS (cTBS) of the right DLPFC are safe and feasible strategies for patients( 29 , 30 ), therefore, we adapt this model of rTMS stimulation. The cTBS mode consists of a cluster stimulus delivered every 0.2 seconds (5 Hz), with each cluster stimulus consisting of three burst stimuli with a 50 Hz body frequency (Fig. 2 ). The duration of a single stimulus was approximately 40 seconds, for a total of 600 pulses. Stimulation takes place in the right dorsolateral prefrontal cortex (RDLPFC). Additionally, all interventions will be performed by qualified therapists, and the responses of the subjects will be recorded. Active rTMS Group A stimulation set will be administered to each participant in the rTMS group per day. Active treatment will be delivered over the right DLPFC at 100% of the resting motor threshold. On postoperative days 1 to 5, or the day of discharge, the stimulation set will be given at 9:00–10:00 every day. Sham Stimulation Group In the sham stimulation group, there will be no stimulation. Sham stimulation uses the same protocol (600 pulses per session, 3 sessions per set, ISI ≥ 30 min, 3 sets). Sham stimulation uses a coil placed vertically to the skull, whereas actual stimulation uses a coil placed centrally over the right DLPFC. As for the stimulation time points, they will be the same as those of the rTMS group. To improve participant adherence, we have contacted attending surgeons anesthesiologists, and other staff to obtain their research support. We will provide detailed information about research-related issues during recruitment, consultation, hospitalization, and follow-up to improve adherence. Measurements There is a detailed breakdown of all study assessments and timeframes in Fig. 3 . Below are a few brief descriptions of the assessments: Baseline Preoperative Visits Baseline assessments are conducted in the Cardiovascular Surgery Ward. Demographic information, past medical history, medication history, baseline laboratory tests, electrocardiography, and imaging examination are collected from electronic medical records. Vital signs (e.g., blood pressure, heart rate, blood oxygen saturation, respiratory rate) are recorded from the monitor. MMSE and MOCA scores are assessed before operation. When the MMSE score is greater than 24 and the MOCA score is greater than 26, the patient meets the inclusion criteria. A 32-channel EEG cap was used to record the baseline EEG activity. The schedule of the planned investigation is presented in Fig. 2 . Intraoperative Protocols Participants enrolled in this trial are sent to the operating room on the surgery day and monitored with blood pressure, electrocardiography, and oxygen saturation. Oxygen is given by mask and an intravenous line is established. Perform radial artery cannulation to monitor arterial pressure. The dose and infusion rate of anesthetic drugs are adjusted by anesthesiologists according to age, general conditions, complications, blood pressure, and surgical needs. The partial pressure of end-tidal carbon dioxide is maintained between 35 to 45 mmHg. Blood pressure is monitored every 5 minutes. The last recorded blood pressure before the operation is defined as the baseline blood pressure. Vasoactive drugs (e.g., epinephrine, norepinephrine, ephedrine, or isosorbide mononitrate) are given to participants to maintain blood pressure as appropriate. Hemodynamic and ventilation abnormalities (e.g., hypertension, hypoxemia), and vasoactive drugs are recorded during the operation. We have emergency medicine on hand to treat symptoms promptly. Primary outcome measurement The incidence of PND on day 30 post-surgery. PND will be defined according to MMSE and MOCA, which can evaluate various cognitive functions including attention, motor skills, executive function, learning, and memory. Patients were tested using the MMSE and MOCA scale on preoperative day 1, postoperative day 7, and postoperative day 30 to calculate their scores. During the testing process, it is important to ensure that the patient does not experience any physical discomfort and that only the patient and the tester are present. Use unified explanatory standards to ensure that patients have fully understood the test before testing. To reduce the learning effect of repeated neuropsychological tests in this study, we also recruited 40 controls who did not receive surgery. They are usually family members of patients, and their age is similar to patients. The inclusion and exclusion criteria for the control group are the same as for surgical patients. Patients and volunteers were given neuropsychological tests on the same day. By comparing the changes in test scores between each patient and the control group of healthy volunteers, learning outcomes can be alleviated, thereby identifying patients with postoperative cognitive impairment. We evaluated the changes in the postoperative cognitive function status of patients based on the Z-score of the International Postoperative Cognitive Dysfunction Research Group 1 (ISPOCD1) and calculated the difference between the scores of the patient and healthy volunteers before and after the test, including the difference between the preoperative scale scores and the test scores on the 7th, and 30th days after the surgery. The average difference per person in the healthy volunteer group is the learning effect (△X) and its standard deviation (SD△X) is calculated. For each patient, subtract △X from the difference in each test scale and divide the result by the corresponding SD△X for the healthy volunteer group to obtain the Z-score for each individual. When the Z-scores of both scales are 1.96 or higher, it is considered that the patient has experienced delayed postoperative cognitive function recovery. Z=△Xi-△X/SD△X Secondary outcomes 1. Postoperative delirium incidence within 7 days after surgery. We will use the Confusion Assessment Method (CAM)(31), which offers four entries: inattention and disorganized thinking along with the altered level of consciousness and acute onset. A diagnosis of delirium requires both the first and second criteria, as well as the third and/or fourth criteria. Consequently, everyone will be assessed twice daily, the first time at 9:00–10:00 a.m. and the second time at 4:00–5:00 p.m. every day for 7 days postoperatively. Additionally, nurses on duty will refer to records to determine the incidence of postoperative delirium. 2. Perioperative pain within 7 days after surgery. Visual Analogue Scale (VAS) will be used to measure pain severity. Participants will be scored according to the intensity of their pain, from no pain (0) to most painful (10). 3. Sleep quality at postoperative day 7. We will use the Pittsburgh Sleep Quality Index (PSQI) to evaluate sleep quality. PSQI uses a 19-item questionnaire to assess sleep quality over one month. Each PSQI component score reflects a specific aspect of sleep, such as tardiness or efficiency at falling asleep. Based on the total component scores, the global PSQI is calculated. An increased score indicates poor quality sleep. The sum of the component scores represents the global PSQI. 4. Depressive symptom at postoperative day 7. Depressive disorder and depression symptom severity will be measured using the 9-item patient health questionnaire (PHQ-9). Generally, it is self-administered and carries a score ranging from 0 to 27, with a score range of 0 to 3. Five, ten, fifteen, and twenty are the thresholds for mild, moderate, and moderately severe depression (32). 5. Activities of daily living（ADL）at postoperative day 7, discharge, and postoperative day 30. As part of the pre-surgery and post-surgery evaluations, the Chinese version of the ADL scale will be used, including a Physical Self-Maintenance Scale and an Instrumental ADL scale. ADL consists of 14 items and the total score ranges between 14 and 56 points, with higher scores indicating a lower level of functioning. An impairment in ADL will be defined as a score above 22 points (the cut-off score)(33). 6. Length of hospital stay and ICU length of stay A hospital length of stay is the number of days the patient spends in the hospital following surgery. Similarly, the ICU length of stay was defined as the number of days the patient spent in the ICU before transferring to a general inpatient cardiac surgery ward. 7. Rate of complication and mortality during the hospital stay Every participant complication will be recorded to calculate the complication rate. Sample size calculation This study aims to examine the effectiveness of rTMS for cognitive function in people after cardiac surgery. There is about a 20%-46% incidence of PND 30 days after elective cardiac surgery, according to previous studies( 34 , 35 ). Nevertheless, no studies have investigated the effects of rTMS on PND. As rTMS significantly reduced the incidence of major depression by over half, we hypothesize that rTMS would reduce PND by up to half (from 40–20%) in our study. We, therefore, set bilateral α = 0.05 and β = 0.2. Applying PASS15.0 software, we calculated that 158 participants in each group would be necessary, and considering a 10% lost visit rate and random block length, the expanded sample size of two groups together required a sample size of 174 cases, 87 cases per group. Statistical analysis Intention to Treat Analysis Initially, the analysis will be based on the intent to treat principle (ITT) and then complemented by a per-protocol analysis (PP)( 36 ). The term non-compliance refers to patients who do not receive the intervention or placebo after randomization because their operation was canceled or they refused to participate on the day of surgery. A sensitivity analysis will be conducted to determine if non-compliance with the allocated arm will affect the analysis. Baseline Analyses As a baseline characteristic, continuous variables will be allocated as means with standard deviations (SDs) for normal distributions or medians with interquartile ranges (IQRs) for skewed distributions. Student’s t-test or Mann-Whitney U test for continuous variables was used to compare clinical characteristics between the two groups of patients, and for categorical variables, the χ2 test or Fisher exact test should be used. Primary Outcome Analysis We will compare the PND incidences in two groups using a χ2 test, and calculate a 95% CI for the difference. Secondary Outcome Analysis When analyzing secondary outcomes, we will use the Mann–Whitney U test for the length of hospital stay and ICU length of stay, as, the Fisher exact test for categorical variables, such as including the incidence of POD within 7 days after surgery, postoperative pain, sleep quality, depressive symptom, ADL and adverse events. The Cox proportional hazard model will be used to estimate the hazard ratio among patients in the rTMS group compared with those with sham rTMS while adjusting for potential confounding factors( 37 ). We will perform statistical analysis with SPSS 22.0 software (SPSS Inc, USA) using two-sided tests. A P value less than 0.05 constitutes statistical significance. Pre-set substudies The incidence of PND at postoperative day 30 served as our primary measure of the clinical effect of rTMS. Moreover, we collected data on EEG behavior and clinical outcomes. We encourage sub-studies derived from this trial, aiming to provide more insight into clinically relevant outcomes. (1) EEG behaviors and postoperative cognitive outcomes It has been suggested that neuromonitoring through electroencephalograms (EEGs) can reduce postoperative delirium and is recommended for every adult undergoing general anesthesia by the European Society of Anesthesiology( 38 ) and Intensive Care (ESAIC). However, EEG patterns are still inconclusive in predicting and detecting postoperative neurological outcomes ( 39 , 40 ). Since EEG data (including BIS and 32-channel EEG) is collected on baseline, intraoperative, and postoperative days, this study allows for this investigation. We are interested in exploring the association between EEG behaviors and postoperative outcomes (such as postoperative delirium and neurocognitive impairment results). (2) Depression symptoms during perioperative surgery Major surgery can cause depression symptoms, which can negatively impact the quality of life and even mortality ( 41 , 42 ). At postoperative day 7 depression symptoms will be assessed, and risk factors, pain, and general health status will be evaluated as potential mechanisms. (3) Sleep quality and postoperative outcomes Patients undergoing surgery may experience sleep disturbances during their recovery, which can contribute to delayed recovery( 43 , 44 ). An assessment of the effects of preoperative insomnia on postoperative outcomes will be conducted in this study. Safety and adverse event reporting Researchers will notify the principal investigator of any adverse events during the study as soon as possible, and the principal investigator and research doctor will jointly decide how to proceed. The following adverse events will be reported: those possibly related to the rTMS, such as headache, dizziness, decreased sleep quality, and serious events, including death and life-threatening events. In the event of a serious adverse event, the main investigator, ethics committee, and relevant administrative departments will be informed within 24 hours and will be processed as soon as possible. Discussion In addition to posing an increased risk of long-term disability and mortality, PND is an important but often under-recognized complication( 5 , 45 ). Consequently, we need to find a treatment that is both effective and safe to reduce their incidence. Since RTMS is painless, noninvasive, and well-tolerated, it has become a popular treatment for psychiatric disorders( 46 ). The development of rTMS offers new opportunities for treating PND after cardiac surgery. A randomized single-blind clinical trial protocol was developed to investigate whether rTMS after cardiac surgery is more effective than sham rTMS at reducing the incidence of PND. Obtaining complete follow-up data is the main challenge of this study. Under the influence of COVID-19, several patients were unable to attend their reviews on time due to their respective occupations. Thus, it is uncertain whether we will be able to reach all participants 30 days after surgery to obtain the primary outcome measure for all participants. The sample size seems reasonable based on previous studies. In the event that dropout rates are too high, we will notify the IRB and recruit participants as per protocol. We believe this is the first randomized, controlled trial evaluating the effects of rTMS on the treatment of PND after cardiac surgery. In addition, several neurocognitive as well as 32-channel EEG measures will be examined in this study to determine how rTMS induces its effects in individuals. This study has limitations that must be addressed. There is no double-blind control group, which could be a potential limitation. In all nonpharmacological studies, making everyone blind is not always possible ( 47 ). To eliminate the placebo effect of rTMS intervention, we set up a sham stimulation group. As well, the small sample size of participants and only one medical center may limit the generalizability of the results. Trial status The trial has not yet been recruited. Any amendments made to the protocol will be submitted to and approved by the Beijing Chaoyang Hospital IRB. The trial is registered with Clinical Trials (trial number NCT 05668559). The first registration was completed on June 6, 2022. The trial recruitment is planned to start on October 1, 2023, and the recruitment of subjects is planned to be completed on April 1, 2026.The current version of protocol is V1.0. Strengths and limitations of this study This is a prospective, randomized clinical trial, which provides the best clinical evidence and support for repetitive transcranial magnetic stimulation (rTMS) as an intervention to bring down the incidence of perioperative neurocognitive disorders. Using two cognitive scales that can fully reflect the changes in cognitive function of patients before and after surgery. A multi-channel (32-channel) EEG was attempted to explore the EEG characteristics changes of patients before and after surgery. The small sample size of this single-center study limited the study design. The results of this study may not apply to other institutions since it was conducted at a single location. Declarations Funding This project is supported by the Multidisciplinary Clinical Research Innovation Team Program of Beijing Chao-Yang Hospital, Capital Medical University (CYDXK202210). The funding institutions have no influence on the design of the study, execution, management, interpretation of the data, or deciding to submit the manuscript for publication. Ethics approval and consent to participate Beijing Chaoyang Hospital Ethics Committee approved this study and has number 2022-ke-487. It is registered with Clinical Trials (trial number NCT05668559). Informed consent must be provided by all participants. The study result will be published in a peer-reviewed journal. Consent for publication I am attaching our manuscript entitled “The Effect of Transcranial Magnetic Stimulation (TMS) on Perioperative Neurocognitive Disorders in Patients after Cardiac Surgery: Study Protocol for a Randomized Controlled Trial”, which we would like to submit for publication as a study protocol in Trails. Availability of data and material All data generated or analyzed during this study are included in this published article Competing interests All authors disclosed no relevant relationships. Funding This project is supported by the Multidisciplinary Clinical Research Innovation Team Program of Beijing Chao-Yang Hospital, Capital Medical University (CYDXK202210). The funding institutions have no influence on the design of the study, execution, management, interpretation of the data, or deciding to submit the manuscript for publication. Authors' contributions Jing Wang and Xuyang Wang are responsible for writing the original draft. Sijie Li and Jinrong Yang are responsible for the visualization. Xiang Yan, Jie Gao, Xiuqin Jia, and Long Zuo are responsible for the validation. Anshi Wu is responsible for visualization. Changwei Wei is responsible for the conceptualization and editing of the draft. Acknowledgments This manuscript has not been published or presented elsewhere in part or entirety and is not under consideration by another journal. All study participants provided informed consent, and the study design was approved by the appropriate ethics review board. We have read and understood your journal’s policies and believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare. References Evered L, Silbert B, Knopman DS, et al. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. Br J Anaesth. 2018;121(5):1005–12. Androsova G, Krause R, Winterer G, et al. 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The absence of dominant alpha-oscillatory EEG activity during emergence from delta-dominant anesthesia predicts neurocognitive impairment- results from a prospective observational trial. J Clin Anesth. 2022;82:110949. Punjasawadwong Y, Chau-In W, Laopaiboon M, et al. Processed electroencephalogram and evoked potential techniques for amelioration of postoperative delirium and cognitive dysfunction following non-cardiac and non-neurosurgical procedures in adults. Cochrane Database Syst Rev. 2018;5(5):CD011283. Lee NK, Won SJ, Lee JY, et al. Presence of Night Pain, Neuropathic Pain, or Depressive Disorder Does Not Adversely Affect Outcomes After Total Knee Arthroplasty: A Prospective Cohort Study. J Korean Med Sci. 2022;37(43):e309. Soria-Utrilla V, Sanchez-Torralvo FJ, Gonzalez-Poveda I et al. Prevalence of Anxiety and Depression Symptoms and Their Relationship with Nutritional Status and Mortality in Patients with Colorectal Cancer. Int J Environ Res Public Health. 2022;19(20). Varallo G, Giusti EM, Manna C, et al. Sleep disturbances and sleep disorders as risk factors for chronic postsurgical pain: A systematic review and meta-analysis. Sleep Med Rev. 2022;63:101630. Rhon DI, Snodgrass SJ, Cleland JA, et al. Comorbid Insomnia and Sleep Apnea are Associated with Greater Downstream Health Care Utilization and Chronic Opioid Use after Arthroscopic Hip Surgery. Pain Physician. 2019;22(4):E351–60. Vu T, Smith JA. An Update on Postoperative Cognitive Dysfunction Following Cardiac Surgery. Front Psychiatry. 2022;13:884907. Bulteau S, Sebille V, Fayet G, et al. Efficacy of intermittent Theta Burst Stimulation (iTBS) and 10-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant unipolar depression: study protocol for a randomised controlled trial. Trials. 2017;18(1):17. Boutron I, Moher D, Altman DG, et al. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med. 2008;148(4):295–309. Supplementary Files SPIRIT.doc Cite Share Download PDF Status: Published Journal Publication published 24 Jul, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Major revision 29 Apr, 2024 Reviewers agreed at journal 30 Mar, 2024 Reviewers invited by journal 29 Mar, 2024 Editor assigned by journal 28 Mar, 2024 First submitted to journal 12 Mar, 2024 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. We do this by developing innovative software and high quality services for the global research community. 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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-3298051","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":285357382,"identity":"403ddd89-0974-475e-bd8d-6f02ddee8c86","order_by":0,"name":"Jing Wang","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Wang","suffix":""},{"id":285357383,"identity":"18f8b0c5-d7ae-4029-9e22-318d15e10e36","order_by":1,"name":"Xuyang Wang","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xuyang","middleName":"","lastName":"Wang","suffix":""},{"id":285357384,"identity":"9f989103-c60a-4553-8f7b-32aeb175b6f5","order_by":2,"name":"Sijie Li","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sijie","middleName":"","lastName":"Li","suffix":""},{"id":285357385,"identity":"0e6a61ca-39ce-4e91-b53c-fb9ecd1daebc","order_by":3,"name":"Jinrong Yang","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinrong","middleName":"","lastName":"Yang","suffix":""},{"id":285357386,"identity":"6dd7e103-c3f4-45ee-b335-46cb6fc7f84c","order_by":4,"name":"Xiang Yan","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Yan","suffix":""},{"id":285357387,"identity":"5b49de80-57db-4d09-98af-6bed6198253a","order_by":5,"name":"Jie Gao","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Gao","suffix":""},{"id":285357388,"identity":"a306e8ad-aeb9-468f-886d-91c088971c4c","order_by":6,"name":"XiuQin Jia","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":false,"prefix":"","firstName":"XiuQin","middleName":"","lastName":"Jia","suffix":""},{"id":285357389,"identity":"15e4a8c2-a244-461a-8c09-b4d94279145e","order_by":7,"name":"long Zuo","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":false,"prefix":"","firstName":"long","middleName":"","lastName":"Zuo","suffix":""},{"id":285357390,"identity":"0e406b95-5cc2-4007-987c-5d4c1990594f","order_by":8,"name":"Anshi Wu","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Anshi","middleName":"","lastName":"Wu","suffix":""},{"id":285357391,"identity":"015b61cb-5d91-4b34-9af0-d10e89ac03cb","order_by":9,"name":"Changwei Wei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYDACCQjFAyIOfEAVJELLwRmkaAEDZh5itPDPbn728GubjQyDRPLBwzY1dtEGB5gP3uZhsMvDacmdY+bGsm1pPAwSaQmHc44l5244wJZszcOQXIxLi4FEgpm05LbDPAzSOQaHcxsOALXwmEnzMBxIbMCpJf0bUMt/oJb8D4ctwVr4vxHQkmMm+XHbAZAtDIcZIbaw4dUicSOnTJrxXzIPm/wzg4M9QL/MPMxmbDnHIBmnFv4Z6dskf5yxs+fnOfz4w48au9y+480Pb7ypsMOpBQTA0cGG4IIdjEc9EDD+wC8/CkbBKBgFIx0AADLQU+K0+nbcAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-5652-600X","institution":"Beijing Chao-Yang Hospital Capital Medical University: Beijing Chaoyang Hospital","correspondingAuthor":true,"prefix":"","firstName":"Changwei","middleName":"","lastName":"Wei","suffix":""}],"badges":[],"createdAt":"2023-08-26 09:10:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3298051/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3298051/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-08988-3","type":"published","date":"2025-07-24T15:57:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":54036146,"identity":"d1f02bda-50eb-4d5d-b915-02113ecd8c02","added_by":"auto","created_at":"2024-04-03 17:01:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":218726,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chart. The present study is a randomized controlled trial. The enrolled participants will be randomized equally into two groups. After surgery, each participant will be allocated to receive sham or active stimulation. The incidence of the PND following rTMS or sham stimulation will be recorded and analyzed to determine potential differences between the two cohorts. cTBS, continuous theta burst stimulation; ISI, intersession interval; RMT, resting motor threshold.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3298051/v1/75b77f6d2474fc1274c30ffe.png"},{"id":54036145,"identity":"0f9b9739-ebfc-414c-971f-d09963f31be5","added_by":"auto","created_at":"2024-04-03 17:01:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":127386,"visible":true,"origin":"","legend":"\u003cp\u003eContinuous theta short burst fast pulse mode (cTBS) stimulation protocol\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3298051/v1/46606357318b04cac53b63f8.png"},{"id":54036148,"identity":"7b2725b5-d4f7-4e15-ad29-05804ee9f3dc","added_by":"auto","created_at":"2024-04-03 17:01:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":186186,"visible":true,"origin":"","legend":"\u003cp\u003eStudy Schedule. ADL, activities of daily living; BIS, bispectral index; CAM, Confusion Assessment Method; CAM-ICU, Confusion Assessment Method for intensive care unit; ICF, Informed Consent Form; MMSE, Mini-Mental State Examination; MOCA, Montreal Cognitive Assessment; PSQI， Pittsburgh sleep quality index; PHQ-9, Patient Health Questionnaire; rTMS, repetitive Transcranial Magnetic Stimulation; VAS, Visual Analogue Scale.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3298051/v1/8d746adce4ed7ff839ab6ac2.png"},{"id":87756606,"identity":"f31e8a91-3728-49aa-a73b-420aa3b80448","added_by":"auto","created_at":"2025-07-28 16:05:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1414585,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3298051/v1/50d5ac81-658c-4c83-a7f2-c7afd28a04e9.pdf"},{"id":54036147,"identity":"3c297add-9977-460c-baee-a745ff4d92c2","added_by":"auto","created_at":"2024-04-03 17:01:45","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":130016,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRIT.doc","url":"https://assets-eu.researchsquare.com/files/rs-3298051/v1/646c15af730884919b19e5a7.doc"}],"financialInterests":"","formattedTitle":"The Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) on Perioperative Neurocognitive Disorders in Patients after Cardiac Surgery: Study Protocol for a Randomized Controlled Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThere is a relatively high incidence of perioperative neurocognitive disorders(PND) after surgeries, which are characterized by impairments in memory, learning, and attention(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The incidence of PND in elderly patients (above 65 years old) has been reported as 9\u0026thinsp;~\u0026thinsp;46% and increases with age(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Compounding this, the incidence is even higher in the geriatric population undergoing cardiac surgery(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). As a result of PND, patients are more likely to die from the condition, suffer from long-term cognitive decline and dementia, and end up requiring multiple hospital stays(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In addition, it is one of the fastest-growing public health problems with huge financial burdens(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere is confusion as to what causes PND, but the etiology is widely believed to be multiple. Several predisposing factors have been identified, including old age, concomitant medical conditions like diabetes mellitus, and neurological disorders(\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Etiology can also be categorized based on potential pathophysiologic processes, including inflammation(\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), neuronal damage(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), vascular damage/embolism(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), cerebral autoregulation and oxygen delivery(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), neurodegenerative disease pathology, and brain network dysfunction(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). However, inflammatory responses triggered by surgery and anesthesia contribute significantly to PND. Also, A significant impairment in executive function was observed following cardiac surgery, which may be caused by decreased functional connectivity of executive control networks and their anticorrelation with default mode networks(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). This appears to indicate that inflammation may be responsible for these transient changes in FC and executive function impairments. However, there are currently few effective treatments for PND. Therefore, it is essential to identify effective interventions to treat or prevent PND.\u003c/p\u003e \u003cp\u003eIt has been shown that brain stimulation can improve cognitive function in mild cognitively impaired patients(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The repetitive transcranial magnetic stimulation (rTMS) technique is a noninvasive method of modulating the excitability of the cortex that has been widely used to study brain activity(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Researchers can investigate the properties and organization of neural function using rTMS, which has the ability to alter brain plasticity(\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). A significant increase in connectivity has been observed with low-frequency rTMS applied to the right dorsolateral prefrontal cortex (DLPFC) in previous studies. Furthermore, it appeared to steer functional brain network reconfiguration which was associated with an increase in cognitive abilities(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Previous research has confirmed that the rTMS can improve cognitive function in multiple diseases or dysfunctions, including anxiety disorders, major depressive disorder, sleep disorders, and so on. In light of the fact that rTMS may improve cognitive abilities, rTMS might be an effective intervening technique to prevent or treat PND in patients.\u003c/p\u003e \u003cp\u003eTherefore, the current protocol is designed to conduct a randomized controlled single-blind study in participants undergoing elective cardiac surgeries to determine whether rTMS can reduce the incidence of PND in this patient population. Secondarily, we aim to explore the underlying mechanisms behind the efficacy. We hypothesize that postoperative rTMS intervention will reduce the incidence of PND.\u003c/p\u003e"},{"header":"Methods/design","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eA randomized, controlled single-center study was conducted at Beijing Chaoyang Hospital affiliated with Capital Medical University. 174 patients undergoing elective cardiac surgery will be recruited and randomly (1:1) assigned to either the rTMS group or the control group (sham rTMS). Studies included in this review selected the right DLPFC (RDLPFC) as the target for stimulation almost universally. A series of evaluations will be conducted before the intervention, within 7 days after surgery, and 30 days after surgery. SPIRIT recommendations were followed for the protocol study. See the additional file for the SPIRIT checklist. The overall study design is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, and the study schedule is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEthical Considerations/Guidelines\u003c/h2\u003e \u003cp\u003eBeijing Chaoyang Hospital Ethics Committee approved this study and has number 2022-ke-487. It is registered with Clinical Trials (trial number NCT05668559). Informed consent must be provided by all participants. The study result will be published in a peer-reviewed journal.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eInclusion and Exclusion Criteria\u003c/h2\u003e \u003cp\u003e \u003cb\u003eInclusion criteria\u003c/b\u003e are:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAge 18 years or older.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eASA class I \u0026ndash; III, patients undergoing elective cardiac surgery (coronary artery bypass grafting, aortic or mitral valve surgery).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving a normal cognitive function at the time of enrolment with a Mini-Mental State Examination (MMSE) score equal to or above 24, and a Montreal Cognitive Assessment (MOCA)score equal to or above 26.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eUsing Mandarin as their native language.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSign the informed consent.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAble to complete follow-up visits.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eExclusion criteria\u003c/b\u003e are:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eA history of psychopathology and/or taking medication.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePrevious history of neurological disease.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving severe organic diseases.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving rTMS contraindications(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) (such as a history of epileptic seizures, and metal implants near the head).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving delirium, assessed by CAM, before surgery.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eParticipating in other clinical studies at the time of screening.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving a severe hearing or visual impairment.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving a cardiopulmonary arrest and cardiopulmonary resuscitation.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving a short-term second operation.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eRandomization and allocation concealment\u003c/h2\u003e \u003cp\u003eRandomization and allocation will be carried out by an independent researcher at the beginning of the study. An independent statistician from the Center of Evidence-Based Medicine will generate the randomized number and sequence using SPSS Version 25, and they will not participate in assessments or execution in this trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBlinding\u003c/h2\u003e \u003cp\u003eAs soon as consent was obtained, eligibility was established, and baseline assessments completed, the technician received the corresponding envelope of the participant's ID before the first rTMS session. The clinical research coordinator who administers the rTMS will open the sealed envelope containing the allocation and randomization number 1 day before the intervention. Another research assistant who is blinded to the randomization and allocations will perform the assessments on the participants.\u003c/p\u003e \u003cp\u003eNext, statistical analysis was completed by an independent research statistician following the completion of the trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudy Process\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eStudy Intervention Description\u003c/h2\u003e \u003cp\u003eEach participant is required to receive all five sets of stimulations from postoperative day 1 to postoperative day 5. Data from participants who fail to accept the minimum stimulations for any reason will be used for intention-to-treat analysis.\u003c/p\u003e \u003cp\u003erTMS will be applied using a commercially available magnetic stimulator (YRD CCY-I, Wuhan Yiruide Medical Equipment, Wuhan, China) equipped with 70-mm figure-of-eight coils. Before joining the experiment, all subjects should undergo a diagnosis from a neuro-rehabilitation or neurology department to ensure that they are suitable.\u003c/p\u003e \u003cp\u003eStimulation schedule: According to previous studies, intermittent theta burst continuous TBS (cTBS) of the right DLPFC are safe and feasible strategies for patients(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), therefore, we adapt this model of rTMS stimulation. The cTBS mode consists of a cluster stimulus delivered every 0.2 seconds (5 Hz), with each cluster stimulus consisting of three burst stimuli with a 50 Hz body frequency (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The duration of a single stimulus was approximately 40 seconds, for a total of 600 pulses. Stimulation takes place in the right dorsolateral prefrontal cortex (RDLPFC). Additionally, all interventions will be performed by qualified therapists, and the responses of the subjects will be recorded.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eActive rTMS Group\u003c/h2\u003e \u003cp\u003eA stimulation set will be administered to each participant in the rTMS group per day. Active treatment will be delivered over the right DLPFC at 100% of the resting motor threshold. On postoperative days 1 to 5, or the day of discharge, the stimulation set will be given at 9:00\u0026ndash;10:00 every day.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSham Stimulation Group\u003c/h2\u003e \u003cp\u003eIn the sham stimulation group, there will be no stimulation. Sham stimulation uses the same protocol (600 pulses per session, 3 sessions per set, ISI\u0026thinsp;\u0026ge;\u0026thinsp;30 min, 3 sets). Sham stimulation uses a coil placed vertically to the skull, whereas actual stimulation uses a coil placed centrally over the right DLPFC. As for the stimulation time points, they will be the same as those of the rTMS group. To improve participant adherence, we have contacted attending surgeons anesthesiologists, and other staff to obtain their research support.\u003c/p\u003e \u003cp\u003eWe will provide detailed information about research-related issues during recruitment, consultation, hospitalization, and follow-up to improve adherence.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eMeasurements\u003c/h2\u003e \u003cp\u003eThere is a detailed breakdown of all study assessments and timeframes in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Below are a few brief descriptions of the assessments:\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Preoperative Visits\u003c/h2\u003e \u003cp\u003eBaseline assessments are conducted in the Cardiovascular Surgery Ward. Demographic information, past medical history, medication history, baseline laboratory tests, electrocardiography, and imaging examination are collected from electronic medical records. Vital signs (e.g., blood pressure, heart rate, blood oxygen saturation, respiratory rate) are recorded from the monitor. MMSE and MOCA scores are assessed before operation. When the MMSE score is greater than 24 and the MOCA score is greater than 26, the patient meets the inclusion criteria. A 32-channel EEG cap was used to record the baseline EEG activity. The schedule of the planned investigation is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eIntraoperative Protocols\u003c/h2\u003e \u003cp\u003eParticipants enrolled in this trial are sent to the operating room on the surgery day and monitored with blood pressure, electrocardiography, and oxygen saturation. Oxygen is given by mask and an intravenous line is established. Perform radial artery cannulation to monitor arterial pressure. The dose and infusion rate of anesthetic drugs are adjusted by anesthesiologists according to age, general conditions, complications, blood pressure, and surgical needs. The partial pressure of end-tidal carbon dioxide is maintained between 35 to 45 mmHg. Blood pressure is monitored every 5 minutes. The last recorded blood pressure before the operation is defined as the baseline blood pressure. Vasoactive drugs (e.g., epinephrine, norepinephrine, ephedrine, or isosorbide mononitrate) are given to participants to maintain blood pressure as appropriate. Hemodynamic and ventilation abnormalities (e.g., hypertension, hypoxemia), and vasoactive drugs are recorded during the operation. We have emergency medicine on hand to treat symptoms promptly.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcome measurement\u003c/h2\u003e \u003cp\u003e \u003cb\u003eThe incidence of PND on day 30 post-surgery.\u003c/b\u003e \u003c/p\u003e \u003cp\u003ePND will be defined according to MMSE and MOCA, which can evaluate various cognitive functions including attention, motor skills, executive function, learning, and memory.\u003c/p\u003e \u003cp\u003ePatients were tested using the MMSE and MOCA scale on preoperative day 1, postoperative day 7, and postoperative day 30 to calculate their scores. During the testing process, it is important to ensure that the patient does not experience any physical discomfort and that only the patient and the tester are present. Use unified explanatory standards to ensure that patients have fully understood the test before testing. To reduce the learning effect of repeated neuropsychological tests in this study, we also recruited 40 controls who did not receive surgery. They are usually family members of patients, and their age is similar to patients. The inclusion and exclusion criteria for the control group are the same as for surgical patients. Patients and volunteers were given neuropsychological tests on the same day. By comparing the changes in test scores between each patient and the control group of healthy volunteers, learning outcomes can be alleviated, thereby identifying patients with postoperative cognitive impairment.\u003c/p\u003e \u003cp\u003eWe evaluated the changes in the postoperative cognitive function status of patients based on the Z-score of the International Postoperative Cognitive Dysfunction Research Group 1 (ISPOCD1) and calculated the difference between the scores of the patient and healthy volunteers before and after the test, including the difference between the preoperative scale scores and the test scores on the 7th, and 30th days after the surgery. The average difference per person in the healthy volunteer group is the learning effect (△X) and its standard deviation (SD△X) is calculated. For each patient, subtract △X from the difference in each test scale and divide the result by the corresponding SD△X for the healthy volunteer group to obtain the Z-score for each individual. When the Z-scores of both scales are 1.96 or higher, it is considered that the patient has experienced delayed postoperative cognitive function recovery.\u003c/p\u003e \u003cp\u003eZ=△Xi-△X/SD△X\u003c/p\u003e \u003c/div\u003e \u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Postoperative delirium incidence within 7 days after surgery.\u003c/p\u003e\n\u003cp\u003eWe will use the Confusion Assessment Method (CAM)(31), which offers four entries: inattention and disorganized thinking along with the altered level of consciousness and acute onset. A diagnosis of delirium requires both the first and second criteria, as well as the third and/or fourth criteria. Consequently, everyone will be assessed twice daily, the first time at 9:00\u0026ndash;10:00 a.m. and the second time at 4:00\u0026ndash;5:00 p.m. every day for 7 days postoperatively. Additionally, nurses on duty will refer to records to determine the incidence of postoperative delirium.\u003c/p\u003e\n\u003cp\u003e2. Perioperative pain within 7 days after surgery.\u003c/p\u003e\n\u003cp\u003eVisual Analogue Scale (VAS) will be used to measure pain severity. Participants will be scored according to the intensity of their pain, from no pain (0) to most painful (10).\u003c/p\u003e\n\u003cp\u003e3. Sleep quality at postoperative day 7.\u003c/p\u003e\n\u003cp\u003eWe will use the Pittsburgh Sleep Quality Index (PSQI) to evaluate sleep quality. PSQI uses a 19-item questionnaire to assess sleep quality over one month. Each PSQI component score reflects a specific aspect of sleep, such as tardiness or efficiency at falling asleep. Based on the total component scores, the global PSQI is calculated. An increased score indicates poor quality sleep. The sum of the component scores represents the global PSQI.\u003c/p\u003e\n\u003cp\u003e4. Depressive symptom at postoperative day 7.\u003c/p\u003e\n\u003cp\u003eDepressive disorder and depression symptom severity will be measured using the 9-item patient health questionnaire (PHQ-9). Generally, it is self-administered and carries a score ranging from 0 to 27, with a score range of 0 to 3. Five, ten, fifteen, and twenty are the thresholds for mild, moderate, and moderately severe depression\u0026nbsp;(32).\u003c/p\u003e\n\u003cp\u003e5. Activities of daily living（ADL）at postoperative day 7, discharge, and postoperative day 30.\u003c/p\u003e\n\u003cp\u003eAs part of the pre-surgery and post-surgery evaluations, the Chinese version of the ADL scale will be used, including a Physical Self-Maintenance Scale and an Instrumental ADL scale. ADL consists of 14 items and the total score ranges between 14 and 56 points, with higher scores indicating a lower level of functioning. An impairment in ADL will be defined as a score above 22 points (the cut-off score)(33).\u003c/p\u003e\n\u003cp\u003e6. Length of hospital stay and ICU length of stay\u003c/p\u003e\n\u003cp\u003eA hospital length of stay is the number of days the patient spends in the hospital following surgery. Similarly, the ICU length of stay was defined as the number of days the patient spent in the ICU before transferring to a general inpatient cardiac surgery ward.\u003c/p\u003e\n\u003cp\u003e7. Rate of complication and mortality during the hospital stay\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEvery participant complication will be recorded to calculate the complication rate.\u003c/p\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSample size calculation\u003c/h2\u003e \u003cp\u003eThis study aims to examine the effectiveness of rTMS for cognitive function in people after cardiac surgery. There is about a 20%-46% incidence of PND 30 days after elective cardiac surgery, according to previous studies(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Nevertheless, no studies have investigated the effects of rTMS on PND. As rTMS significantly reduced the incidence of major depression by over half, we hypothesize that rTMS would reduce PND by up to half (from 40\u0026ndash;20%) in our study. We, therefore, set bilateral α\u0026thinsp;=\u0026thinsp;0.05 and β\u0026thinsp;=\u0026thinsp;0.2. Applying PASS15.0 software, we calculated that 158 participants in each group would be necessary, and considering a 10% lost visit rate and random block length, the expanded sample size of two groups together required a sample size of 174 cases, 87 cases per group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003e \u003cb\u003eIntention to Treat Analysis\u003c/b\u003eInitially, the analysis will be based on the intent to treat principle (ITT) and then complemented by a per-protocol analysis (PP)(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). The term non-compliance refers to patients who do not receive the intervention or placebo after randomization because their operation was canceled or they refused to participate on the day of surgery. A sensitivity analysis will be conducted to determine if non-compliance with the allocated arm will affect the analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Analyses\u003c/h2\u003e \u003cp\u003eAs a baseline characteristic, continuous variables will be allocated as means with standard deviations (SDs) for normal distributions or medians with interquartile ranges (IQRs) for skewed distributions. Student\u0026rsquo;s t-test or Mann-Whitney U test for continuous variables was used to compare clinical characteristics between the two groups of patients, and for categorical variables, the χ2 test or Fisher exact test should be used.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcome Analysis\u003c/h2\u003e \u003cp\u003eWe will compare the PND incidences in two groups using a χ2 test, and calculate a 95% CI for the difference.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcome Analysis\u003c/h2\u003e \u003cp\u003eWhen analyzing secondary outcomes, we will use the Mann\u0026ndash;Whitney U test for the length of hospital stay and ICU length of stay, as, the Fisher exact test for categorical variables, such as including the incidence of POD within 7 days after surgery, postoperative pain, sleep quality, depressive symptom, ADL and adverse events. The Cox proportional hazard model will be used to estimate the hazard ratio among patients in the rTMS group compared with those with sham rTMS while adjusting for potential confounding factors(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe will perform statistical analysis with SPSS 22.0 software (SPSS Inc, USA) using two-sided tests. A P value less than 0.05 constitutes statistical significance.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003ePre-set substudies\u003c/h2\u003e \u003cp\u003eThe incidence of PND at postoperative day 30 served as our primary measure of the clinical effect of rTMS. Moreover, we collected data on EEG behavior and clinical outcomes. We encourage sub-studies derived from this trial, aiming to provide more insight into clinically relevant outcomes.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e(1) EEG behaviors and postoperative cognitive outcomes\u003c/h2\u003e \u003cp\u003eIt has been suggested that neuromonitoring through electroencephalograms (EEGs) can reduce postoperative delirium and is recommended for every adult undergoing general anesthesia by the European Society of Anesthesiology(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) and Intensive Care (ESAIC). However, EEG patterns are still inconclusive in predicting and detecting postoperative neurological outcomes (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Since EEG data (including BIS and 32-channel EEG) is collected on baseline, intraoperative, and postoperative days, this study allows for this investigation. We are interested in exploring the association between EEG behaviors and postoperative outcomes (such as postoperative delirium and neurocognitive impairment results).\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003e(2) Depression symptoms during perioperative surgery\u003c/h2\u003e \u003cp\u003eMajor surgery can cause depression symptoms, which can negatively impact the quality of life and even mortality (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). At postoperative day 7 depression symptoms will be assessed, and risk factors, pain, and general health status will be evaluated as potential mechanisms.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003e(3) Sleep quality and postoperative outcomes\u003c/h2\u003e \u003cp\u003ePatients undergoing surgery may experience sleep disturbances during their recovery, which can contribute to delayed recovery(\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). An assessment of the effects of preoperative insomnia on postoperative outcomes will be conducted in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eSafety and adverse event reporting\u003c/h2\u003e \u003cp\u003eResearchers will notify the principal investigator of any adverse events during the study as soon as possible, and the principal investigator and research doctor will jointly decide how to proceed. The following adverse events will be reported: those possibly related to the rTMS, such as headache, dizziness, decreased sleep quality, and serious events, including death and life-threatening events. In the event of a serious adverse event, the main investigator, ethics committee, and relevant administrative departments will be informed within 24 hours and will be processed as soon as possible.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn addition to posing an increased risk of long-term disability and mortality, PND is an important but often under-recognized complication(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Consequently, we need to find a treatment that is both effective and safe to reduce their incidence. Since RTMS is painless, noninvasive, and well-tolerated, it has become a popular treatment for psychiatric disorders(\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). The development of rTMS offers new opportunities for treating PND after cardiac surgery. A randomized single-blind clinical trial protocol was developed to investigate whether rTMS after cardiac surgery is more effective than sham rTMS at reducing the incidence of PND.\u003c/p\u003e \u003cp\u003eObtaining complete follow-up data is the main challenge of this study. Under the influence of COVID-19, several patients were unable to attend their reviews on time due to their respective occupations. Thus, it is uncertain whether we will be able to reach all participants 30 days after surgery to obtain the primary outcome measure for all participants. The sample size seems reasonable based on previous studies. In the event that dropout rates are too high, we will notify the IRB and recruit participants as per protocol.\u003c/p\u003e \u003cp\u003eWe believe this is the first randomized, controlled trial evaluating the effects of rTMS on the treatment of PND after cardiac surgery. In addition, several neurocognitive as well as 32-channel EEG measures will be examined in this study to determine how rTMS induces its effects in individuals.\u003c/p\u003e \u003cp\u003eThis study has limitations that must be addressed. There is no double-blind control group, which could be a potential limitation. In all nonpharmacological studies, making everyone blind is not always possible (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). To eliminate the placebo effect of rTMS intervention, we set up a sham stimulation group. As well, the small sample size of participants and only one medical center may limit the generalizability of the results.\u003c/p\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003eThe trial has not yet been recruited. Any amendments made to the protocol will be submitted to and approved by the Beijing Chaoyang Hospital IRB. The trial is registered with Clinical Trials (trial number NCT 05668559). The first registration was completed on June 6, 2022. The trial recruitment is planned to start on October 1, 2023, and the recruitment of subjects is planned to be completed on April 1, 2026.The current version of protocol is V1.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"Strengths and limitations of this study","content":"\u003cp\u003e\u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThis is a prospective, randomized clinical trial, which provides the best clinical evidence and support for repetitive transcranial magnetic stimulation (rTMS) as an intervention to bring down the incidence of perioperative neurocognitive disorders.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eUsing two cognitive scales that can fully reflect the changes in cognitive function of patients before and after surgery.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eA multi-channel (32-channel) EEG was attempted to explore the EEG characteristics changes of patients before and after surgery.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe small sample size of this single-center study limited the study design.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe results of this study may not apply to other institutions since it was conducted at a single location.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project is supported by the Multidisciplinary Clinical Research Innovation Team Program of Beijing Chao-Yang Hospital, Capital Medical University (CYDXK202210). \u0026nbsp;The funding institutions have no influence on the design of the study, execution, management, interpretation of the data, or deciding to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBeijing Chaoyang Hospital Ethics Committee approved this study and has number 2022-ke-487. It is registered with Clinical Trials (trial number\u0026nbsp;NCT05668559). Informed consent must be provided by all participants. The study result will be published in a peer-reviewed journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI am attaching our manuscript entitled \u0026ldquo;The Effect of Transcranial Magnetic Stimulation (TMS) on Perioperative Neurocognitive Disorders in Patients after Cardiac Surgery: Study Protocol for a Randomized Controlled Trial\u0026rdquo;, which we would like to submit for publication as a study protocol in\u0026nbsp;Trails.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors disclosed no relevant relationships.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project is supported by the Multidisciplinary Clinical Research Innovation Team Program of Beijing Chao-Yang Hospital, Capital Medical University (CYDXK202210). \u0026nbsp;The funding institutions have no influence on the design of the study, execution, management, interpretation of the data, or deciding to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJing Wang\u0026nbsp;and Xuyang Wang are responsible for writing the original draft.\u003c/p\u003e\n\u003cp\u003eSijie Li\u0026nbsp;and\u0026nbsp;Jinrong Yang are responsible for\u0026nbsp;the visualization.\u003c/p\u003e\n\u003cp\u003eXiang Yan,\u0026nbsp;Jie Gao,\u0026nbsp;Xiuqin Jia,\u0026nbsp;and\u0026nbsp;Long Zuo\u0026nbsp;are responsible for the validation.\u003c/p\u003e\n\u003cp\u003eAnshi Wu is responsible for visualization.\u003c/p\u003e\n\u003cp\u003eChangwei Wei\u0026nbsp;is responsible for the conceptualization and editing of the draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript has not been published or presented elsewhere in part or entirety and is not under consideration by another journal. All study participants provided informed consent, and the study design was approved by the appropriate ethics review board. We have read and understood your journal\u0026rsquo;s policies and believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEvered L, Silbert B, Knopman DS, et al. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. Br J Anaesth. 2018;121(5):1005\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndrosova G, Krause R, Winterer G, et al. Biomarkers of postoperative delirium and cognitive dysfunction. Front Aging Neurosci. 2015;7:112.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKong H, Xu LM, Wang DX. Perioperative neurocognitive disorders: A narrative review focusing on diagnosis, prevention, and treatment. CNS Neurosci Ther. 2022;28(8):1147\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlotu C. Postoperative neurocognitive disorders. Curr Opin Anaesthesiol. 2020;33(1):101\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRelander K, Hietanen M, Rantanen K, et al. Postoperative cognitive change after cardiac surgery predicts long-term cognitive outcome. Brain Behav. 2020;10(9):e01750.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhera T, Helfand J, Kelly L, et al. Twelve-Month Cognitive and Functional Outcomes Following Cardiac Surgery: The DEXACET Trial of Intravenous Acetaminophen Versus Placebo. Front Pharmacol. 2022;13:803903.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTropea J, LoGiudice D, Liew D, et al. Poorer outcomes and greater healthcare costs for hospitalised older people with dementia and delirium: a retrospective cohort study. 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Front Psychiatry. 2022;13:884907.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBulteau S, Sebille V, Fayet G, et al. Efficacy of intermittent Theta Burst Stimulation (iTBS) and 10-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant unipolar depression: study protocol for a randomised controlled trial. Trials. 2017;18(1):17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoutron I, Moher D, Altman DG, et al. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med. 2008;148(4):295\u0026ndash;309.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"clinical trials, Perioperative neurocognitive disorders(PND), transcranial magnetic stimulation (TMS), psychiatry, protocol","lastPublishedDoi":"10.21203/rs.3.rs-3298051/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3298051/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cb\u003eIntroduction\u003c/b\u003e: Perioperative neurocognitive disorders(PND)is one of the most common postoperative complications among elderly patients (above 65 years old) undergoing cardiac surgery. However, thus far, there have not been any effective therapies for managing PND. Recent research has shown that repetitive transcranial magnetic stimulation (rTMS) alters brain plasticity and improves cognitive function in several neurodegenerative disorders and psychiatric disorders. However, the potential benefits of rTMS in reducing PND in patients undergoing cardiac surgery have not been investigated. Therefore, the current protocol is designed to determine whether rTMS can reduce the incidence of PND in patients undergoing cardiac surgery.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods and analysis\u003c/b\u003e: The study will be a single-blinded, randomized controlled trial. Participants undergoing elective cardiac surgery will be randomized to receive either rTMS or sham stimulation with a focal figure of eight coils over the right dorsolateral prefrontal cortex. A series of neuropsychological tests will be completed to evaluate cognitive function in surgery patients before, on day 7, and on day 30 after cardiac surgery. The primary outcome is the prevalence of PND in cardiac surgery patients. The secondary outcomes will be the incidence of postoperative delirium, pain, sleep quality, depressive symptoms, activities of daily living, length of hospital stay and ICU length of stay, and rate of complication and mortality during the hospital stay.\u003c/p\u003e \u003cp\u003e\u003cb\u003eEthics and dissemination\u003c/b\u003e: Beijing Chaoyang Hospital Ethics Committee approved this study and has number 2022-ke-487. It is registered with Clinical Trials (trial number NCT 05668559). Informed consent must be provided by all participants. The study result will be published in a peer-reviewed journal.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTrial registration number\u003c/b\u003e: NCT05668559\u003c/p\u003e","manuscriptTitle":"The Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) on Perioperative Neurocognitive Disorders in Patients after Cardiac Surgery: Study Protocol for a Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-03 17:01:40","doi":"10.21203/rs.3.rs-3298051/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-04-29T04:24:30+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-03-30T08:56:53+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-29T11:30:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-28T07:46:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-03-13T00:35:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7210c9c4-702c-4ac7-a3b5-2b2d7e18f784","owner":[],"postedDate":"April 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T15:59:14+00:00","versionOfRecord":{"articleIdentity":"rs-3298051","link":"https://doi.org/10.1186/s13063-025-08988-3","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-07-24 15:57:01","publishedOnDateReadable":"July 24th, 2025"},"versionCreatedAt":"2024-04-03 17:01:40","video":"","vorDoi":"10.1186/s13063-025-08988-3","vorDoiUrl":"https://doi.org/10.1186/s13063-025-08988-3","workflowStages":[]},"version":"v1","identity":"rs-3298051","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3298051","identity":"rs-3298051","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}