{"paper_id":"894c56e1-8740-478a-a06b-08b5f1b1a2ea","body_text":"Wang et al. Trials           (2023) 24:40  \nhttps://doi.org/10.1186/s13063-023-07082-w\nSTUDY PROTOCOL\n© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco \nmmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nOpen Access\nTrials\nEffect of high-frequency repetitive \ntranscranial magnetic stimulation \nunder different intensities upon rehabilitation \nof chronic pelvic pain syndrome: protocol \nfor a randomized controlled trial\nMengyang Wang1, Rui Xia2, Jiao Shi2, Chunhua Yang1, Yongqing Zhang1, Zhengxian Xu1, Cancan Yu1, Ziyi Wu2, \nMin Wang1, Shangjie Chen2* and Hongdang Qu1* \nAbstract \nIntroduction Nearly one in seven women worldwide suffers from chronic pelvic pain syndrome (CPPS) each year. \nOften, CPPS necessitates a combination of treatments. Studies have shown the good therapeutic effects of repetitive \ntranscranial magnetic stimulation (rTMS) upon CPPS. We wish to undertake a randomized controlled trial (RCT) to \nobserve the effect of high-frequency rTMS at different intensities upon CPPS.\nMethods and analyses In this prospective, double-blinded RCT, 63 female CPPS participants will be recruited and \nrandomized (1:1:1) to high-intensity rTMS, low-intensity rTMS, or sham rTMS. The control group will receive a 10-day \ncourse of conventional pelvic floor (PF) rehabilitation (neuromuscular stimulation, magnetic therapy, or light therapy \nof the PF). On the basis of conventional treatment, participants in the high-intensity rTMS group will receive pulses of \n10 Hz with a resting motor threshold (RMT) of 110% for a total of 15,000 pulses. Participants in the low-intensity rTMS \ngroup will receive pulses of 10 Hz with an RMT of 80% with 15,000 pulses. The sham rTMS group will be subjected to \nsham stimulation with the same sound as produced by the real magnetic stimulation coil. The primary outcome will \nbe determined using a visual analog scale, the Genitourinary Pain Index, Zung Self-Rating Anxiety Scale, and Zung \nSelf-Rating Depression Scale. The secondary outcome will be determined by electromyography of the surface of PF \nmuscles at baseline and after treatment completion.\nEthics and dissemination This study is approved by the Ethics Committee of Bao’an People’s Hospital, Shenzhen, \nGuangdong Province (approval number: BYL20211203). The results will be submitted for publication in peer-reviewed \njournals and disseminated at scientific conferences (Protocol version 1.0-20220709).\nTrial registration Chictr.org.cn, ID: ChiCTR2200055615. Registered on 14 January 2022, http:// www. chictr. org. cn/ \nshowp roj. aspx? proj= 146720. Protocol version 1.0-20220709.\nKeywords rTMS, CPPS, Randomized controlled trial, RCT protocol\n*Correspondence:\nShangjie Chen\ncsjmesz@sina.com\nHongdang Qu\nqhd820@sohu.com\n1 The First Affiliated Hospital of Bengbu Medical College, Bengbu, China\n2 Second Affiliated Hospital of Shenzhen University, Shenzhen, China\n\nPage 2 of 10Wang et al. Trials           (2023) 24:40 \nStrengths and limitations of this RCT design\n• This is the first randomized controlled trial (RCT) \nfocusing on the efficacy and acceptability of differ -\nent intensities of repetitive transcranial magnetic \nstimulation (rTMS) for chronic pelvic pain syndrome \n(CPPS).\n• Participants will be patients who come to Bao’an Peo-\nple’s Hospital needing pelvic floor (PF) rehabilitation \nand who have agreed to treatment of gynecological \nor urological diseases. Also, Bao’an People’s Hospital \nmust have the relevant equipment.\n• Treatment will be implemented and followed up by \nan experienced therapist. Sixty-three female partici -\npants with CPPS will be enrolled in this prospective, \nassessor-blind, three-arm RCT. They will be assigned \n(1:1:1) randomly to a high-intensity rTMS group, \nlow-intensity rTMS group, or conventional-treat -\nment group. This scheme can truly reflect the inter -\nvention effect of different intensities of rTMS upon \nCPPS.\n• Electromyography of the surface of PF muscle will be \nundertaken before and after the intervention. We aim \nto investigate the effect of rTMS on the neuromuscu-\nlar bioelectrical activity of PF muscles after treatment \nof CPPS.\n• A methodological challenge will arise from blinded \nimplementation and quality control of the interven -\ntion. The therapist and physician cannot act in a \nblinded manner. To minimize a performance bias, \ntherapists and physicians will not be involved in \nrecruitment or data analyses.\nBackground\nSince the 1990s, pelvic floor (PF) dysfunction has become \na major problem affecting human health. In females, PF \nligaments provide cord-like suspension and support for \nthe stability of the uterus, ovaries, and vesicorectal ure -\nthra. PF muscles support internal organs like “bridges. ” \nTherefore, the entire abdominopelvic region may be \naffected if disease occurs [1–3]. With women taking \nemployment in all walks of life, the requirements for PF \nsupport are increasing, and mechanical imbalance in the \npelvis and various triggers can promote the occurrence \nand development of various diseases.\nChronic pelvic pain syndrome (CPPS) can be defined \nas idiopathic pain in the lower abdomen that persists or \nis intermittent for >6 months and which causes stress to \na woman’s psychology, life, and work [4]. Surveys have \nsuggested only 2–10% of those who can receive effica -\ncious treatment receive the diagnosis in the outpatient \nsetting [5]. The impact of CPPS on women is reflected in \nemotional anxiety and depression in addition to pain, a \ndecrease in quality of life (QoL), and abnormal aspects of \nphysical sensitivity.\nCPPS manifests as several peripheral symptoms, and \nstudies have suggested that chronic pain involves sys -\ntemic dysfunction in pain systems [6]. Patients with \nCPPS have a reduced pain threshold. Long-term pain \nleads to continuous transmission of pain-sensitizing \ninhibitory substances (e.g., glutamate) through nerve \nbundles in the spinal cord. This action increases the level \nof such substances in cerebrospinal fluid but also in key \npain-processing areas, whereas the level of excitatory \nanalgesic substances (e.g., opioid peptides) decreases [7]. \nAll of these actions affect the occurrence and develop -\nment of central sensitization and are the result of physi -\nological plasticity and persistent changes in the central \nnervous system (CNS) [8, 9].\nThe CNS regulates the excitation and inhibition of \nnerves. The prefrontal cortex is a key region involved in \nthe regulation of slow-acting pain and cognitive process -\ning [10, 11]. Studies have shown the mechanism by which \ncentral regulation is feasible [12]. Imaging findings have \ndemonstrated that the long-term effects of chronic pain \ncan cause changes in gray matter density in the primary \nsomatosensory cortex, hippocampus, and left amygdala \n[13].\nEven these changes are related to not only pain pro -\nduction, but the occurrence of depression is significantly \ncorrelated with right hippocampal weight, but also the \nduration of pain; for example, symptom duration of less \nthan 7.5 years was significantly related to the left amyg -\ndala [14, 15]. After receiving repetitive transcranial mag -\nnetic stimulation (rTMS), the increase in motor cortex \n(M1) excitability also elicits a potent analgesic effect [16]. \nThis action can increase the concentrations of glutamate \nand glutamine, and biochemical tests have demonstrated \nglutamate in the prefrontal cortex of women suffering \nfrom CPPS [17, 18]. A change in the glutamine concen -\ntration has a negative correlation with the pain thresh -\nold [19]. Also, M1 is related to the pain level of healthy \npeople and patients suffering from pelvic pain. M1 has a \npositive correlation with the pain threshold, which may \nbe because M1 is involved mostly in pain loops [20, 21].\nTherefore, in treatment programs used commonly for \nCPPS patients (e.g., myofascial manipulation, medium/\nlow-frequency electrical stimulation, aerobic exercise, \nand traditional Chinese medicine) [22, 23], the treat -\nment concept of central regulation from cortical targets \nis a rational approach [24, 25]. Also, rTMS (i) stimulates \nthe brain area within 2 cm of the scalp, (ii) can trigger \ndescending inhibitory neural pathways to act at the level \nof the dorsal horn to reduce chronic pain, (iii) can change \n\nPage 3 of 10\nWang et al. Trials           (2023) 24:40 \n \nneuronal activity, and (iv) affects the cerebral cortex asso-\nciated with pain perception (e.g., prefrontal cortex and \nprimary somatosensory cortex) [26, 27].\nThe allodynia and hyperalgesia elicited in the corti -\ncal projection pain areas of the pelvis in CPPS patients \nsuggest that dysfunction of the central pain system may \nbe very important in CPPS [6, 28]. Paresthesia and pain \noccur due to PF dysfunction. As the pain persists, sys -\ntemic changes in the CNS occur, and the CNS remains in \na state of high activity, showing disruption of pain regula-\ntion and enhanced central sensitization processes.\nrTMS is considered to be a non-invasive method of \nbrain stimulation [29]. rTMS has been shown to regulate \nthe central lesions caused by chronic diseases by inhib -\niting and reversing neuronal sensitization [20, 30, 31]. \nTreatment guidelines based on TMS studies have sug -\ngested that the left prefrontal cortex could be a target \nfor experimental application of chronic pain. rTMS was \nfirst used to treat pelvic and perineal pain in 2012 [32]. \nLouppe and colleagues carried out rTMS for 4 weeks \nwith a high-frequency resting motor threshold (RMT) of \n100% in two female patients (average pain duration >7.5 \nyears) by stimulating M1. These two patients had con -\ntinuous improvement in pain and QoL during 3 weeks of \ntreatment and follow-up. In subsequent studies, high-fre-\nquency stimulation with an RMT of 110% [33] and 80% \n[34] was used as a more reliable option for treatment. In \nmechanistic studies, different intensities were considered \nto bring different outcomes, but the effect size was not \nuniformly positively correlated with intensity. In studies \nusing a RMT of 80% and 110%, a RMT of 80% stimulated \nimprovement of disease symptoms, but a reduction in \npain was not obvious. Those studies were also influenced \nby non-consistent results caused by different disease \nsubtypes and interventions. Therefore, design of a rand -\nomized controlled trial (RCT) to ascertain if treatment at \ndifferent intensities of rTMS will have different effects on \nCPPS development is warranted.\nWe hypothesized that the treatment effect of rTMS \nupon CPPS is different at different intensities. We suggest \nthat the effect in a low-intensity group will be different \ncompared with that elicited by conventional treatment. \nIn this way, we could determine the efficacy and safety of \nrTMS in CPPS treatment.\nStudy design and methods\nStudy design\nOur study will be a triple-arm RCT with a 1:1:1 allocation \nratio with allocation concealment and assessor blind -\ning. A design framework of three groups in a RCT can \nminimize (as much as possible) the interference of other \nfactors in the comparison between groups. Simultane -\nously, multiple comparisons can be made to ascertain \nthe differences between the stimulated group and non-\nstimulated group, as well as between groups with differ -\nent levels of stimulation. Sixty-three eligible participants \nwill be randomly assigned to 10 high-intensity or low-\nintensity TMS (15 min each, five times a week) or sham \nstimulation groups, all receiving these stimuli in addi -\ntion to their usual pelvic disease treatments. Results for \npain and other symptoms will be assessed at baseline and \n2 weeks (at the end of the intervention). Data collectors \nwill be blinded to group assignments. The study proce -\ndure and schedule for outcome assessment for our RCT \nare presented in Fig. 1 and Table 1.\nStudy population\nThe study population will be women between 20 and 60 \nyears of age suffering from CPPS.\nStudy setting\nResearchers will be recruited from Bao’an People’s Hos -\npital, a class III, class A university, affiliated community \nhospital in Shenzhen, China. Treatment will take place in \nthe Department of Rehabilitation Medicine.\nDiagnostic criteria\nAccording to European Association of Urology (EAU) \nGuidelines on Chronic Pelvic Pain (2019 version) and \nEUA Guidelines on Chronic Pelvic Pain (2019 updated \nversion), participants with CPPS should have chronic \npelvic pain: (i) with no proven infection or other obvious \nlocal disease that can explain the pain; (ii) associated with \nnegative cognitive, behavioral, sexual, or emotional con -\nsequences; and (iii) with symptoms suggestive of lower \nurinary, sexual, intestinal, or gynecological dysfunction.\nInclusion criteria\nEligible participants must meet the following criteria: (i) \nthe diagnostic criteria and classification for CPPS in the \nEUA Guidelines on Chronic Pelvic Pain (2019 updated \nversion) [4] must be met; (ii) aged 20–60 years with a his -\ntory of CPPS; (iii) gynecological examination and auxil -\niary examination do not reveal clear pathologic changes; \n(iv) written informed consent will be obtained and sub -\njects will voluntarily participate in randomized con -\ntrolled trials; (v) no treatment within 3 months before \nRCT initiation; and (vi) conforming to the habit of right-\nhanded hands.\nExclusion criteria\nPatients who have absolute and relative contraindica -\ntions for rTMS will be excluded according to evidence-\nbased guidelines for the use of rTMS therapy. The \nexclusion criteria will be patients (1) with a contrain -\ndication to TMS due to acute systemic or intracranial \n\nPage 4 of 10Wang et al. Trials           (2023) 24:40 \nhemorrhagic diseases; (2) with cardiac metal mem -\nbrane or a cardiac pacemaker; (3) with a tendency to \nbleed; (4) with severe heart disease, severe hyperten -\nsion, or severe dysfunction of the heart, liver, lungs, or \nkidneys; (5) who use implantable electronic devices; (6) \nwith intracranial infection/tumor; (7) with intracranial \nvascular metal stent implantation; (8) with fever; (9) \nfor whom data on vital signs are not available; (10) with \nadverse reactions to magnetic therapy; (11) with open \nwounds or infections at the treatment site; (12) with \nmalignant effusions, active pulmonary tuberculosis, or \ncancer; (13) with severe mental illness or epilepsy; and \n(14) who are pregnant.\nFig. 1 Flowchart of the RCT \n\nPage 5 of 10\nWang et al. Trials           (2023) 24:40 \n \nWithdrawal criteria and management\nParticipants will be allowed or required to withdraw from \nthe RCT if they (i) are determined after evaluation to be \nunable to continue treatment due to adverse reactions \nor changes in condition; (ii) do not follow the treatment \nplan strictly or take other therapies while participating in \nthe RCT; (iii) have significant changes in blood pressure, \nheart rate, or respiration during treatment; (iv) wish to \nleave the RCT; and (v) lost visitors.\nRecruitment\nRecruitment will be conducted in the Rehabilitation \nDepartment of Shenzhen Bao’an People’s Hospital \nthrough online and offline methods such as networking, \noutpatient departments, and screening of inpatient medi-\ncal records. Patients whose condition may worsen will be \nevaluated and screened to determine eligibility for par -\nticipation based on the inclusion and exclusion criteria \nstated above. Inpatients wishing to participate will obtain \npermission from a physician, and a research assistant will \nobtain written informed consent from the participation \nbefore a therapeutic intervention.\nRandomization, allocation concealment, and blinding\nAfter assessment at baseline, eligible participants will be \nassigned randomly to high-intensity stimulation, low-\nintensity stimulation, or conventional treatment. Ran -\ndomly assigned sequences will be generated using the \n“PLAN” program of SAS 9.2 (Cary, NC, USA). Random \nserial numbers will be generated and placed in opaque, \nsealed envelopes. They will be administered indepen -\ndently by statisticians not involved in the recruitment, \nevaluation, or engagement of participants. Eligible par -\nticipants will be notified of the assignment results by \nan independent research assistant over the telephone. \nWe cannot allow therapists, or attending physicians, to \nbe blinded to assigned treatment, but participants, out -\ncome assessors, and statisticians will be blinded to group \nassignments.\nUnblinding\nIf there was a situation such as a medical need or emer -\ngency which required unblinding, the principal investiga-\ntor will be informed and make the final decision.\nIntervention\nIndividuals will be assigned to a family physician at the \nintervention center. RCT compliance can be obtained \ndaily through treatment records in the treatment instru -\nment. Treatment will be recorded in the electronic medi-\ncal record of participants. Relevant concomitant care and \ninterventions that are permitted during the RCT will be \nshown to each participant.\nAll three groups will receive routine radiotherapy floor \nrehabilitation, including neuromuscular stimulation, \nmagnetic therapy, or PF phototherapy. The instrument \nwhich will be used to administer neuromuscular stimula -\ntion of PF muscles will be Phenix-USB4 (Vivaltis, Paris, \nTable 1 Schedule of enrollment, assessments, and interventions in the RCT \n“×” indicates at which point of the RCT the respective assessments will take place\n\nPage 6 of 10Wang et al. Trials           (2023) 24:40 \nFrance). It uses 10-min low-frequency electrical stimu -\nlation and 15-min exercises for PF muscles for a total of \n25 min per day. Magnetic therapy of the PF will be done \nusing a Magneuro 60F system (Vishee Medical Technol -\nogy, Nanjing, China). Moderate analgesic high-frequency \nstimulation for 20 min per day will be carried out. Light \ntherapy will be undertaken using Hydrosun ® Irradia -\ntor 500 (Hydrosun Medizintechnik, Müllheim, Ger -\nmany). This employs direct irradiation of the pain site at \na distance of 20–30 cm for 20 min per day. Conventional \ntreatments will be carried out five times per week.\nSham rTMS group\nThe sham group will receive rTMS with no actual out -\nput, stimulated with a fake magnetic stimulation coil that \nproduces the same sound as the real stimulation coil, but \nwithout the magnetic field, and has induced a non-stim -\nulating effect.\nHigh‑intensity rTMS group\nThe high-intensity rTMS group will receive high-inten -\nsity rTMS in addition to conventional treatment. rTMS \ntreatment will be administered using the CCY 1 stimu -\nlator (Yiruide, Wuhan, China). An “8”-shaped coil will \nfocus the stimulation. The maximum output will be 2.2 \nT. The coil will be located in the center of the left M1, \nplaced at 45° inclination from the scalp. The output inten-\nsity will be a RMT of 110%. A total of 1500 pulses will be \nadministered at each treatment (10 pulses delivered in \neach sequence, repeat 150 times, 5 s apart). rTMS will be \ngiven at 10 Hz for 15 min, and the stimulation site will be \nM1. rTMS will be administered once a day, five times a \nweek for 2 weeks. Ten sessions, for a total of 15,000 stim -\nulations, will be administered.\nLow‑intensity rTMS group\nPatients in the low-intensity rTMS group will use identi -\ncal equipment to those in the high-intensity group. How -\never, the stimulation intensity will be a RMT of 80%. The \nnumber of pulses, interval between pulses, and stimu -\nlation frequency will be identical to those in the high-\nintensity group.\nOutcome assessment\nThe variables to be assessed will be patient characteris -\ntics, primary outcome, and secondary outcome. Patient \ncharacteristics at baseline will be documented. Primary \nand secondary outcomes will be measured at baseline \nand at the end of the intervention. The time points of \nresult recording will be denoted as T0 and T10. Primary \nand secondary outcomes will be evaluated by experi -\nenced staff at Shenzhen Bao’an People’s Hospital, who \nwill not be aware of the results of participant allocation.\nPatient characteristics\nRecruiters will use a self-designed questionnaire to col -\nlect demographic characteristics (e.g., sex, age, height, \nweight, and reproductive status) as well as a history \nof disease or drug use. Scores for a visual analog scale \n(VAS), the Genitourinary Pain Index (GUPI), Zung \nSelf-Rating Anxiety Scale (SAS), and Zung Self-Rating \nDepression Scale (SDS) will be calculated. Measurements \nat baseline will be completed before the first treatment.\nPrimary outcome\nPain severity will be based on the VAS score [35]. A VAS \nis a 100-mm line where “zero” indicates complete pain -\nlessness and “10” indicates the most severe pain imagi -\nnable. The patient marks pain severity on this line. The \nsimplicity of a VAS enables its use for pain assessment. \nChanges before and after treatment were compared by \nthe decrease in VAS.\nSecondary outcomes\nGUPI [36] will be employed to assess the severity of \nsymptoms in women with urogenital pain. GUPI is \na modification of the National Institutes of Health–\nChronic Prostatitis Symptom Index and includes female-\nspecific pain (pain at the vaginal entrance, urethral pain, \npain during/after sexual intercourse). There are 10 pain \nitems with a total pain subscale score of 0–13, two uri -\nnary symptom items with a total urine subscale score \nof 0–10, and three QoL items with a total QoL subscale \nscore of 0–12.\nSAS [37, 38] is a norm-referenced scale which enjoys \nwidespread use as a screening device for anxiety disor -\nders. The scale measures mood over the previous week \nwith a score that is multiplied by 1.25. An SAS score of \n<50 suggests a “normal” mood, that of 50–59 indicates \n“mild depression, ” that of 60–69 denotes “moderate \ndepression, ” and that of ≥70 indicates “major depression. ” \nStudies [6, 39] have suggested that the mood changes of \npatients with long-term pain are obvious and that a self-\nrating scale can be used to distinguish their emotions in a \npreliminary manner.\nSDS [40] consists of 20 items divided into four self-rat -\ning scales. SDS is used to evaluate the subjective feelings \nof anxious patients within 2 weeks. The score is multi -\nplied by 1.25. A final SDS score of <50 denotes a “normal” \nmood, that of 50–59 indicates “mild depression, ” that of \n60–69 denotes “moderate depression, ” and that of ≥70 \nindicates “major depression” [41].\nData for electromyography at the PF surface will be \ncollected at baseline and after the intervention. Electro -\nmyography will be conducted in the Rehabilitation Room \nof Bao’an People’s Hospital. Participants will be assessed \nbased on the Glazer procedure using a myoelectric PF \n\nPage 7 of 10\nWang et al. Trials           (2023) 24:40 \n \nbiofeedback instrument (Medlander Technology, Nan -\njing, China). The data collected will be as follows: pre-\nresting phase, variogram 1, rapid-contraction phase, rise \ntime, recovery time, slow-muscle phase, variogram 2l \nendurance-test phase, variogram 3, post-first 10-s ratio, \npost-resting phase, and variogram 4 [42–44].\nSafety and participant compensation\nDuring the intervention, participants will be monitored \nfor adverse events. Participants will be asked about \nadverse events after each treatment until the adverse \nevent is resolved. If headache occurs after treatment, \nrelaxation therapy will be given. Or other conditions \nsuch as a fall during the treatment will be treated free \nof charge by a professional therapist until recovery. A \nparticipant who is found to be at risk (e.g., suicide and \nneglect) to him/herself or others, or who has a serious \nadverse event, will be referred to the relevant clinical ser -\nvices. Causality will be assessed in relation to rTMS and \nthe severity of the adverse event. Serious adverse events \nwill be reported to the Ethics Committee of Bao’an Peo -\nple’s Hospital within 72 h.\nSample size\nAccording to the study by Pinot-Monange and colleagues \n[33], the effect size was 0.49 using β = 0.15 and α = \n0.05. Pain scores will be taken as the main measurement \nstandard, and G*Power 1.9.2 (www. psych ologie. hhu. de/) \nwill be employed. The study cohort was calculated to be \n~51 patients. Taking into account a dropout of 20%, each \ngroup will include 21 people from each group. Sixty-\nthree participants will be required for this RCT.\nStatistical analyses\nSPSS 26 (IBM, Armonk, NY, USA) will be employed \nto analyze data. Statistical analyses will be conducted \nby independent statisticians. First, the Kolmogorov–\nSmirnov test will be used to ascertain if a normal dis -\ntribution of data is present. If the data have a normal \ndistribution, then analysis of variance with repeated \nmeasures will be used to compare the mean pain scores \nfor each group. P < 0.05 will be considered significant. \nContinuous variables in the measures of primary and \nsecondary outcomes will be expressed as the mean and \nstandard deviation (normal distribution) or median value \n(non-normal distribution). Categorical variables will be \ndescribed as frequencies or percentages. Subgroup analy -\nsis is not applicable in this RCT. Missing data (loss to fol -\nlow-up, death, withdrawal, etc.) will be updated using the \nmultiple-imputation approach.\nThe significance of adverse reactions will be analyzed \nusing the chi-square test or Fisher’s exact test. If statis -\ntical analyses between groups are not possible due to \ninsufficient power, adverse events will be tabulated and \nsummarized using descriptive statistics.\nCollection and management of data\nData will be collected by an outcome evaluator using \na case report form. The letter will be transcribed into a \npassword-protected document by a research assistant \nuntil being “unlocked” at the end of the study. Addition -\nally, missing data (loss to follow-up, death, withdrawal, \netc.) will be updated using the multiple-imputation \napproach.\nOversight and monitoring\nThe principal investigator and other co-investigators \nare doctors and professors of rehabilitation who will be \nresponsible for overseeing and monitoring the entire \ntrial. Subject diagnosis, recruitment, and informed con -\nsent signing will be handled by an independent hospital-\naffiliated rehabilitation physician. The progress, adverse \nevents, and data quality of the trial will be evaluated by an \nindependent data testing committee composed of Bao’an \nPeople’s Hospital Ethics Committee members and inde -\npendent therapists who are not affiliated with the study \nteam or sponsors. The study team will meet monthly with \nthe data testing committee to monitor the progress and \nquality of the study. There will be no interim analysis. \nStatistical analysis is conducted only after the trial, and \nif individual participants report serious adverse effects or \ndeterioration during the course of the trial, the principal \ninvestigator will make a decision to terminate the trial.\nInvolvement of patients and the public\nBefore recruitment, individual patients and experi -\nenced therapists not associated with recruitment will be \ninvited to investigate the RCT design and feasibility of \nthe intervention. Based on their comments, the evalua -\ntion method and timing of treatment will be adjusted to \navoid interference with routine treatment arrangements. \nPatients or members of the public will not be involved in \nrecruitment or data implementation and measurement. \nResults will be sent to participants via written reports \nand email. The burden of the interventions included in \nthis RCT will not be assessed by patients. During the \nintervention, participants were contracted to a family \nphysician at the hospital (including records of all visits \nand regular follow-up visits). The data of the participants \nin the intervention interruption or the intervention pro -\ngram are retained, and the reasonable and exposed data \ncan be excluded and counted according to the needs of \nthe participants.\n\nPage 8 of 10Wang et al. Trials           (2023) 24:40 \nEthical approval and communication\nThe protocol for this RCT was approved (BYL-20211203) \nby the Ethics Committee of Shenzhen Bao’an People’s \nHospital in December 2021. Changes to the protocol will \nbe submitted to this Ethics Committee for approval. This \nRCT was registered on 14 January 2022 at www. ChiCTR. \norg and can be identified as ChiCTR2200055615. Writ -\nten informed consent of all participants will be obtained \nafter they have read an information manual describing \nthe project and potential risks and benefits and if they \nhave questions to discuss with the investigator. Col -\nlected digital data will be stored in password-protected \nfiles. Only the data analyst will have access to the data \nat the end of the RCT. RCT results will be published in \na peer-reviewed journal following standards set by the \nInternational Board of Medical Journal Editors and will \nnot involve professional authors, with undetermined data \nbeing available in a public repository at the time of pub -\nlication. RCT results will also be communicated through \nscientific meetings.\nDiscussion\nAs a non-invasive method of brain stimulation, rTMS has \na deeper role than other methods used to study periph -\neral regulation [17, 31, 45, 46]. Several studies have \nrevealed that high-frequency rTMS in M1 has therapeu -\ntic value for chronic intractable pain and generalized pain \nand compared it with other methods of central regula -\ntion. rTMS has been supported by more RCT data and \nhas a higher level of evidence than that of other methods \n[39]. An analgesic effect can be maintained for 2–3 days \nand up to 8 days after rTMS of M1 [47]. High-frequency \nrTMS of M1 appears to be suitable for middle-aged \nwomen with recurrent idiopathic pain attacks.\nOur RCT has been designed to compare rTMS of dif -\nferent intensities. Thordstein and colleagues [48] dem -\nonstrated that the central region affected by rTMS may \nelicit no response at high or low levels of intensity but \nthat an increase in stimulus of just 10% may produce sig -\nnificant changes. For diseases such as epilepsy [48–50], \nschizophrenia, and cognitive impairment, experimen -\ntal studies have suggested that different intensities of \nrTMS affect astrocytes and cerebral blood flow. In stud -\nies investigating use of rTMS for CPPS or other types of \nchronic pain, uniform parameters (frequency, intensity, \nduration) or type of stimulation (transcranial magnetic \ncoil) has not been used. In some sessions with an RMT \nof 80%, the improvement in QoL, anxiety, and depression \nwas not significant. Therefore, we believe in the necessity \nof designing a RCT to investigate if there is a difference \nin CPPS if high-frequency rTMS at different intensities is \nemployed.\nThe emotional and psychological problems of CPPS \ncannot be ignored [6 , 51, 52]. Chronic pain causes \nabnormal changes in the strength of PF muscles but \nalso affects intestinal activity, urinary system, somatic \npsychology, QoL, anxiety, and depression. Therefore, \nwe consider it necessary to include pain, urinary out -\ncome, anxiety, depression, and surface electromyogra -\nphy in outcome assessments.\nIn this study, the age of the subjects was considered \nto be over 20 years old, which may affect the validity \nof the experiment. However, we referred to the age \nof marriage and childbearing that met the criteria. In \naddition, the factors such as region and race may also \nhave an influence, so this single-center experiment \nneeds to be improved.\nConclusions\nThis will be the first RCT to evaluate the impact of \nhigh-frequency rTMS at different intensities upon \nCPPS. It may provide a reference for future clinical \ntreatment and research of CPPS.\nRCT status\nRecruiting patients is ongoing at the time of manuscript submission. \nRecruitment began on 1 February 2022 and is expected to be complete by \nSeptember 2022.\nProvenance and peer review\nNot commissioned; peer reviewed externally.\nAuthors’ contributions\nAll authors (MYW, RX, JS, CHY, YQZ, XXZ, CCY, ZYW, MW, SJC, HDQ) have been \ninvolved in RCT design. All authors contributed to drafting the manuscript \nand have approved the final version. The Ethics Committee of Bao’an People’s \nHospital will be responsible for supervision of this RCT.\nFunding\nGuangdong Basic and Applied Basic Research Foundation \n(2021A1515110764). The trial conduct is independent of the funder/sponsor.\nAvailability of data and materials\nNot applicable. No data have been generated. Raw data sharing will be avail-\nable after 31 December 2023 by contacting the author of this article.\nDeclarations\nEthics approval and consent to participate\nThe protocol for this RCT was approved (BYL-20211203) by the Ethics Com-\nmittee of Shenzhen Bao’an People’s Hospital in December 2021. Changes to \nthe protocol will be submitted to this Ethics Committee for approval. This RCT \nwas registered on 14 January 2022 at www. ChiCTR. org and can be identified \nas ChiCTR2200055615. Written informed consent of all participants will be \nobtained after they have read an information manual describing the project \nand potential risks and benefits and if they have questions to discuss with the \ninvestigator.\nCompeting interests\nNone.\n\nPage 9 of 10\nWang et al. Trials           (2023) 24:40 \n \nReceived: 9 July 2022   Accepted: 6 January 2023\nReferences\n 1. Ashton-Miller JA, Delancey JO. Functional anatomy of the female pelvic \nfloor. Ann N Y Acad Sci. 2007;1101:266–96.\n 2. 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Factors affecting the efficacy of repetitive \ntranscranial magnetic stimulation for patients with Alzheimer’s disease. \nZhejiang Da Xue Xue Bao Yi Xue Ban. 2021;50(3):383–9.\n 50. Padberg F, Zwanzger P , Keck ME, et al. Repetitive transcranial magnetic \nstimulation (rTMS) in major depression: relation between efficacy and \nstimulation intensity. Neuropsychopharmacology. 2002;27(4):638–45.\n 51. Passavanti MB, Pota V, Sansone P , et al. Chronic pelvic pain: assessment, \nevaluation, and objectivation. Pain Res Treat. 2017;2017:9472925.\n 52. Clemens JQ, Mullins C, Kusek JW, et al. The MAPP research network: \na novel study of urologic chronic pelvic pain syndromes. BMC Urol. \n2014;14:57.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}