Effect of high-frequency repetitive transcranial magnetic stimulation under different intensities upon rehabilitation of chronic pelvic pain syndrome: protocol for a randomized controlled trial

Introduction Nearly one in seven women worldwide suffers from chronic pelvic pain syndrome (CPPS) each year. Often, CPPS necessitates a combination of treatments. Studies have shown the good therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) upon CPPS. We wish to undertake a randomized controlled trial (RCT) to observe the effect of high-frequency rTMS at different intensities upon CPPS.

and analyses In this prospective, double-blinded RCT, 63 female CPPS participants will be recruited and randomized (1:1:1) to high-intensity rTMS, low-intensity rTMS, or sham rTMS. The control group will receive a 10-day course of conventional pelvic floor (PF) rehabilitation (neuromuscular stimulation, magnetic therapy, or light therapy of the PF). On the basis of conventional treatment, participants in the high-intensity rTMS group will receive pulses of 10 Hz with a resting motor threshold (RMT) of 110% for a total of 15,000 pulses. Participants in the low-intensity rTMS group will receive pulses of 10 Hz with an RMT of 80% with 15,000 pulses. The sham rTMS group will be subjected to sham stimulation with the same sound as produced by the real magnetic stimulation coil. The primary outcome will be determined using a visual analog scale, the Genitourinary Pain Index, Zung Self-Rating Anxiety Scale, and Zung Self-Rating Depression Scale. The secondary outcome will be determined by electromyography of the surface of PF muscles at baseline and after treatment completion. Ethics and dissemination This study is approved by the Ethics Committee of Bao’an People’s Hospital, Shenzhen, Guangdong Province (approval number: BYL20211203). The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences (Protocol version 1.0-20220709). Trial registration Chictr.org.cn, ID: ChiCTR2200055615. Registered on 14 January 2022, http:// www. chictr. org. cn/ showp roj. aspx? proj= 146720. Protocol version 1.0-20220709.

rTMS, CPPS, Randomized controlled trial, RCT protocol *Correspondence: Shangjie Chen [email protected] Hongdang Qu [email protected] 1 The First Affiliated Hospital of Bengbu Medical College, Bengbu, China 2 Second Affiliated Hospital of Shenzhen University, Shenzhen, China Page 2 of 10Wang et al. Trials (2023) 24:40 Strengths and limitations of this RCT design • This is the first randomized controlled trial (RCT) focusing on the efficacy and acceptability of differ - ent intensities of repetitive transcranial magnetic stimulation (rTMS) for chronic pelvic pain syndrome (CPPS). • Participants will be patients who come to Bao’an Peo- ple’s Hospital needing pelvic floor (PF) rehabilitation and who have agreed to treatment of gynecological or urological diseases. Also, Bao’an People’s Hospital must have the relevant equipment. • Treatment will be implemented and followed up by an experienced therapist. Sixty-three female partici - pants with CPPS will be enrolled in this prospective, assessor-blind, three-arm RCT. They will be assigned (1:1:1) randomly to a high-intensity rTMS group, low-intensity rTMS group, or conventional-treat - ment group. This scheme can truly reflect the inter - vention effect of different intensities of rTMS upon CPPS. • Electromyography of the surface of PF muscle will be undertaken before and after the intervention. We aim to investigate the effect of rTMS on the neuromuscu- lar bioelectrical activity of PF muscles after treatment of CPPS. • A methodological challenge will arise from blinded implementation and quality control of the interven - tion. The therapist and physician cannot act in a blinded manner. To minimize a performance bias, therapists and physicians will not be involved in recruitment or data analyses.

Since the 1990s, pelvic floor (PF) dysfunction has become a major problem affecting human health. In females, PF ligaments provide cord-like suspension and support for the stability of the uterus, ovaries, and vesicorectal ure - thra. PF muscles support internal organs like “bridges. ” Therefore, the entire abdominopelvic region may be affected if disease occurs [1–3]. With women taking employment in all walks of life, the requirements for PF support are increasing, and mechanical imbalance in the pelvis and various triggers can promote the occurrence and development of various diseases. Chronic pelvic pain syndrome (CPPS) can be defined as idiopathic pain in the lower abdomen that persists or is intermittent for >6 months and which causes stress to a woman’s psychology, life, and work [4]. Surveys have suggested only 2–10% of those who can receive effica - cious treatment receive the diagnosis in the outpatient setting [5]. The impact of CPPS on women is reflected in emotional anxiety and depression in addition to pain, a decrease in quality of life (QoL), and abnormal aspects of physical sensitivity. CPPS manifests as several peripheral symptoms, and studies have suggested that chronic pain involves sys - temic dysfunction in pain systems [6]. Patients with CPPS have a reduced pain threshold. Long-term pain leads to continuous transmission of pain-sensitizing inhibitory substances (e.g., glutamate) through nerve bundles in the spinal cord. This action increases the level of such substances in cerebrospinal fluid but also in key pain-processing areas, whereas the level of excitatory analgesic substances (e.g., opioid peptides) decreases [7]. All of these actions affect the occurrence and develop - ment of central sensitization and are the result of physi - ological plasticity and persistent changes in the central nervous system (CNS) [8, 9]. The CNS regulates the excitation and inhibition of nerves. The prefrontal cortex is a key region involved in the regulation of slow-acting pain and cognitive process - ing [10, 11]. Studies have shown the mechanism by which central regulation is feasible [12]. Imaging findings have demonstrated that the long-term effects of chronic pain can cause changes in gray matter density in the primary somatosensory cortex, hippocampus, and left amygdala [13]. Even these changes are related to not only pain pro - duction, but the occurrence of depression is significantly correlated with right hippocampal weight, but also the duration of pain; for example, symptom duration of less than 7.5 years was significantly related to the left amyg - dala [14, 15]. After receiving repetitive transcranial mag - netic stimulation (rTMS), the increase in motor cortex (M1) excitability also elicits a potent analgesic effect [16]. This action can increase the concentrations of glutamate and glutamine, and biochemical tests have demonstrated glutamate in the prefrontal cortex of women suffering from CPPS [17, 18]. A change in the glutamine concen - tration has a negative correlation with the pain thresh - old [19]. Also, M1 is related to the pain level of healthy people and patients suffering from pelvic pain. M1 has a positive correlation with the pain threshold, which may be because M1 is involved mostly in pain loops [20, 21]. Therefore, in treatment programs used commonly for CPPS patients (e.g., myofascial manipulation, medium/ low-frequency electrical stimulation, aerobic exercise, and traditional Chinese medicine) [22, 23], the treat - ment concept of central regulation from cortical targets is a rational approach [24, 25]. Also, rTMS (i) stimulates the brain area within 2 cm of the scalp, (ii) can trigger descending inhibitory neural pathways to act at the level of the dorsal horn to reduce chronic pain, (iii) can change Page 3 of 10 Wang et al. Trials (2023) 24:40 neuronal activity, and (iv) affects the cerebral cortex asso- ciated with pain perception (e.g., prefrontal cortex and primary somatosensory cortex) [26, 27]. The allodynia and hyperalgesia elicited in the corti - cal projection pain areas of the pelvis in CPPS patients suggest that dysfunction of the central pain system may be very important in CPPS [6, 28]. Paresthesia and pain occur due to PF dysfunction. As the pain persists, sys - temic changes in the CNS occur, and the CNS remains in a state of high activity, showing disruption of pain regula- tion and enhanced central sensitization processes. rTMS is considered to be a non-invasive method of brain stimulation [29]. rTMS has been shown to regulate the central lesions caused by chronic diseases by inhib - iting and reversing neuronal sensitization [20, 30, 31]. Treatment guidelines based on TMS studies have sug - gested that the left prefrontal cortex could be a target for experimental application of chronic pain. rTMS was first used to treat pelvic and perineal pain in 2012 [32]. Louppe and colleagues carried out rTMS for 4 weeks with a high-frequency resting motor threshold (RMT) of 100% in two female patients (average pain duration >7.5 years) by stimulating M1. These two patients had con - tinuous improvement in pain and QoL during 3 weeks of treatment and follow-up. In subsequent studies, high-fre- quency stimulation with an RMT of 110% [33] and 80% [34] was used as a more reliable option for treatment. In mechanistic studies, different intensities were considered to bring different outcomes, but the effect size was not uniformly positively correlated with intensity. In studies using a RMT of 80% and 110%, a RMT of 80% stimulated improvement of disease symptoms, but a reduction in pain was not obvious. Those studies were also influenced by non-consistent results caused by different disease subtypes and interventions. Therefore, design of a rand - omized controlled trial (RCT) to ascertain if treatment at different intensities of rTMS will have different effects on CPPS development is warranted. We hypothesized that the treatment effect of rTMS upon CPPS is different at different intensities. We suggest that the effect in a low-intensity group will be different compared with that elicited by conventional treatment. In this way, we could determine the efficacy and safety of rTMS in CPPS treatment. Study design and methods Study design Our study will be a triple-arm RCT with a 1:1:1 allocation ratio with allocation concealment and assessor blind - ing. A design framework of three groups in a RCT can minimize (as much as possible) the interference of other factors in the comparison between groups. Simultane - ously, multiple comparisons can be made to ascertain the differences between the stimulated group and non- stimulated group, as well as between groups with differ - ent levels of stimulation. Sixty-three eligible participants will be randomly assigned to 10 high-intensity or low- intensity TMS (15 min each, five times a week) or sham stimulation groups, all receiving these stimuli in addi - tion to their usual pelvic disease treatments. Results for pain and other symptoms will be assessed at baseline and 2 weeks (at the end of the intervention). Data collectors will be blinded to group assignments. The study proce - dure and schedule for outcome assessment for our RCT are presented in Fig. 1 and Table 1. Study population The study population will be women between 20 and 60 years of age suffering from CPPS. Study setting Researchers will be recruited from Bao’an People’s Hos - pital, a class III, class A university, affiliated community hospital in Shenzhen, China. Treatment will take place in the Department of Rehabilitation Medicine. Diagnostic criteria According to European Association of Urology (EAU) Guidelines on Chronic Pelvic Pain (2019 version) and EUA Guidelines on Chronic Pelvic Pain (2019 updated version), participants with CPPS should have chronic pelvic pain: (i) with no proven infection or other obvious local disease that can explain the pain; (ii) associated with negative cognitive, behavioral, sexual, or emotional con - sequences; and (iii) with symptoms suggestive of lower urinary, sexual, intestinal, or gynecological dysfunction. Inclusion criteria Eligible participants must meet the following criteria: (i) the diagnostic criteria and classification for CPPS in the EUA Guidelines on Chronic Pelvic Pain (2019 updated version) [4] must be met; (ii) aged 20–60 years with a his - tory of CPPS; (iii) gynecological examination and auxil - iary examination do not reveal clear pathologic changes; (iv) written informed consent will be obtained and sub - jects will voluntarily participate in randomized con - trolled trials; (v) no treatment within 3 months before RCT initiation; and (vi) conforming to the habit of right- handed hands. Exclusion criteria Patients who have absolute and relative contraindica - tions for rTMS will be excluded according to evidence- based guidelines for the use of rTMS therapy. The exclusion criteria will be patients (1) with a contrain - dication to TMS due to acute systemic or intracranial Page 4 of 10Wang et al. Trials (2023) 24:40 hemorrhagic diseases; (2) with cardiac metal mem - brane or a cardiac pacemaker; (3) with a tendency to bleed; (4) with severe heart disease, severe hyperten - sion, or severe dysfunction of the heart, liver, lungs, or kidneys; (5) who use implantable electronic devices; (6) with intracranial infection/tumor; (7) with intracranial vascular metal stent implantation; (8) with fever; (9) for whom data on vital signs are not available; (10) with adverse reactions to magnetic therapy; (11) with open wounds or infections at the treatment site; (12) with malignant effusions, active pulmonary tuberculosis, or cancer; (13) with severe mental illness or epilepsy; and (14) who are pregnant. Fig. 1 Flowchart of the RCT Page 5 of 10 Wang et al. Trials (2023) 24:40 Withdrawal criteria and management Participants will be allowed or required to withdraw from the RCT if they (i) are determined after evaluation to be unable to continue treatment due to adverse reactions or changes in condition; (ii) do not follow the treatment plan strictly or take other therapies while participating in the RCT; (iii) have significant changes in blood pressure, heart rate, or respiration during treatment; (iv) wish to leave the RCT; and (v) lost visitors. Recruitment Recruitment will be conducted in the Rehabilitation Department of Shenzhen Bao’an People’s Hospital through online and offline methods such as networking, outpatient departments, and screening of inpatient medi- cal records. Patients whose condition may worsen will be evaluated and screened to determine eligibility for par - ticipation based on the inclusion and exclusion criteria stated above. Inpatients wishing to participate will obtain permission from a physician, and a research assistant will obtain written informed consent from the participation before a therapeutic intervention. Randomization, allocation concealment, and blinding After assessment at baseline, eligible participants will be assigned randomly to high-intensity stimulation, low- intensity stimulation, or conventional treatment. Ran - domly assigned sequences will be generated using the “PLAN” program of SAS 9.2 (Cary, NC, USA). Random serial numbers will be generated and placed in opaque, sealed envelopes. They will be administered indepen - dently by statisticians not involved in the recruitment, evaluation, or engagement of participants. Eligible par - ticipants will be notified of the assignment results by an independent research assistant over the telephone. We cannot allow therapists, or attending physicians, to be blinded to assigned treatment, but participants, out - come assessors, and statisticians will be blinded to group assignments. Unblinding If there was a situation such as a medical need or emer - gency which required unblinding, the principal investiga- tor will be informed and make the final decision. Intervention Individuals will be assigned to a family physician at the intervention center. RCT compliance can be obtained daily through treatment records in the treatment instru - ment. Treatment will be recorded in the electronic medi- cal record of participants. Relevant concomitant care and interventions that are permitted during the RCT will be shown to each participant. All three groups will receive routine radiotherapy floor rehabilitation, including neuromuscular stimulation, magnetic therapy, or PF phototherapy. The instrument which will be used to administer neuromuscular stimula - tion of PF muscles will be Phenix-USB4 (Vivaltis, Paris, Table 1 Schedule of enrollment, assessments, and interventions in the RCT “×” indicates at which point of the RCT the respective assessments will take place Page 6 of 10Wang et al. Trials (2023) 24:40 France). It uses 10-min low-frequency electrical stimu - lation and 15-min exercises for PF muscles for a total of 25 min per day. Magnetic therapy of the PF will be done using a Magneuro 60F system (Vishee Medical Technol - ogy, Nanjing, China). Moderate analgesic high-frequency stimulation for 20 min per day will be carried out. Light therapy will be undertaken using Hydrosun ® Irradia - tor 500 (Hydrosun Medizintechnik, Müllheim, Ger - many). This employs direct irradiation of the pain site at a distance of 20–30 cm for 20 min per day. Conventional treatments will be carried out five times per week. Sham rTMS group The sham group will receive rTMS with no actual out - put, stimulated with a fake magnetic stimulation coil that produces the same sound as the real stimulation coil, but without the magnetic field, and has induced a non-stim - ulating effect. High‑intensity rTMS group The high-intensity rTMS group will receive high-inten - sity rTMS in addition to conventional treatment. rTMS treatment will be administered using the CCY 1 stimu - lator (Yiruide, Wuhan, China). An “8”-shaped coil will focus the stimulation. The maximum output will be 2.2 T. The coil will be located in the center of the left M1, placed at 45° inclination from the scalp. The output inten- sity will be a RMT of 110%. A total of 1500 pulses will be administered at each treatment (10 pulses delivered in each sequence, repeat 150 times, 5 s apart). rTMS will be given at 10 Hz for 15 min, and the stimulation site will be M1. rTMS will be administered once a day, five times a week for 2 weeks. Ten sessions, for a total of 15,000 stim - ulations, will be administered. Low‑intensity rTMS group Patients in the low-intensity rTMS group will use identi - cal equipment to those in the high-intensity group. How - ever, the stimulation intensity will be a RMT of 80%. The number of pulses, interval between pulses, and stimu - lation frequency will be identical to those in the high- intensity group. Outcome assessment The variables to be assessed will be patient characteris - tics, primary outcome, and secondary outcome. Patient characteristics at baseline will be documented. Primary and secondary outcomes will be measured at baseline and at the end of the intervention. The time points of

recording will be denoted as T0 and T10. Primary and secondary outcomes will be evaluated by experi - enced staff at Shenzhen Bao’an People’s Hospital, who will not be aware of the results of participant allocation. Patient characteristics Recruiters will use a self-designed questionnaire to col - lect demographic characteristics (e.g., sex, age, height, weight, and reproductive status) as well as a history of disease or drug use. Scores for a visual analog scale (VAS), the Genitourinary Pain Index (GUPI), Zung Self-Rating Anxiety Scale (SAS), and Zung Self-Rating Depression Scale (SDS) will be calculated. Measurements at baseline will be completed before the first treatment. Primary outcome Pain severity will be based on the VAS score [35]. A VAS is a 100-mm line where “zero” indicates complete pain - lessness and “10” indicates the most severe pain imagi - nable. The patient marks pain severity on this line. The simplicity of a VAS enables its use for pain assessment. Changes before and after treatment were compared by the decrease in VAS. Secondary outcomes GUPI [36] will be employed to assess the severity of symptoms in women with urogenital pain. GUPI is a modification of the National Institutes of Health– Chronic Prostatitis Symptom Index and includes female- specific pain (pain at the vaginal entrance, urethral pain, pain during/after sexual intercourse). There are 10 pain items with a total pain subscale score of 0–13, two uri - nary symptom items with a total urine subscale score of 0–10, and three QoL items with a total QoL subscale score of 0–12. SAS [37, 38] is a norm-referenced scale which enjoys widespread use as a screening device for anxiety disor - ders. The scale measures mood over the previous week with a score that is multiplied by 1.25. An SAS score of <50 suggests a “normal” mood, that of 50–59 indicates “mild depression, ” that of 60–69 denotes “moderate depression, ” and that of ≥70 indicates “major depression. ” Studies [6, 39] have suggested that the mood changes of patients with long-term pain are obvious and that a self- rating scale can be used to distinguish their emotions in a preliminary manner. SDS [40] consists of 20 items divided into four self-rat - ing scales. SDS is used to evaluate the subjective feelings of anxious patients within 2 weeks. The score is multi - plied by 1.25. A final SDS score of <50 denotes a “normal” mood, that of 50–59 indicates “mild depression, ” that of 60–69 denotes “moderate depression, ” and that of ≥70 indicates “major depression” [41]. Data for electromyography at the PF surface will be collected at baseline and after the intervention. Electro - myography will be conducted in the Rehabilitation Room of Bao’an People’s Hospital. Participants will be assessed based on the Glazer procedure using a myoelectric PF Page 7 of 10 Wang et al. Trials (2023) 24:40 biofeedback instrument (Medlander Technology, Nan - jing, China). The data collected will be as follows: pre- resting phase, variogram 1, rapid-contraction phase, rise time, recovery time, slow-muscle phase, variogram 2l endurance-test phase, variogram 3, post-first 10-s ratio, post-resting phase, and variogram 4 [42–44]. Safety and participant compensation During the intervention, participants will be monitored for adverse events. Participants will be asked about adverse events after each treatment until the adverse event is resolved. If headache occurs after treatment, relaxation therapy will be given. Or other conditions such as a fall during the treatment will be treated free of charge by a professional therapist until recovery. A participant who is found to be at risk (e.g., suicide and neglect) to him/herself or others, or who has a serious adverse event, will be referred to the relevant clinical ser - vices. Causality will be assessed in relation to rTMS and the severity of the adverse event. Serious adverse events will be reported to the Ethics Committee of Bao’an Peo - ple’s Hospital within 72 h. Sample size According to the study by Pinot-Monange and colleagues [33], the effect size was 0.49 using β = 0.15 and α = 0.05. Pain scores will be taken as the main measurement standard, and G*Power 1.9.2 (www. psych ologie. hhu. de/) will be employed. The study cohort was calculated to be ~51 patients. Taking into account a dropout of 20%, each group will include 21 people from each group. Sixty- three participants will be required for this RCT. Statistical analyses SPSS 26 (IBM, Armonk, NY, USA) will be employed to analyze data. Statistical analyses will be conducted by independent statisticians. First, the Kolmogorov– Smirnov test will be used to ascertain if a normal dis - tribution of data is present. If the data have a normal distribution, then analysis of variance with repeated measures will be used to compare the mean pain scores for each group. P < 0.05 will be considered significant. Continuous variables in the measures of primary and secondary outcomes will be expressed as the mean and standard deviation (normal distribution) or median value (non-normal distribution). Categorical variables will be described as frequencies or percentages. Subgroup analy - sis is not applicable in this RCT. Missing data (loss to fol - low-up, death, withdrawal, etc.) will be updated using the multiple-imputation approach. The significance of adverse reactions will be analyzed using the chi-square test or Fisher’s exact test. If statis - tical analyses between groups are not possible due to insufficient power, adverse events will be tabulated and summarized using descriptive statistics. Collection and management of data Data will be collected by an outcome evaluator using a case report form. The letter will be transcribed into a password-protected document by a research assistant until being “unlocked” at the end of the study. Addition - ally, missing data (loss to follow-up, death, withdrawal, etc.) will be updated using the multiple-imputation approach. Oversight and monitoring The principal investigator and other co-investigators are doctors and professors of rehabilitation who will be responsible for overseeing and monitoring the entire trial. Subject diagnosis, recruitment, and informed con - sent signing will be handled by an independent hospital- affiliated rehabilitation physician. The progress, adverse events, and data quality of the trial will be evaluated by an independent data testing committee composed of Bao’an People’s Hospital Ethics Committee members and inde - pendent therapists who are not affiliated with the study team or sponsors. The study team will meet monthly with the data testing committee to monitor the progress and quality of the study. There will be no interim analysis. Statistical analysis is conducted only after the trial, and if individual participants report serious adverse effects or deterioration during the course of the trial, the principal investigator will make a decision to terminate the trial. Involvement of patients and the public Before recruitment, individual patients and experi - enced therapists not associated with recruitment will be invited to investigate the RCT design and feasibility of the intervention. Based on their comments, the evalua - tion method and timing of treatment will be adjusted to avoid interference with routine treatment arrangements. Patients or members of the public will not be involved in recruitment or data implementation and measurement.

will be sent to participants via written reports and email. The burden of the interventions included in this RCT will not be assessed by patients. During the intervention, participants were contracted to a family physician at the hospital (including records of all visits and regular follow-up visits). The data of the participants in the intervention interruption or the intervention pro - gram are retained, and the reasonable and exposed data can be excluded and counted according to the needs of the participants. Page 8 of 10Wang et al. Trials (2023) 24:40 Ethical approval and communication The protocol for this RCT was approved (BYL-20211203) by the Ethics Committee of Shenzhen Bao’an People’s Hospital in December 2021. Changes to the protocol will be submitted to this Ethics Committee for approval. This RCT was registered on 14 January 2022 at www. ChiCTR. org and can be identified as ChiCTR2200055615. Writ - ten informed consent of all participants will be obtained after they have read an information manual describing the project and potential risks and benefits and if they have questions to discuss with the investigator. Col - lected digital data will be stored in password-protected files. Only the data analyst will have access to the data at the end of the RCT. RCT results will be published in a peer-reviewed journal following standards set by the International Board of Medical Journal Editors and will not involve professional authors, with undetermined data being available in a public repository at the time of pub - lication. RCT results will also be communicated through scientific meetings.

As a non-invasive method of brain stimulation, rTMS has a deeper role than other methods used to study periph - eral regulation [17, 31, 45, 46]. Several studies have revealed that high-frequency rTMS in M1 has therapeu - tic value for chronic intractable pain and generalized pain and compared it with other methods of central regula - tion. rTMS has been supported by more RCT data and has a higher level of evidence than that of other methods [39]. An analgesic effect can be maintained for 2–3 days and up to 8 days after rTMS of M1 [47]. High-frequency rTMS of M1 appears to be suitable for middle-aged women with recurrent idiopathic pain attacks. Our RCT has been designed to compare rTMS of dif - ferent intensities. Thordstein and colleagues [48] dem - onstrated that the central region affected by rTMS may elicit no response at high or low levels of intensity but that an increase in stimulus of just 10% may produce sig - nificant changes. For diseases such as epilepsy [48–50], schizophrenia, and cognitive impairment, experimen - tal studies have suggested that different intensities of rTMS affect astrocytes and cerebral blood flow. In stud - ies investigating use of rTMS for CPPS or other types of chronic pain, uniform parameters (frequency, intensity, duration) or type of stimulation (transcranial magnetic coil) has not been used. In some sessions with an RMT of 80%, the improvement in QoL, anxiety, and depression was not significant. Therefore, we believe in the necessity of designing a RCT to investigate if there is a difference in CPPS if high-frequency rTMS at different intensities is employed. The emotional and psychological problems of CPPS cannot be ignored [6 , 51, 52]. Chronic pain causes abnormal changes in the strength of PF muscles but also affects intestinal activity, urinary system, somatic psychology, QoL, anxiety, and depression. Therefore, we consider it necessary to include pain, urinary out - come, anxiety, depression, and surface electromyogra - phy in outcome assessments. In this study, the age of the subjects was considered to be over 20 years old, which may affect the validity of the experiment. However, we referred to the age of marriage and childbearing that met the criteria. In addition, the factors such as region and race may also have an influence, so this single-center experiment needs to be improved.

This will be the first RCT to evaluate the impact of high-frequency rTMS at different intensities upon CPPS. It may provide a reference for future clinical treatment and research of CPPS. RCT status Recruiting patients is ongoing at the time of manuscript submission. Recruitment began on 1 February 2022 and is expected to be complete by September 2022. Provenance and peer review Not commissioned; peer reviewed externally. Authors’ contributions All authors (MYW, RX, JS, CHY, YQZ, XXZ, CCY, ZYW, MW, SJC, HDQ) have been involved in RCT design. All authors contributed to drafting the manuscript and have approved the final version. The Ethics Committee of Bao’an People’s Hospital will be responsible for supervision of this RCT. Funding Guangdong Basic and Applied Basic Research Foundation (2021A1515110764). The trial conduct is independent of the funder/sponsor. Availability of data and materials Not applicable. No data have been generated. Raw data sharing will be avail- able after 31 December 2023 by contacting the author of this article. Declarations Ethics approval and consent to participate The protocol for this RCT was approved (BYL-20211203) by the Ethics Com- mittee of Shenzhen Bao’an People’s Hospital in December 2021. Changes to the protocol will be submitted to this Ethics Committee for approval. This RCT was registered on 14 January 2022 at www. ChiCTR. org and can be identified as ChiCTR2200055615. Written informed consent of all participants will be obtained after they have read an information manual describing the project and potential risks and benefits and if they have questions to discuss with the investigator. Competing interests None. Page 9 of 10 Wang et al. Trials (2023) 24:40 Received: 9 July 2022 Accepted: 6 January 2023

1. Ashton-Miller JA, Delancey JO. Functional anatomy of the female pelvic floor. Ann N Y Acad Sci. 2007;1101:266–96. 2. Easley DC, Abramowitch SD, Moalli PA. Female pelvic floor biomechanics: bridging the gap. Curr Opin Urol. 2017;27(3):262–7. 3. Xu W, Wang H, Jiang Y, et al. Effects of pelvic biomechanical changes on female pelvic floor dysfunction. J Med Biomech. 2021;36(02):330–4. 4. Guidelines E. EAU guidelines on chronic pelvic pain: EAU Annual Con- gress Barcelona; 2019. 5. Till SR, As-Sanie S, Schrepf A. Psychology of chronic pelvic pain: preva- lence, neurobiological vulnerabilities, and treatment. Clin Obstet Gynecol. 2019;62(1):22–36. 6. Grinberg K, Sela Y, Nissanholtz-Gannot R. New insights about chronic pelvic pain syndrome (CPPS). Int J Environ Res Public Health. 2020;17(9):3005. 7. Yang S, Chang MC. Chronic pain: structural and functional changes in brain structures and associated negative affective states. Int J Mol Sci. 2019;20(13):3130. 8. Sluka KA, Clauw DJ. Neurobiology of fibromyalgia and chronic wide- spread pain. Neuroscience. 2016;338:114–29. 9. Kuner R. Central mechanisms of pathological pain. Nat Med. 2010;16(11):1258–66. 10. Thompson JM, Neugebauer V. Cortico-limbic pain mechanisms. Neurosci Lett. 2019;702:15–23. 11. Kang D, McAuley JH, Kassem MS, et al. What does the grey matter decrease in the medial prefrontal cortex reflect in people with chronic pain? Eur J Pain. 2019;23(2):203–19. 12. Yang S, Chang MC. Effect of repetitive transcranial magnetic stimula- tion on pain management: a systematic narrative review. Front Neurol. 2020;11:114. 13. Huang X, Chen J, Liu S, et al. Impaired frontal-parietal control network in chronic prostatitis/chronic pelvic pain syndrome revealed by graph theoretical analysis: a DTI study. Eur J Neurosci. 2021;53(4):1060–71. 14. Baheti AD, Nicola R, Bennett GL, et al. Magnetic resonance imaging of abdominal and pelvic pain in the pregnant patient. Magn Reson Imaging Clin N Am. 2016;24(2):403–17. https:// pubmed. ncbi. nlm. nih. gov/ 27150 326/. 15. Morotti M, Vincent K, Becker CM. Mechanisms of pain in endometriosis. Eur J Obstet Gynecol Reprod Biol. 2017;209:8–13. 16. Attal N, Poindessous-Jazat F, De Chauvigny E, et al. Repetitive transcranial magnetic stimulation for neuropathic pain: a randomized multicentre sham-controlled trial. Brain. 2021;144(11):3328–39. 17. Lefaucheur JP , Aleman A, Baeken C, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018). Clin Neurophysiol. 2020;131(2):474–528. 18. Che X, Cash RFH, Luo X, et al. High-frequency rTMS over the dorsolateral prefrontal cortex on chronic and provoked pain: a systematic review and meta-analysis. Brain Stimul. 2021;14(5):1135–46. 19. Simis M, Reidler JS, Duarte Macea D, et al. Investigation of central nervous system dysfunction in chronic pelvic pain using magnetic resonance spectroscopy and noninvasive brain stimulation. Pain Pract. 2015;15(5):423–32. 20. Nardone R, Versace V, Sebastianelli L, et al. Transcranial magnetic stimula- tion and bladder function: a systematic review. Clin Neurophysiol. 2019;130(11):2032–7. 21. Giannoni-Luza S, Pacheco-Barrios K, Cardenas-Rojas A, et al. Noninva- sive motor cortex stimulation effects on quantitative sensory testing in healthy and chronic pain subjects: a systematic review and meta-analysis. Pain. 2020;161(9):1955–75. 22. Cottrell AM, Schneider MP , Goonewardene S, et al. Benefits and harms of electrical neuromodulation for chronic pelvic pain: a systematic review. Eur Urol Focus. 2020;6(3):559–71. 23. Carey ET, Moore K. Updates in the approach to chronic pelvic pain: what the treating gynecologist should know. Clin Obstet Gynecol. 2019;62(4):666–76. 24. Perry CP . Current concepts of pelvic congestion and chronic pelvic pain. Jsls. 2001;5(2):105–10. 25. Wozniak S. Chronic pelvic pain. Ann Agric Environ Med. 2016;23(2):223–6. 26. Leung A, Donohue M, Xu R, et al. rTMS for suppressing neuropathic pain: a meta-analysis. J Pain. 2009;10(12):1205–16. 27. Garland EL. Pain processing in the human nervous system: a selec- tive review of nociceptive and biobehavioral pathways. Prim Care. 2012;39(3):561–71. 28. Kaya S, Hermans L, Willems T, et al. Central sensitization in urogyneco- logical chronic pelvic pain: a systematic literature review. Pain Physician. 2013;16(4):291–308. 29. Rossi S, Antal A, Bestmann S, et al. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on train- ing, ethical and regulatory issues: expert guidelines. Clin Neurophysiol. 2021;132(1):269–306. 30. Zhang KL, Yuan H, Wu FF, et al. Analgesic effect of noninvasive brain stimulation for neuropathic pain patients: a systematic review. Pain Ther. 2021;10(1):315–32. 31. O’Connell NE, Marston L, Spencer S, et al. Non-invasive brain stimu- lation techniques for chronic pain. Cochrane Database Syst Rev. 2018;4(4):Cd008208. 32. Louppe JM, Nguyen JP , Robert R, et al. Motor cortex stimulation in refrac- tory pelvic and perineal pain: report of two successful cases. Neurourol Urodyn. 2013;32(1):53–7. 33. Pinot-Monange A, Moisset X, Chauvet P , et al. Repetitive transcranial magnetic stimulation therapy (rTMS) for endometriosis patients with refractory pelvic chronic pain: a pilot study. J Clin Med. 2019;8(4):508. 34. Cervigni M, Onesti E, Ceccanti M, et al. Repetitive transcranial magnetic stimulation for chronic neuropathic pain in patients with bladder pain syndrome/interstitial cystitis. Neurourol Urodyn. 2018;37(8):2678–87. 35. Senechal Q, Echegut P , Bravetti M, et al. Endovascular treatment of pelvic congestion syndrome: visual analog scale follow-up. Front Cardiovasc Med. 2021;8:751178. 36. Clemens JQ, Calhoun EA, Litwin MS, et al. Validation of a modified National Institutes of Health chronic prostatitis symptom index to assess genitourinary pain in both men and women. Urology. 2009;74(5):983–7 quiz 87.e1-3. 37. Dunstan DA, Scott N. Norms for Zung’s self-rating anxiety scale. BMC Psychiatry. 2020;20(1):90. 38. Zung WW. A rating instrument for anxiety disorders. Psychosomatics. 1971;12(6):371–9. 39. Jin Y, Xing G, Li G, et al. High frequency repetitive transcranial magnetic stimulation therapy for chronic neuropathic pain: a meta-analysis. Pain Physician. 2015;18(6):E1029–46. 40. Zung WW. A self-rating depression scale. Arch Gen Psychiatry. 1965;12:63–70. 41. Grandi G, Xholli A, Ferrari S, et al. Intermenstrual pelvic pain, quality of life and mood. Gynecol Obstet Invest. 2013;75(2):97–100. 42. Rocca Rossetti S. Functional anatomy of pelvic floor. Arch Ital Urol Androl. 2016;88(1):28–37. 43. Hagen S, Elders A, Stratton S, et al. Effectiveness of pelvic floor muscle training with and without electromyographic biofeedback for urinary incontinence in women: multicentre randomised controlled trial. BMJ. 2020;371:m3719. 44. Chmielewska D, Stania M, Kucab-Klich K, et al. Electromyographic characteristics of pelvic floor muscles in women with stress urinary incontinence following sEMG-assisted biofeedback training and Pilates exercises. PLoS One. 2019;14(12):e0225647. 45. Moisset X, Lanteri-Minet M, Fontaine D. Neurostimulation methods in the treatment of chronic pain. J Neural Transm (Vienna). 2020;127(4):673–86. 46. Knotkova H, Hamani C, Sivanesan E, et al. Neuromodulation for chronic pain. Lancet. 2021;397(10289):2111–24. 47. Lefaucheur JP , Drouot X, Nguyen JP . Interventional neurophysiology for pain control: duration of pain relief following repetitive transcra- nial magnetic stimulation of the motor cortex. Neurophysiol Clin. 2001;31(4):247–52. 48. Thordstein M, Saar K, Pegenius G, et al. Individual effects of varying stimulation intensity and response criteria on area of activation for differ- ent muscles in humans. A study using navigated transcranial magnetic stimulation. Brain Stimul. 2013;6(1):49–53. Page 10 of 10Wang et al. Trials (2023) 24:40 • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year • At BMC, research is always in progress. Learn more biomedcentral.com/submissions Ready to submit y our researc hReady to submit y our researc h ? Choose BMC and benefit fr om: ? Choose BMC and benefit fr om: 49. Wang J, Huang L, Wei L, et al. Factors affecting the efficacy of repetitive transcranial magnetic stimulation for patients with Alzheimer’s disease. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021;50(3):383–9. 50. Padberg F, Zwanzger P , Keck ME, et al. Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity. Neuropsychopharmacology. 2002;27(4):638–45. 51. Passavanti MB, Pota V, Sansone P , et al. Chronic pelvic pain: assessment, evaluation, and objectivation. Pain Res Treat. 2017;2017:9472925. 52. Clemens JQ, Mullins C, Kusek JW, et al. The MAPP research network: a novel study of urologic chronic pelvic pain syndromes. BMC Urol. 2014;14:57. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations.