Motor cortical neuromodulation in women with Interstitial Cystitis/Bladder Pain Syndrome: reducing pain by improving brain and muscle activity

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Johnson, Molly Bachmann, DPT, Moheb S. Yani, Giselle I. Garcia, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3953427/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Sep, 2024 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Introduction: Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic pain condition creating a wide range of urologic and pain symptoms. There is currently limited evidence to understand the mechanisms of IC/BPS. There have been recent studies suggesting that altered function in brain motor areas, particularly the supplementary motor cortex (SMA), relate to altered bladder sensorimotor control and may play an important role in IC/BPS. This study aims to provide evidence that non-invasive stimulation targeting the motor cortex may help reduce IC/BPS pain, as well as better understand the neural mechanism by which this stimulation targets neuromuscular dysfunction. Methods and analyses: This study is a two-group quadruple-blinded randomized controlled trial (RCT) of active vs. sham repetitive transmagnetic stimulation (rTMS). In addition, our study will also include functional magnetic resonance imaging (fMRI), pelvic floor electromyography (EMG), pelvic exam and outcome measures and questionnaires to further study outcomes. Ethics and dissemination: All aspects of the study were approved by the Institutional Review Board of the University of Southern California (protocol HS-20-01021). All participants provided informed consent by the research coordinator/assistants. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences. Trials Registration: Clinicaltrials.gov NCT04734847 Registered on 2021-02-01. Chronic Pain Transcranial Magnetic Stimulation Pelvic floor muscles Bladder Pain Syndrome BPS Interstitial Cystitis IC Pelvic Pain Chronic Overlapping Pain Condition Motor Cortical Neuromodulation Functional magnetic resonance imaging Supplementary motor area Figures Figure 1 Figure 2 Strengths and limitations of this RCT design Randomized controlled trial (RCT) examining the changes in functional magnetic resonance imaging (fMRI) and brain or pelvic floo r muscle electromyographic (EMG) activity to determine the mechanism of rTMS for IC/BPS. Study design quadruple-blinded RCT with an interventional model of parallel assignment and multiple levels of blinding (Participant, Care Provider, Investigator, Outcomes Assessor) High frequency Repetitive Transcranial Magnetic Stimulation (rTMS) to the pelvic region of supplementary motor area, which we refer to as pelvic-SMA , that regulates pelvic floor muscle activity. Pelvic-SMA was previously identified to be a region of neural dysfunction in IC/BPS. Functional magnetic resonance imaging (fMRI) to measure changes in pelvic-SMA target previously described, performed one hour before and after rTMS treatment to show the comparative change in brain activity post-rTMS treatment. Electromyography (EMG) via internal pelvic floor sensor will be examined during the first treatment (day one) and during the last treatment (day 5) to assess rTMS-related changes in pelvic floor muscle (PFM) activity. Study design reduces risk of treatment variables impacting the effect of rTMS on outcomes, as participants are asked to discontinue other IC/BPS treatments during the 6-week participation in the study, if possible. If this is not medically-advised by the study physician, participants will be asked to report other concurrent treatments. Limitations include not varying the stimulation intensity or number of sessions per group. Background New potential mechanisms of interstitial cystitis/bladder pain syndrome (IC/BPS) in women have recently been proposed.[ 1 ] One newly proposed mechanism identified by functional magnetic resonance imaging (fMRI) is altered activity in sensorimotor cortex, particularly supplementary motor area (SMA), that may lead to dysregulated pelvic floor activity.[ 2 , 3 ] This mechanism is of particular interest because there is strong evidence showing the benefits of motor cortical rTMS, aligned with the cortical representation of the painful body region, in treating neuropathic pain[ 4 ]. Previous studies of rTMS for pain do not typically target a particular marker of altered brain function. Therefore, we designed a study to evaluate whether active rTMS can improve IC/BPS symptoms and whether these changes are related to fMRI-identified changes in brain function would be valuable. Objectives : 1) Primary Objective: To reduce pain in IC/BPS, 2) To improve brain and muscle activity in IC/BPS, 3) Tertiary Objective: To explore if reduced pain is mediated by brain and muscle activity marker improvements. Study design and methods Study design : Two group randomized controlled trial (RCT) of active versus sham rTMS. rTMS uses pulses of magnetic energy to non-invasively stimulate the brain. The rTMS device to be used in this study is the Magstim Rapid 2 . The rTMS device can either connect to a “active” coil (used in the active group) which rests against the scalp and delivers the magnetic energy to the brain or can be connected to an identically-appearing “sham” coil (used in the sham group) that also rests against the scalp but does not deliver any magnetic energy to the brain. The rTMS protocol is specified by the parameters of pulse frequency, duration of pulse delivery (“Train Duration”), intensity, and stimulation location. Our study proposes to have the active rTMS group receive a previously-described rTMS protocol for treatment of patients with chronic pain in research studies (a “high-frequency protocol”)[ 4 ]: a pulse frequency of 10 pulses per second, with 10 second pulse trains, at an intensity of 80% of resting motor threshold, delivered over the pelvic-SMA region, defined in Montreal Neurological Institute (MNI) Coordinates to be X=-2, Y=-16, and Z = 68 mm. A “session” of rTMS in our study will consist of 20 pulse trains, each separated by 50 seconds. Study population: Our study population is actively being recruited through various avenues, including the University of Southern California’s broad medical system, focusing on, but not limited to those in the greater Los Angeles area. Additionally, recruitment has been mindful of inclusivity and equity within our system, recruiting from various settings, including but not limited to our USC Keck hospitals and LA County General Hospital, and outpatient PT clinics in the greater Los Angeles area, in hopes to improve diversity in our participants. Study setting: Participants will be treated at the University of Southern California Division of Biokinesiology and Physical Therapy Applied Movement and Pain Laboratory (AMPL) with MRI being performed onsite at the USC Stevens Institute for Neuroimaging and Neuroinformatics. Study workflow is summarized in Fig. 1 . Inclusion criteria : Female at least 18 years old. Have a diagnosis of IC/BPS by a physician Urologic symptoms present a majority of the time during the most recent 3 months Report 4/10 pain or greater pain in response to “At its worst, on scale 0–10 how bad did your pelvic pain get in the past 3 months?” asked at screening. Exclusion criteria: This study uses several measures to exclude individuals who have a known physical cause of their symptoms such as an active infection, urethral strictures, active cancer treatments/pelvic malignancies, and neurological conditions affecting the bladder. In addition, rTMS and fMRI pose higher than average health consequences to individuals with personal factors such as pregnancy, seizure disorders and chronic headaches. As such, participants with these factors were designated ineligible for this study. Participants will be excluded from the study if they report : Symptomatic urethral stricture On-going neurological conditions affecting the bladder or bowel Active auto-immune or infectious disorders History of cystitis caused by tuberculosis or radiation or chemotherapies History of non-dermatologic cancer Current major psychiatric disorders Severe cardiac, pulmonary, renal, or hepatic disease Conditions or the use of medical devices that are contraindications for either fMRI or rTMS procedures, including pregnancy, seizure disorders, or chronic headaches. Physicians with expertise in clinical TMS or IC/BPS are consulted if there are any questions about eligibility for the study, and their expert opinion documented. Deferral criteria and management: Participants are deferred if They test positive on the McKesson Urinalysis test during the baseline visit or They report having started any new treatments or medications for IC/BPS in the past 3 months during screening For either of the following, interested participants will be re-evaluated in no sooner than 6 weeks. Recruitment: Recruitment for this study was conducted through the Applied Movement and Pain Laboratory (AMPL) in the Department of Biokinesiology and Physical Therapy at the University of Southern California (USC). This study worked with providers in the USC Medical System and outpatient Pelvic Health Physical Therapy centers in the greater Los Angeles area to identify potentially appropriate participants. Additionally, research coordinators used digital platforms such as YouTube, social media and email to inform the broader population of this study as well as subscribers and members of the national support groups. Interested participants were then screened for appropriateness and safety for the trial. Randomization, allocation concealment, and blinding: We will randomize treatment assignments using a randomized block sequence as implemented in the blockrand function in the R statistical package.[ 5 ] To ensure approximately equal allocation to the two arms throughout the study, randomization is conducted in blocks of sizes 2, 4 and 6. The randomization order will be administered by a statistician independent of the participant recruitment and evaluation. A list of 50 record IDs was generated paired with a 4-letter code for the active and sham coil. As participants are enrolled in the study, they are assigned a record ID and matched to the subsequent coil/treatment group. Study staff delivering the intervention know the coil only by code and are specifically instructed that they must remain blinded to which coil is active. This is a double quadruple-blinded study where both the interventionists and participants are blinded to which treatment group they have been assigned (sham vs. active), as are the investigators and outcome assessors. Intervention: The active and sham groups will undergo identical protocol, with the only difference being that the active vs. sham coil used per designated group for the 5-day treatment week. During the participant’s 6-week participation and treatment period, they will be asked to discontinue any other IC/BPS treatments and therapies, to reduce any confounding treatment variables. If this is not medically-advised by the study physician, participants will be asked to report other concurrent treatments. Outcome assessment: Outcomes will be assessed at the initial baseline visit, throughout the treatment week, and at a follow up visit 3 weeks later. At baseline, participants will complete a urine dip test, subjective questionnaires, and a pelvic floor muscle exam. Day 1 of treatment will involve outcome assessment via subjective questionnaires, and fMRI pre and post rTMS, and pelvic floor muscle assessment during rTMS via a surface electromyographic (EMG) sensor that rests just inside the rectum. Treatments 2 through 4 involve outcome assessment via questionnaires and rTMS treatments. Treatments 5 involve outcome assessment via questionnaires (listed below) and rTMS treatment with pelvic floor muscle assessment. A follow up visit 3 weeks later and will include outcome assessment via questionnaires, fMRI, and pelvic exam. Outcome measured assessed include: Demographic information, Genitourinary Pain Index (GUPI), Interstitial Cystitis Symptom Index (ICSI), Overactive Bladder Questionnaire (OAB-q), Urinary Distress Inventory (UDI-6), Complex Multisystem Inventory (CMSI), Collaborative Health Outcomes Registry Body Map (CHOIR), Patient-Reported Outcomes Measurement Information System (PROMIS), Coping Strategies Questionnaire (CSQ), Hospital Anxiety and Depression Scale (HADS), and The Positive and Negative Affect Schedule (PANAS). Primary outcomes: Subjective ratings of pain symptoms are the primary outcome measures of the study. Pain will be assessed using a visual analog scale (VAS): the scale ranges from 0 (no pain) to 10 (worst pain imaginable). Pain will also be assessed using a global response assessment (GRA) asking “As compared to when you started the study treatment, how would you rate your interstitial cystitis/bladder pain syndrome (IC/BPS) symptoms now?”. The 3 pain primary outcome measures are: Longer-term VAS change: before first treatment to 3 weeks after last treatment Shorter-term VAS change: before first treatment to 1 day later just before second treatment GRA: 3 weeks after last treatment Secondary outcomes: Secondary outcomes from fMRI and pelvic EMG will be computed exactly as described previously. [ 3 ] In summary: 1. Change in fractional amplitude of low frequency fluctuations (fALFF) in pelvic-SMA determined from fMRI. This change will be assessed between one hour before and one hour after first treatment. 2. Change in pelvic floor muscle activity from pelvic EMG. This change will be assessed between just before to between five and ten minutes after the start of first treatment. Safety and participant compensation: Transient headache is one of the known side effects of rTMS treatment. During and following every TMS session, we will ask the participant about any incidence of headache, neck pain. If the participant complains of any discomfort or pain during the TMS session, the session will be terminated immediately. The participant’s symptoms and side-effects will be monitored both during treatment and longer-term side effects will be assessed at the follow-up visit (Fig. 2 ). The rTMS is being performed at a low intensity (80% of the FDI-thresholding) and the treatment duration is brief, no dosage changes are proposed. If a participant were to miss a treatment session, they can continue with the remaining scheduled visits and no treatment sessions will be rescheduled. Any moderate or severe side-effect will be reported to the IRB as an adverse event within 24 hours. The participant can withdraw from the study at any time for any reason. Treatment will be discontinued and all side effects will be documented. The study personnel will notify the PI as soon as any possible adverse event occurs and the PI will submit the adverse event reports. IRB will be notified immediately of all adverse and serious adverse events and the DSMB will be notified, as well as receive an annual summary of all adverse events. Oversight and monitoring: A 3-member Data and Safety Monitoring Board (DSMB) has been established for this study in accordance with NIH guidelines. The study’s full case report forms and standard operating procedures (CRF + SOP) stored in secure files. All data collected will be stored in a secure REDCap database without any participant identifying information. Identifying information will be kept securely by the principal investigator (PI). A single password-protected spreadsheet will be maintained by the PI with the participant’s name and contact information as a key to codes and this spreadsheet will be destroyed at study completion to ensure all data analyses are de-identified. Sample size: We designed our study to have N = 50 participants, with N = 25 for each of the two groups (N = 25 sham, N = 25 high-frequency rTMS, to provide 84% power for the primary hypothesis. The primary hypothesis will be tested with a two-sample t-test for a difference in mean pain outcome measure in the high-frequency rTMS group versus the sham group. We performed this power calculation using G*Power Version 3.1 under the assumptions of a two-sided hypothesis test, a type I error rate of 0.05, and the following effect sizes from the literature. In a prior study with N = 13 [ 6 ], pain (measured on a 100 point scale) was reduced an average of 15 points in the high-frequency rTMS group (SD = 20) and 3 points in the sham group (SD = 22) at 3 weeks after the last rTMS session, compared to baseline. Statistical analyses: Data will be analyzed using R [ 7 ] by a blinded statistician not involved with participants or data collection. Initiative descriptive analyses will include evaluation of the distributions of all variables to evaluate modeling assumptions (e.g., Shapiro-Wilk test for normality) and identify potential extreme values. All data will be included in the primary analysis, but any extreme values will be discussed with the study team and potentially excluded in a sensitivity analysis should the extreme value be suspected to be erroneous. Hypothesis tests will be two-tailed, using a significance level of α = 0.05. The primary hypotheses will be evaluated using a two sample t-test for a difference in mean pain outcome between the two groups, assuming normality of the outcome (or its natural log transformation) in each group. If normality assumptions are not satisfied, we will instead use the nonparametric alternative to the two sample t-test, the Wilcoxon Rank Sum test to test for a difference in medians between the two groups. The number of adverse events will be tabulated and compared across the two groups using a chi-square test or Fisher’s exact test. Final primary hypothesis results and R code for producing these results will be presented to the Independent Monitoring Committee by the blinded statistician for certification. The independent DSMB statistician will unblind the results and assign the true group labels. Secondary and tertiary analyses will be performed unblinded, using two-sample t-tests (or Wilcoxon Rank Sum tests) and standard mediation analysis methods. [ 8 ] Collection and management of data: Participants will receive seven in-person visits at the University of Southern California Health Science Campus Applied Movement and Pain Laboratory (AMPL) over the course of approximately 1 month. On the first (baseline) in-person visit, the participant will be tested to rule out any urinary tract infection (UTI) and pending the test is negative, they will proceed with the process of collecting EMG data and a pelvic examination. Additionally, the participant will complete a series of online questionnaires. Treatment week, which consists of 5-in person (Monday-Friday) sessions, is then scheduled no greater than 2 weeks post-baseline visit. In the 3 days preceding this treatment week, the participants will fill out several online questionnaires pertaining to their pain level each morning, as well as the same questionnaires prior to each rTMS treatment. During the treatment week, the participant will receive rTMS treatment, based on their randomization group (treatment vs. sham). On the first of the 5 day treatments, brain imaging fMRI will be taken before and after brain stimulation (rTMS). Additionally, the use of a rectal EMG sensor will be used Monday and Friday during rTMS treatment. The final portion of data collection occurs 3 weeks post Friday of the 5-day treatment week, preceded by 3 days of the same questionnaires to understand any changes in their pelvic pain or urinary urgency. During this final in-person visit, the participant completed the same set of questionnaires administered at the baseline visit, followed by fMRI, an EEG and pelvic examination. Bias: Several measures to reduce bias have been implemented, including that all questionnaires are self-reported and have the option of being provided in English or Spanish, with the option for the participant given the option of “I prefer not to answer” for any questions, due to the sensitive and intimate nature of some questionnaires. Standardized screening processes are utilized, which can be provided either in English or Spanish, depending on the potential participants preference to improve communication, understanding and inclusivity. While we are recruiting from various settings, one bias noted is that the majority of our participants captured from advertisements/flyers (ICD-10 code based) are those with healthcare insurance vs. those without health care insurance, which can be linked to differences in socioeconomic factors. Additionally, our study is recruiting females only, assuming they not only identify as female but have female anatomy, however we realize this is a limit in our inclusion criteria description, as we are basing our recruitment on female anatomy and not gender. Discussion Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a debilitating condition occurring in millions of women in the United States.[ 9 , 10 ] The underlying mechanism of IC/BPS is not well understood; clinical trials of agents directed at potential targets in the bladder have not identified any generally effective treatments.[ 11 ] Recent studies have suggested that altered function in brain motor areas, not directly related to bladder sensation, may play a critical role in IC/BPS.[ 2 , 12 – 14 ] Emerging evidence suggests that altered control of pelvic floor muscles may contribute to IC/BPS. Patients with IC/BPS have increased pelvic floor muscle activity,[ 15 ] potentially caused by changes in supplementary motor area (SMA).[ 2 ] Although pelvic floor physical therapy may be beneficial,[ 16 ] its results may be suboptimal since it may not directly target dysfunction in SMA. Our laboratory has demonstrated unique expertise in understanding the neural control of pelvic floor muscles.[ 17 – 19 ] We have found that women with IC/BPS have altered activity compared to healthy women in a subregion of SMA that controls pelvic floor muscles (that we refer to as pelvic-SMA).[ 2 ] Our findings fit with an expanding literature suggesting that chronic pain is caused by motor cortical changes that, while initially beneficial to generate protective muscle activity, are ultimately maladaptive and perpetuate pain through involuntary and uncomfortable muscle activity.[ 20 – 22 ] Because pelvic-SMA is a superficial cortical region, it may be possible to use repetitive transcranial magnetic stimulation (rTMS) to treat IC/BPS. Our published resting-state functional magnetic resonance imaging (rs-fMRI) findings hint at reduced activity in pelvic-SMA in women with IC/BPS,[ 2 ] which would be consistent with the large body of evidence suggesting high-frequency excitatory rTMS over motor cortex is the best stimulation protocol to reduce pain.[ 4 ] Increased resting pelvic floor muscle activity in IC/BPS could result, since pelvic-SMA controls pelvic floor muscles with both excitation and inhibition.[ 23 – 25 ] Using rs-fMRI, we will determine if a high-frequency rTMS protocol improves pelvic-SMA activity in women with IC/BPS by moving it in the direction of healthy women. Our published work has identified that pelvic-SMA is an important brain region-of-interest in IC/BPS. Our current trial will test whether modulation of pelvic-SMA function provides a mechanism by which IC/BPS symptoms can be reduced. We will then be able to conduct future studies to determine if neuromodulation of pelvic-SMA, by itself or in conjunction with other therapies, may be able to generate long-term reduction or even remission of IC/BPS symptoms. Declarations Ethics approval and consent to participate: All aspects of the study were approved by the Institutional Review Board of the University of Southern California (protocol HS-20-01021). All participants provided informed consent by the research coordinator/assistants. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences. Consent for publication: Not applicable—no identifiable personal or clinical details or identifying images of images are presented here or will be presented in the reports of the trials results. Availability of data and material: The data from this study will not be shared publicly. Competing Interests: The authors declare that they have no competing interests. Funding: This study is funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) (R01 DK121724), clinicaltrails.gov NCT04734847 Dates 08/2020-04/2025. Author Contributions: JK and LR serve as principal investigators for this study. The authors confirm contribution to the paper as follows: study conception and design: JK and LR; data collection: MY, EJ, GG; analysis and interpretation of results: JK, LR; draft manuscript preparation: MY, EJ, MB, GG, JJ, LR. All authors reviewed the results and approved the final version of the manuscript. Acknowledgements: We would like to thank the participants for their time and willingness to help. References Clemens JQ, Mullins C, Ackerman AL, Bavendam T, van Bokhoven A, Ellingson BM, et al. Urologic chronic pelvic pain syndrome: insights from the MAPP Research Network. Nat Rev Urol. 2019;16:187–200. Kilpatrick LA, Tillisch K, Naliboff B, Labus J, Jiang Z, Farmer M, et al. 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Wang Z, Chang HH, Gao Y, Zhang R, Guo Y, Holschneider DP, et al. Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study. PLoS ONE. 2017;12:e0182976. Kutch JJ, Yani MS, Asavasopon S, Kirages DJ, Rana M, Cosand L, et al. Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network Neuroimaging Study. Neuroimage Clin. 2015;8:493–502. Hodges PW, Tucker K. Moving differently in pain: a new theory to explain the adaptation to pain. Pain. 2011;152:S90–8. Cheney PD, Fetz EE. Functional classes of primate corticomotoneuronal cells and their relation to active force. J Neurophysiol. 1980;44:773–91. Cheney PD, Fetz EE, Palmer SS. Patterns of facilitation and suppression of antagonist forelimb muscles from motor cortex sites in the awake monkey. J Neurophysiol. 1985;53:805–20. Sherrington SCS. The Integrative Action of the Nervous System. 1906. Supplementary Files SPIRITchecklistICBrainStim.docx Cite Share Download PDF Status: Published Journal Publication published 12 Sep, 2024 Read the published version in Trials → Version 1 posted Editorial decision: Major revision 05 Jul, 2024 Reviewers agreed at journal 05 Jul, 2024 Reviewers invited by journal 03 Jul, 2024 Editor assigned by journal 02 May, 2024 First submitted to journal 26 Apr, 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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Johnson","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIie3NPQrCMBTA8RcCcalmTRF6hkjBsV5F6ergARwqhbgorop4B0EQx0jAyQMIOuji5KCjWMHnB7hI29Ehf0IIj/x4ADbbP0ZphDcD/h3Vswh5EzeieQm8CIDUeQkvkM7+sih5/nagqZMEOGnKVOLGJK6M1syv7gzQogrB7Z3SiTRElYuKNeabEEmkQW4yttQM6d7uSGZDJE6ioZZFJCUKD2tMxZMw3CIyiDAkdvuK+WJn5HKiQkesj61Uwgdmeb6qlcfHncP+lAQe74bTVPJphfsANL6cPN+ftV/EZrPZbD97ANdzQNupc6D7AAAAAElFTkSuQmCC","orcid":"","institution":"University of Southern California Division of Biokinesiology and Physical Therapy","correspondingAuthor":true,"prefix":"","firstName":"Eileen","middleName":"V.","lastName":"Johnson","suffix":""},{"id":322176122,"identity":"f2076671-dcbe-47b8-8083-57d946580407","order_by":1,"name":"Molly Bachmann, DPT","email":"","orcid":"","institution":"University of Southern California","correspondingAuthor":false,"prefix":"","firstName":"DPT","middleName":"Molly","lastName":"Bachmann","suffix":""},{"id":322176123,"identity":"edf32a26-3da4-4102-b5a3-362bd17f50ba","order_by":2,"name":"Moheb S. Yani","email":"","orcid":"","institution":"UCLA: University of California Los Angeles","correspondingAuthor":false,"prefix":"","firstName":"Moheb","middleName":"S.","lastName":"Yani","suffix":""},{"id":322176124,"identity":"f8753dbc-29ee-490e-81d5-1bed05e3bec4","order_by":3,"name":"Giselle I. Garcia","email":"","orcid":"","institution":"University of Southern California Division of Biokinesiology and Physical Therapy","correspondingAuthor":false,"prefix":"","firstName":"Giselle","middleName":"I.","lastName":"Garcia","suffix":""},{"id":322176125,"identity":"84d26ebe-fdbd-4845-b548-3562a1a746dc","order_by":4,"name":"Larissa V. Rodriguez","email":"","orcid":"","institution":"Cornell University","correspondingAuthor":false,"prefix":"","firstName":"Larissa","middleName":"V.","lastName":"Rodriguez","suffix":""},{"id":322176126,"identity":"aff98b00-84a0-483d-b78d-3a4d40433bef","order_by":5,"name":"Jason J. Kutch","email":"","orcid":"","institution":"University of Southern California Division of Biokinesiology and Physical Therapy","correspondingAuthor":false,"prefix":"","firstName":"Jason","middleName":"J.","lastName":"Kutch","suffix":""}],"badges":[],"createdAt":"2024-02-13 11:39:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3953427/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3953427/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-024-08450-w","type":"published","date":"2024-09-12T15:58:25+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":61197637,"identity":"f33a65a2-6b24-4329-bcff-954f6d2624e3","added_by":"auto","created_at":"2024-07-27 00:33:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":162567,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy workflow\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3953427/v1/7dbcc8434cd60f92400b29e8.png"},{"id":61197636,"identity":"c92249ea-40e4-4217-9967-54695f8e65c5","added_by":"auto","created_at":"2024-07-27 00:33:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":65134,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy Schedule of Enrolment, Event and Assessments\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3953427/v1/841156a8e0d4fd21b10c33b5.png"},{"id":64619278,"identity":"d17aaf39-4416-4a62-8952-9b8fb9c73843","added_by":"auto","created_at":"2024-09-16 16:13:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":697822,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3953427/v1/4e5cdb83-15f4-4be1-973a-11be716c81f8.pdf"},{"id":61197635,"identity":"7686b15d-32b6-4517-893b-dda37e3d217d","added_by":"auto","created_at":"2024-07-27 00:33:31","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":40032,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklistICBrainStim.docx","url":"https://assets-eu.researchsquare.com/files/rs-3953427/v1/d411a41f19fdd5f3a5287699.docx"}],"financialInterests":"","formattedTitle":"Motor cortical neuromodulation in women with Interstitial Cystitis/Bladder Pain Syndrome: reducing pain by improving brain and muscle activity","fulltext":[{"header":"Strengths and limitations of this RCT design","content":"\u003cul\u003e\n \u003cli\u003eRandomized controlled trial (RCT) examining the\u0026nbsp;changes\u0026nbsp;in\u0026nbsp;functional magnetic resonance imaging (fMRI) and\u0026nbsp;brain\u0026nbsp;or pelvic floo\u003cstrong\u003er\u0026nbsp;\u003c/strong\u003emuscle electromyographic (EMG)\u0026nbsp;activity\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eto determine the mechanism of rTMS for IC/BPS.\u003c/li\u003e\n \u003cli\u003eStudy design\u0026nbsp;quadruple-blinded RCT with an interventional model of parallel assignment and\u0026nbsp;multiple levels of blinding (Participant, Care Provider, Investigator, Outcomes Assessor)\u003c/li\u003e\n \u003cli\u003eHigh frequency Repetitive Transcranial Magnetic Stimulation (rTMS) to the pelvic region of supplementary motor area, which we refer to as pelvic-SMA\u003cem\u003e,\u003c/em\u003e that regulates pelvic floor\u0026nbsp;muscle\u0026nbsp;activity. Pelvic-SMA was previously identified to be a region of neural dysfunction in IC/BPS.\u003c/li\u003e\n \u003cli\u003eFunctional magnetic resonance imaging (fMRI) to measure changes in pelvic-SMA target previously described, performed one hour before and after rTMS treatment to show the comparative change in brain activity post-rTMS treatment.\u003c/li\u003e\n \u003cli\u003eElectromyography (EMG) via internal pelvic floor sensor will be examined during the first treatment (day one) and during the last treatment (day 5) to assess rTMS-related changes in pelvic floor muscle (PFM) activity.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eStudy design reduces risk of treatment variables impacting the effect of rTMS on outcomes, as participants are asked to\u0026nbsp;discontinue other IC/BPS treatments during the 6-week participation in the study, if possible. If this is not medically-advised by the study physician, participants will be asked to report other concurrent treatments.\u003c/li\u003e\n \u003cli\u003eLimitations include not varying the stimulation intensity or number of sessions per group.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Background","content":"\u003cp\u003eNew potential mechanisms of interstitial cystitis/bladder pain syndrome (IC/BPS) in women have recently been proposed.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] One newly proposed mechanism identified by functional magnetic resonance imaging (fMRI) is altered activity in sensorimotor cortex, particularly supplementary motor area (SMA), that may lead to dysregulated pelvic floor activity.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] This mechanism is of particular interest because there is strong evidence showing the benefits of motor cortical rTMS, aligned with the cortical representation of the painful body region, in treating neuropathic pain[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Previous studies of rTMS for pain do not typically target a particular marker of altered brain function. Therefore, we designed a study to evaluate whether active rTMS can improve IC/BPS symptoms and whether these changes are related to fMRI-identified changes in brain function would be valuable.\u003c/p\u003e \u003cp\u003e \u003cb\u003eObjectives\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e1) Primary Objective: To reduce pain in IC/BPS, 2) To improve brain and muscle activity in IC/BPS, 3) Tertiary Objective: To explore if reduced pain is mediated by brain and muscle activity marker improvements.\u003c/p\u003e"},{"header":"Study design and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e\u003cem\u003eStudy design\u003c/em\u003e:\u003c/h2\u003e \u003cp\u003eTwo group randomized controlled trial (RCT) of active versus sham rTMS. rTMS uses pulses of magnetic energy to non-invasively stimulate the brain. The rTMS device to be used in this study is the Magstim Rapid\u003csup\u003e2\u003c/sup\u003e. The rTMS device can either connect to a \u0026ldquo;active\u0026rdquo; coil (used in the active group) which rests against the scalp and delivers the magnetic energy to the brain or can be connected to an identically-appearing \u0026ldquo;sham\u0026rdquo; coil (used in the sham group) that also rests against the scalp but does not deliver any magnetic energy to the brain. The rTMS protocol is specified by the parameters of pulse frequency, duration of pulse delivery (\u0026ldquo;Train Duration\u0026rdquo;), intensity, and stimulation location.\u003c/p\u003e \u003cp\u003eOur study proposes to have the active rTMS group receive a previously-described rTMS protocol for treatment of patients with chronic pain in research studies (a \u0026ldquo;high-frequency protocol\u0026rdquo;)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]: a pulse frequency of 10 pulses per second, with 10 second pulse trains, at an intensity of 80% of resting motor threshold, delivered over the pelvic-SMA region, defined in Montreal Neurological Institute (MNI) Coordinates to be X=-2, Y=-16, and Z\u0026thinsp;=\u0026thinsp;68 mm. A \u0026ldquo;session\u0026rdquo; of rTMS in our study will consist of 20 pulse trains, each separated by 50 seconds.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population:\u003c/h2\u003e \u003cp\u003eOur study population is actively being recruited through various avenues, including the University of Southern California\u0026rsquo;s broad medical system, focusing on, but not limited to those in the greater Los Angeles area. Additionally, recruitment has been mindful of inclusivity and equity within our system, recruiting from various settings, including but not limited to our USC Keck hospitals and LA County General Hospital, and outpatient PT clinics in the greater Los Angeles area, in hopes to improve diversity in our participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy setting:\u003c/h2\u003e \u003cp\u003e Participants will be treated at the University of Southern California Division of Biokinesiology and Physical Therapy Applied Movement and Pain Laboratory (AMPL) with MRI being performed onsite at the USC Stevens Institute for Neuroimaging and Neuroinformatics. Study workflow is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInclusion criteria\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFemale at least 18 years old.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHave a diagnosis of IC/BPS by a physician\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eUrologic symptoms present a majority of the time during the most recent 3 months\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eReport 4/10 pain or greater pain in response to \u0026ldquo;At its worst, on scale 0\u0026ndash;10 how bad did your pelvic pain get in the past 3 months?\u0026rdquo; asked at screening.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eExclusion criteria:\u003c/h2\u003e \u003cp\u003eThis study uses several measures to exclude individuals who have a known physical cause of their symptoms such as an active infection, urethral strictures, active cancer treatments/pelvic malignancies, and neurological conditions affecting the bladder. In addition, rTMS and fMRI pose higher than average health consequences to individuals with personal factors such as pregnancy, seizure disorders and chronic headaches. As such, participants with these factors were designated ineligible for this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eParticipants will be excluded from the study if they report\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSymptomatic urethral stricture\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eOn-going neurological conditions affecting the bladder or bowel\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eActive auto-immune or infectious disorders\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHistory of cystitis caused by tuberculosis or radiation or chemotherapies\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHistory of non-dermatologic cancer\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCurrent major psychiatric disorders\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSevere cardiac, pulmonary, renal, or hepatic disease\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eConditions or the use of medical devices that are contraindications for either fMRI or rTMS procedures, including pregnancy, seizure disorders, or chronic headaches.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003ePhysicians with expertise in clinical TMS or IC/BPS are consulted if there are any questions about eligibility for the study, and their expert opinion documented.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDeferral criteria and management:\u003c/h2\u003e \u003cp\u003eParticipants are deferred if\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThey test positive on the McKesson Urinalysis test during the baseline visit or\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThey report having started any new treatments or medications for IC/BPS in the past 3 months during screening\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eFor either of the following, interested participants will be re-evaluated in no sooner than 6 weeks.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment:\u003c/h2\u003e \u003cp\u003eRecruitment for this study was conducted through the Applied Movement and Pain Laboratory (AMPL) in the Department of Biokinesiology and Physical Therapy at the University of Southern California (USC). This study worked with providers in the USC Medical System and outpatient Pelvic Health Physical Therapy centers in the greater Los Angeles area to identify potentially appropriate participants. Additionally, research coordinators used digital platforms such as YouTube, social media and email to inform the broader population of this study as well as subscribers and members of the national support groups. Interested participants were then screened for appropriateness and safety for the trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eRandomization, allocation concealment, and blinding:\u003c/h2\u003e \u003cp\u003eWe will randomize treatment assignments using a randomized block sequence as implemented in the blockrand function in the R statistical package.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] To ensure approximately equal allocation to the two arms throughout the study, randomization is conducted in blocks of sizes 2, 4 and 6. The randomization order will be administered by a statistician independent of the participant recruitment and evaluation. A list of 50 record IDs was generated paired with a 4-letter code for the active and sham coil. As participants are enrolled in the study, they are assigned a record ID and matched to the subsequent coil/treatment group. Study staff delivering the intervention know the coil only by code and are specifically instructed that they must remain blinded to which coil is active. This is a double quadruple-blinded study where both the interventionists and participants are blinded to which treatment group they have been assigned (sham vs. active), as are the investigators and outcome assessors.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eIntervention:\u003c/h2\u003e \u003cp\u003eThe active and sham groups will undergo identical protocol, with the only difference being that the active vs. sham coil used per designated group for the 5-day treatment week. During the participant\u0026rsquo;s 6-week participation and treatment period, they will be asked to discontinue any other IC/BPS treatments and therapies, to reduce any confounding treatment variables. If this is not medically-advised by the study physician, participants will be asked to report other concurrent treatments.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eOutcome assessment:\u003c/h2\u003e \u003cp\u003eOutcomes will be assessed at the initial baseline visit, throughout the treatment week, and at a follow up visit 3 weeks later. At baseline, participants will complete a urine dip test, subjective questionnaires, and a pelvic floor muscle exam. Day 1 of treatment will involve outcome assessment via subjective questionnaires, and fMRI pre and post rTMS, and pelvic floor muscle assessment during rTMS via a surface electromyographic (EMG) sensor that rests just inside the rectum. Treatments 2 through 4 involve outcome assessment via questionnaires and rTMS treatments. Treatments 5 involve outcome assessment via questionnaires (listed below) and rTMS treatment with pelvic floor muscle assessment. A follow up visit 3 weeks later and will include outcome assessment via questionnaires, fMRI, and pelvic exam.\u003c/p\u003e \u003cp\u003eOutcome measured assessed include: Demographic information, Genitourinary Pain Index (GUPI), Interstitial Cystitis Symptom Index (ICSI), Overactive Bladder Questionnaire (OAB-q), Urinary Distress Inventory (UDI-6), Complex Multisystem Inventory (CMSI), Collaborative Health Outcomes Registry Body Map (CHOIR), Patient-Reported Outcomes Measurement Information System (PROMIS), Coping Strategies Questionnaire (CSQ), Hospital Anxiety and Depression Scale (HADS), and The Positive and Negative Affect Schedule (PANAS).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcomes:\u003c/h2\u003e \u003cp\u003eSubjective ratings of pain symptoms are the primary outcome measures of the study. Pain will be assessed using a visual analog scale (VAS): the scale ranges from 0 (no pain) to 10 (worst pain imaginable). Pain will also be assessed using a global response assessment (GRA) asking \u0026ldquo;As compared to when you started the study treatment, how would you rate your interstitial cystitis/bladder pain syndrome (IC/BPS) symptoms now?\u0026rdquo;. The 3 pain primary outcome measures are:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eLonger-term VAS change: before first treatment to 3 weeks after last treatment\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eShorter-term VAS change: before first treatment to 1 day later just before second treatment\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eGRA: 3 weeks after last treatment\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes:\u003c/h2\u003e \u003cp\u003eSecondary outcomes from fMRI and pelvic EMG will be computed exactly as described previously. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] In summary:\u003c/p\u003e \u003cp\u003e1. Change in fractional amplitude of low frequency fluctuations (fALFF) in pelvic-SMA determined from fMRI. This change will be assessed between one hour before and one hour after first treatment.\u003c/p\u003e \u003cp\u003e2. Change in pelvic floor muscle activity from pelvic EMG. This change will be assessed between just before to between five and ten minutes after the start of first treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSafety and participant compensation:\u003c/h2\u003e \u003cp\u003eTransient headache is one of the known side effects of rTMS treatment. During and following every TMS session, we will ask the participant about any incidence of headache, neck pain. If the participant complains of any discomfort or pain during the TMS session, the session will be terminated immediately. The participant\u0026rsquo;s symptoms and side-effects will be monitored both during treatment and longer-term side effects will be assessed at the follow-up visit (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The rTMS is being performed at a low intensity (80% of the FDI-thresholding) and the treatment duration is brief, no dosage changes are proposed. If a participant were to miss a treatment session, they can continue with the remaining scheduled visits and no treatment sessions will be rescheduled. Any moderate or severe side-effect will be reported to the IRB as an adverse event within 24 hours.\u003c/p\u003e \u003cp\u003eThe participant can withdraw from the study at any time for any reason. Treatment will be discontinued and all side effects will be documented. The study personnel will notify the PI as soon as any possible adverse event occurs and the PI will submit the adverse event reports. IRB will be notified immediately of all adverse and serious adverse events and the DSMB will be notified, as well as receive an annual summary of all adverse events.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eOversight and monitoring:\u003c/h2\u003e \u003cp\u003e A 3-member Data and Safety Monitoring Board (DSMB) has been established for this study in accordance with NIH guidelines. The study\u0026rsquo;s full case report forms and standard operating procedures (CRF\u0026thinsp;+\u0026thinsp;SOP) stored in secure files. All data collected will be stored in a secure REDCap database without any participant identifying information. Identifying information will be kept securely by the principal investigator (PI). A single password-protected spreadsheet will be maintained by the PI with the participant\u0026rsquo;s name and contact information as a key to codes and this spreadsheet will be destroyed at study completion to ensure all data analyses are de-identified.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSample size:\u003c/h2\u003e \u003cp\u003eWe designed our study to have N\u0026thinsp;=\u0026thinsp;50 participants, with N\u0026thinsp;=\u0026thinsp;25 for each of the two groups (N\u0026thinsp;=\u0026thinsp;25 sham, N\u0026thinsp;=\u0026thinsp;25 high-frequency rTMS, to provide 84% power for the primary hypothesis. The primary hypothesis will be tested with a two-sample t-test for a difference in mean pain outcome measure in the high-frequency rTMS group versus the sham group. We performed this power calculation using G*Power Version 3.1 under the assumptions of a two-sided hypothesis test, a type I error rate of 0.05, and the following effect sizes from the literature. In a prior study with N\u0026thinsp;=\u0026thinsp;13 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], pain (measured on a 100 point scale) was reduced an average of 15 points in the high-frequency rTMS group (SD\u0026thinsp;=\u0026thinsp;20) and 3 points in the sham group (SD\u0026thinsp;=\u0026thinsp;22) at 3 weeks after the last rTMS session, compared to baseline.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses:\u003c/h2\u003e \u003cp\u003eData will be analyzed using R [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] by a blinded statistician not involved with participants or data collection. Initiative descriptive analyses will include evaluation of the distributions of all variables to evaluate modeling assumptions (e.g., Shapiro-Wilk test for normality) and identify potential extreme values. All data will be included in the primary analysis, but any extreme values will be discussed with the study team and potentially excluded in a sensitivity analysis should the extreme value be suspected to be erroneous. Hypothesis tests will be two-tailed, using a significance level of α\u0026thinsp;=\u0026thinsp;0.05. The primary hypotheses will be evaluated using a two sample t-test for a difference in mean pain outcome between the two groups, assuming normality of the outcome (or its natural log transformation) in each group. If normality assumptions are not satisfied, we will instead use the nonparametric alternative to the two sample t-test, the Wilcoxon Rank Sum test to test for a difference in medians between the two groups. The number of adverse events will be tabulated and compared across the two groups using a chi-square test or Fisher\u0026rsquo;s exact test. Final primary hypothesis results and R code for producing these results will be presented to the Independent Monitoring Committee by the blinded statistician for certification. The independent DSMB statistician will unblind the results and assign the true group labels. Secondary and tertiary analyses will be performed unblinded, using two-sample t-tests (or Wilcoxon Rank Sum tests) and standard mediation analysis methods. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eCollection and management of data:\u003c/h2\u003e \u003cp\u003e Participants will receive seven in-person visits at the University of Southern California Health Science Campus Applied Movement and Pain Laboratory (AMPL) over the course of approximately 1 month. On the first (baseline) in-person visit, the participant will be tested to rule out any urinary tract infection (UTI) and pending the test is negative, they will proceed with the process of collecting EMG data and a pelvic examination. Additionally, the participant will complete a series of online questionnaires. Treatment week, which consists of 5-in person (Monday-Friday) sessions, is then scheduled no greater than 2 weeks post-baseline visit. In the 3 days preceding this treatment week, the participants will fill out several online questionnaires pertaining to their pain level each morning, as well as the same questionnaires prior to each rTMS treatment. During the treatment week, the participant will receive rTMS treatment, based on their randomization group (treatment vs. sham). On the first of the 5 day treatments, brain imaging fMRI will be taken before and after brain stimulation (rTMS). Additionally, the use of a rectal EMG sensor will be used Monday and Friday during rTMS treatment.\u003c/p\u003e \u003cp\u003eThe final portion of data collection occurs 3 weeks post Friday of the 5-day treatment week, preceded by 3 days of the same questionnaires to understand any changes in their pelvic pain or urinary urgency. During this final in-person visit, the participant completed the same set of questionnaires administered at the baseline visit, followed by fMRI, an EEG and pelvic examination.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eBias:\u003c/h2\u003e \u003cp\u003eSeveral measures to reduce bias have been implemented, including that all questionnaires are self-reported and have the option of being provided in English or Spanish, with the option for the participant given the option of \u0026ldquo;I prefer not to answer\u0026rdquo; for any questions, due to the sensitive and intimate nature of some questionnaires. Standardized screening processes are utilized, which can be provided either in English or Spanish, depending on the potential participants preference to improve communication, understanding and inclusivity.\u003c/p\u003e \u003cp\u003e While we are recruiting from various settings, one bias noted is that the majority of our participants captured from advertisements/flyers (ICD-10 code based) are those with healthcare insurance vs. those without health care insurance, which can be linked to differences in socioeconomic factors. Additionally, our study is recruiting females only, assuming they not only identify as female but have female anatomy, however we realize this is a limit in our inclusion criteria description, as we are basing our recruitment on female anatomy and not gender.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eInterstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a debilitating condition occurring in millions of women in the United States.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] The underlying mechanism of IC/BPS is not well understood; clinical trials of agents directed at potential targets in the bladder have not identified any generally effective treatments.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Recent studies have suggested that altered function in brain motor areas, not directly related to bladder sensation, may play a critical role in IC/BPS.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eEmerging evidence suggests that altered control of pelvic floor muscles may contribute to IC/BPS. Patients with IC/BPS have increased pelvic floor muscle activity,[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] potentially caused by changes in supplementary motor area (SMA).[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Although pelvic floor physical therapy may be beneficial,[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] its results may be suboptimal since it may not directly target dysfunction in SMA. Our laboratory has demonstrated unique expertise in understanding the neural control of pelvic floor muscles.[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] We have found that women with IC/BPS have altered activity compared to healthy women in a subregion of SMA that controls pelvic floor muscles (that we refer to as pelvic-SMA).[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Our findings fit with an expanding literature suggesting that chronic pain is caused by motor cortical changes that, while initially beneficial to generate protective muscle activity, are ultimately maladaptive and perpetuate pain through involuntary and uncomfortable muscle activity.[\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eBecause pelvic-SMA is a superficial cortical region, it may be possible to use repetitive transcranial magnetic stimulation (rTMS) to treat IC/BPS. Our published resting-state functional magnetic resonance imaging (rs-fMRI) findings hint at reduced activity in pelvic-SMA in women with IC/BPS,[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] which would be consistent with the large body of evidence suggesting high-frequency excitatory rTMS over motor cortex is the best stimulation protocol to reduce pain.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Increased resting pelvic floor muscle activity in IC/BPS could result, since pelvic-SMA controls pelvic floor muscles with both excitation and inhibition.[\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] Using rs-fMRI, we will determine if a high-frequency rTMS protocol improves pelvic-SMA activity in women with IC/BPS by moving it in the direction of healthy women.\u003c/p\u003e \u003cp\u003eOur published work has identified that pelvic-SMA is an important brain region-of-interest in IC/BPS. Our current trial will test whether modulation of pelvic-SMA function provides a mechanism by which IC/BPS symptoms can be reduced. We will then be able to conduct future studies to determine if neuromodulation of pelvic-SMA, by itself or in conjunction with other therapies, may be able to generate long-term reduction or even remission of IC/BPS symptoms.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll aspects of the study were approved by the Institutional Review Board of the University of Southern California (protocol HS-20-01021). All participants provided informed consent by the research coordinator/assistants. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026mdash;no identifiable personal or clinical details or identifying images of images are presented here or will be presented in the reports of the trials results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data from this study will not be shared publicly.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) (R01 DK121724), clinicaltrails.gov NCT04734847 Dates 08/2020-04/2025. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eJK and LR serve as principal investigators for this study. The authors confirm contribution to the paper as follows: study conception and design: JK and LR; data collection: MY, EJ, GG; analysis and interpretation of results: JK, LR; draft manuscript preparation: MY, EJ, MB, GG, JJ, LR. All authors reviewed the results and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements: \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the participants for their time and willingness to help.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eClemens JQ, Mullins C, Ackerman AL, Bavendam T, van Bokhoven A, Ellingson BM, et al. Urologic chronic pelvic pain syndrome: insights from the MAPP Research Network. Nat Rev Urol. 2019;16:187\u0026ndash;200.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKilpatrick LA, Tillisch K, Naliboff B, Labus J, Jiang Z, Farmer M, et al. 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J Urol. 2007;177:1390\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClemens JQ, Mullins C, Kusek JW, Kirkali Z, Mayer EA, Rodr\u0026iacute;guez LV, et al. The MAPP research network: a novel study of urologic chronic pelvic pain syndromes. BMC Urol. 2014;14:57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang L, Kutch JJ, Ellingson BM, Martucci KT, Harris RE, Clauw DJ, et al. Brain white matter changes associated with urological chronic pelvic pain syndrome: multisite neuroimaging from a MAPP case-control study. Pain. 2016;157:2782\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKairys AE, Schmidt-Wilcke T, Puiu T, Ichesco E, Labus JS, Martucci K, et al. Increased brain gray matter in the primary somatosensory cortex is associated with increased pain and mood disturbance in patients with interstitial cystitis/painful bladder syndrome. J Urol. 2015;193:131\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWoodworth D, Mayer E, Leu K, Ashe-McNalley C, Naliboff BD, Labus JS, et al. Unique microstructural changes in the brain associated with urological chronic pelvic pain syndrome (UCPPS) revealed by diffusion tensor MRI, super-resolution track density imaging, and statistical parameter mapping: a MAPP network neuroimaging study. PLoS ONE. 2015;10:e0140250.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAckerman AL, Lee UJ, Jellison FC, Tan N, Patel M, Raman SS, et al. MRI suggests increased tonicity of the levator ani in women with interstitial cystitis/bladder pain syndrome. Int Urogynecol J. 2016;27:77\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFitzGerald MP, Payne CK, Lukacz ES, Yang CC, Peters KM, Chai TC, et al. Randomized multicenter clinical trial of myofascial physical therapy in women with interstitial cystitis/painful bladder syndrome and pelvic floor tenderness. J Urol. 2012;187:2113\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYani MS, Wondolowski JH, Eckel SP, Kulig K, Fisher BE, Gordon JE, et al. Distributed representation of pelvic floor muscles in human motor cortex. Sci Rep. 2018;8:1\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRana M, Yani MS, Asavasopon S, Fisher BE, Kutch JJ. Brain Connectivity Associated with Muscle Synergies in Humans. J Neurosci. 2015;35:14708\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsavasopon S, Rana M, Kirages DJ, Yani MS, Fisher BE, Hwang DH, et al. Cortical activation associated with muscle synergies of the human male pelvic floor. J Neurosci. 2014;34:13811\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Z, Chang HH, Gao Y, Zhang R, Guo Y, Holschneider DP, et al. Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study. PLoS ONE. 2017;12:e0182976.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKutch JJ, Yani MS, Asavasopon S, Kirages DJ, Rana M, Cosand L, et al. Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network Neuroimaging Study. Neuroimage Clin. 2015;8:493\u0026ndash;502.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHodges PW, Tucker K. Moving differently in pain: a new theory to explain the adaptation to pain. Pain. 2011;152:S90\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheney PD, Fetz EE. Functional classes of primate corticomotoneuronal cells and their relation to active force. J Neurophysiol. 1980;44:773\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheney PD, Fetz EE, Palmer SS. Patterns of facilitation and suppression of antagonist forelimb muscles from motor cortex sites in the awake monkey. J Neurophysiol. 1985;53:805\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSherrington SCS. The Integrative Action of the Nervous System. 1906.\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":false,"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":"Chronic Pain, Transcranial Magnetic Stimulation, Pelvic floor muscles, Bladder Pain Syndrome, BPS, Interstitial Cystitis, IC, Pelvic Pain, Chronic Overlapping Pain Condition, Motor Cortical Neuromodulation, Functional magnetic resonance imaging, Supplementary motor area","lastPublishedDoi":"10.21203/rs.3.rs-3953427/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3953427/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eInterstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic pain condition creating a wide range of urologic and pain symptoms. There is currently limited evidence to understand the mechanisms of IC/BPS. There have been recent studies suggesting that altered function in brain motor areas, particularly the supplementary motor cortex (SMA), relate to altered bladder sensorimotor control and may play an important role in IC/BPS. This study aims to provide evidence that non-invasive stimulation targeting the motor cortex may help reduce IC/BPS pain, as well as better understand the neural mechanism by which this stimulation targets neuromuscular dysfunction.\u003c/p\u003e\u003ch2\u003eMethods and analyses:\u003c/h2\u003e \u003cp\u003eThis study is a two-group quadruple-blinded randomized controlled trial (RCT) of active vs. sham repetitive transmagnetic stimulation (rTMS). In addition, our study will also include functional magnetic resonance imaging (fMRI), pelvic floor electromyography (EMG), pelvic exam and outcome measures and questionnaires to further study outcomes.\u003c/p\u003e\u003ch2\u003eEthics and dissemination:\u003c/h2\u003e \u003cp\u003e All aspects of the study were approved by the Institutional Review Board of the University of Southern California (protocol HS-20-01021). All participants provided informed consent by the research coordinator/assistants. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences.\u003c/p\u003e\u003ch2\u003eTrials Registration:\u003c/h2\u003e \u003cp\u003eClinicaltrials.gov NCT04734847 Registered on 2021-02-01.\u003c/p\u003e","manuscriptTitle":"Motor cortical neuromodulation in women with Interstitial Cystitis/Bladder Pain Syndrome: reducing pain by improving brain and muscle activity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-27 00:33:27","doi":"10.21203/rs.3.rs-3953427/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-07-05T17:23:48+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-07-05T10:38:12+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-03T10:46:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-02T11:11:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-04-27T00:14:01+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":"71d20553-652b-4518-9d48-129d0c0aab9f","owner":[],"postedDate":"July 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-16T16:06:07+00:00","versionOfRecord":{"articleIdentity":"rs-3953427","link":"https://doi.org/10.1186/s13063-024-08450-w","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2024-09-12 15:58:25","publishedOnDateReadable":"September 12th, 2024"},"versionCreatedAt":"2024-07-27 00:33:27","video":"","vorDoi":"10.1186/s13063-024-08450-w","vorDoiUrl":"https://doi.org/10.1186/s13063-024-08450-w","workflowStages":[]},"version":"v1","identity":"rs-3953427","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3953427","identity":"rs-3953427","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}