Top

Published in:

Open Access 01-12-2024 | Repetitive Transcranial Magnetic Stimulation | Study Protocol

Evaluating noninvasive brain stimulation to treat overactive bladder in individuals with multiple sclerosis: a randomized controlled trial protocol

Authors: Betsy H. Salazar, Kristopher A. Hoffman, John A. Lincoln, Christof Karmonik, Hamida Rajab, Santosh A. Helekar, Rose Khavari

Published in: BMC Urology | Issue 1/2024

Abstract

Background

Multiple Sclerosis (MS) is an often debilitating disease affecting the myelin sheath that encompasses neurons. It can be accompanied by a myriad of pathologies and adverse effects such as neurogenic lower urinary tract dysfunction (NLUTD). Current treatment modalities for resolving NLUTD focus mainly on alleviating symptoms while the source of the discomfort emanates from a disruption in brain to bladder neural circuitry. Here, we leverage functional magnetic resonance imaging (fMRI), repetitive transcranial magnetic stimulation (rTMS) protocols and the brains innate neural plasticity to aid in resolving overactive bladder (OAB) symptoms associated with NLUTD.

Methods

By employing an advanced neuro-navigation technique along with processed fMRI and diffusion tensor imaging data to help locate specific targets in each participant brain, we are able to deliver tailored neuromodulation protocols and affect either an excitatory (20 min @ 10 Hz, applied to the lateral and medial pre-frontal cortex) or inhibitory (20 min @ 1 Hz, applied to the pelvic supplemental motor area) signal on neural circuitry fundamental to the micturition cycle in humans to restore or reroute autonomic and sensorimotor activity between the brain and bladder. Through a regimen of questionnaires, bladder diaries, stimulation sessions and analysis, we aim to gauge rTMS effectiveness in women with clinically stable MS.

Discussion

Some limitations do exist with this study. In targeting the MS population, the stochastic nature of MS in general highlights difficulties in recruiting enough participants with similar symptomology to make meaningful comparisons. As well, for this neuromodulatory approach to achieve some rate of success, there must be enough intact white matter in specific brain regions to receive effective stimulation. While we understand that our results will represent only a subset of the MS community, we are confident that we will accomplish our goal of increasing the quality of life for those burdened with MS and NLUTD.

Trial registration

This trial is registered at ClinicalTrials.gov (NCT06072703), posted on Oct 10, 2023.

Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. 2003;61(1):37–49. https://doi.org/10.1016/s0090-4295(02)02243-4.CrossRefPubMed

Haylen BT, de Ridder D, Freeman RM, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010;29(1):4–20. https://doi.org/10.1002/nau.20798.CrossRefPubMed

Al Dandan HB, Coote S, McClurg D. Prevalence of lower urinary tract symptoms in people with multiple sclerosis: a systematic review and meta-analysis. Int J MS Care. 2020;22(2):91–9. https://doi.org/10.7224/1537-2073.2019-030.CrossRefPubMedPubMedCentral

Nazari F, Shaygannejad V, Mohammadi Sichani M, Mansourian M, Hajhashemi V. The prevalence of lower urinary tract symptoms based on individual and clinical parameters in patients with multiple sclerosis. BMC Neurol. 2020;20(1):24. https://doi.org/10.1186/s12883-019-1582-1.CrossRefPubMedPubMedCentral

Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. J Urol. 2012;188(6 Suppl):2455–63. https://doi.org/10.1016/j.juro.2012.09.079.CrossRefPubMed

Lightner DJ, Gomelsky A, Souter L, Vasavada SP. Diagnosis and treatment of overactive bladder (Non-Neurogenic) in adults: AUA/SUFU guideline amendment 2019. J Urol. 2019;202(3):558–63. https://doi.org/10.1097/JU.0000000000000309.CrossRefPubMed

Ginsberg DA, Boone TB, Cameron AP, et al. The AUA/SUFU guideline on adult neurogenic lower urinary tract dysfunction: treatment and follow-up. J Urol. 2021;206(5):1106–13. https://doi.org/10.1097/JU.0000000000002239.CrossRefPubMed

Campbell N, Boustani M, Limbil T, et al. The cognitive impact of anticholinergics: a clinical review. Clin Interv Aging. 2009;4:225–33. https://doi.org/10.2147/cia.s5358.CrossRefPubMedPubMedCentral

Chapple C, Khullar V, Gabriel Z, Dooley JA. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol. 2005;48(1):5–26. https://doi.org/10.1016/j.eururo.2005.02.024.CrossRefPubMed

10.

Kay GG, Abou-Donia MB, Messer WS Jr, Murphy DG, Tsao JW, Ouslander JG. Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients. J Am Geriatr Soc. 2005;53(12):2195–201. https://doi.org/10.1111/j.1532-5415.2005.00537.x.CrossRefPubMed

11.

Risacher SL, McDonald BC, Tallman EF, et al. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults. JAMA Neurol. 2016;73(6):721–32. https://doi.org/10.1001/jamaneurol.2016.0580.CrossRefPubMedPubMedCentral

12.

Chartier-Kastler E, Rovner E, Hepp Z, Khalaf K, Ni Q, Chancellor M. Patient-reported goal achievement following onabotulinumtoxinA treatment in patients with neurogenic detrusor overactivity. Neurourol Urodyn. 2016;35(5):595–600. https://doi.org/10.1002/nau.22757.CrossRefPubMed

13.

Phe V, Pakzad M, Curtis C, et al. Urinary tract infections in multiple sclerosis. Mult Scler. 2016;22(7):855–61. https://doi.org/10.1177/1352458516633903.CrossRefPubMed

14.

Zecca C, Digesu GA, Robshaw P, et al. Motor and sensory responses after percutaneous tibial nerve stimulation in multiple sclerosis patients with lower urinary tract symptoms treated in daily practice. Eur J Neurol. 2014;21(3):506–11. https://doi.org/10.1111/ene.12339.CrossRefPubMed

15.

Finazzi-Agro E, Petta F, Sciobica F, Pasqualetti P, Musco S, Bove P. Percutaneous tibial nerve stimulation effects on detrusor overactivity incontinence are not due to a placebo effect: a randomized, double-blind, placebo controlled trial. J Urol. 2010;184(5):2001–6. https://doi.org/10.1016/j.juro.2010.06.113.CrossRefPubMed

16.

Hartmann KE, McPheeters ML, Biller DH, et al. Treatment of overactive bladder in women. Evid Rep Technol Assess (Full Rep). 2009;187:1–120 (https://www.ncbi.nlm.nih.gov/pubmed/19947666).

17.

Herbison GP, Arnold EP. Sacral neuromodulation with implanted devices for urinary storage and voiding dysfunction in adults. Cochrane Database Syst Rev. 2009;2:CD004202. https://doi.org/10.1002/14651858.CD004202.pub2.CrossRef

18.

Peters KM, Carrico DJ, Perez-Marrero RA, et al. Randomized trial of percutaneous tibial nerve stimulation versus Sham efficacy in the treatment of overactive bladder syndrome: results from the SUmiT trial. J Urol. 2010;183(4):1438–43. https://doi.org/10.1016/j.juro.2009.12.036.CrossRefPubMed

19.

Sanford MT, Suskind AM. Neuromodulation in neurogenic bladder. Transl Androl Urol. 2016;5(1):117–26. https://doi.org/10.3978/j.issn.2223-4683.2015.12.01.CrossRefPubMedPubMedCentral

20.

Fregni F, Pascual-Leone A. Technology insight: noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rTMS and tDCS. Nat Clin Pract Neurol. 2007;3(7):383–93. https://doi.org/10.1038/ncpneuro0530.CrossRefPubMed

21.

Huerta PT, Volpe BT. Transcranial magnetic stimulation, synaptic plasticity and network oscillations. J Neuroeng Rehabil. 2009;6:7. https://doi.org/10.1186/1743-0003-6-7.CrossRefPubMedPubMedCentral

22.

Janicak PG, Dokucu ME. Transcranial magnetic stimulation for the treatment of major depression. Neuropsychiatr Dis Treat. 2015;11:1549–60. https://doi.org/10.2147/NDT.S67477.CrossRefPubMedPubMedCentral

23.

Lipton RB, Pearlman SH. Transcranial magnetic simulation in the treatment of migraine. Neurotherapeutics. 2010;7(2):204–12. https://doi.org/10.1016/j.nurt.2010.03.002.CrossRefPubMedPubMedCentral

24.

Martin JL, Barbanoj MJ, Perez V, Sacristan M. Transcranial magnetic stimulation for the treatment of obsessive-compulsive disorder. Cochrane Database Syst Rev. 2003;3:CD003387. https://doi.org/10.1002/14651858.CD003387.CrossRef

25.

Centonze D, Petta F, Versace V, et al. Effects of motor cortex rTMS on lower urinary tract dysfunction in multiple sclerosis. Mult Scler. 2007;13(2):269–71. https://doi.org/10.1177/1352458506070729.CrossRefPubMed

26.

Brusa L, Finazzi Agro E, Petta F, et al. Effects of inhibitory rTMS on bladder function in Parkinson’s disease patients. Mov Disord. 2009;24(3):445–8. https://doi.org/10.1002/mds.22434.CrossRefPubMed

27.

Griffiths D. Neural control of micturition in humans: a working model. Nat Rev Urol. 2015;12(12):695–705. https://doi.org/10.1038/nrurol.2015.266.CrossRefPubMed

28.

Tadic SD, Griffiths D, Schaefer W, Murrin A, Clarkson B, Resnick NM. Brain activity underlying impaired continence control in older women with overactive bladder. Neurourol Urodyn. 2012;31(5):652–8. https://doi.org/10.1002/nau.21240.CrossRefPubMedPubMedCentral

29.

Clarkson BD, Karim HT, Griffiths DJ, Resnick NM. Functional connectivity of the brain in older women with urgency urinary incontinence. Neurourol Urodyn. 2018;37(8):2763–75. https://doi.org/10.1002/nau.23766.CrossRefPubMedPubMedCentral

30.

Elizondo RA, Karmonik C, Boone TB, Khavari R. Protocol for a prospective observational study of cortical lower urinary tract control changes following intradetrusor injection of botulinum toxin-A in patients with multiple sclerosis. BMJ Open. 2017;7(2):e013225. https://doi.org/10.1136/bmjopen-2016-013225.CrossRefPubMedPubMedCentral

31.

Karmonik C, Boone T, Khavari R. Data-driven machine-learning quantifies differences in the voiding initiation network in neurogenic voiding dysfunction in women with multiple sclerosis. Int Neurourol J. 2019;23(3):195–204. https://doi.org/10.5213/inj.1938058.029.CrossRefPubMedPubMedCentral

32.

Khavari R, Chen J, Boone T, Karmonik C. Brain activation patterns of female multiple sclerosis patients with voiding dysfunction. Neurourol Urodyn. 2020;39(3):969–77. https://doi.org/10.1002/nau.24304.CrossRefPubMedPubMedCentral

33.

Khavari R, Elias SN, Boone T, Karmonik C. Similarity of functional connectivity patterns in patients with multiple sclerosis who void spontaneously versus patients with voiding dysfunction. Neurourol Urodyn. 2019;38(1):239–47. https://doi.org/10.1002/nau.23837.CrossRefPubMed

34.

Khavari R, Elias SN, Pande R, Wu KM, Boone TB, Karmonik C. Higher neural correlates in patients with multiple sclerosis and neurogenic overactive bladder following treatment with intradetrusor injection of onabotulinumtoxinA. J Urol. 2019;201(1):135–40. https://doi.org/10.1016/j.juro.2018.07.066.CrossRefPubMedPubMedCentral

35.

Khavari R, Karmonik C, Shy M, Fletcher S, Boone T. Functional magnetic resonance imaging with concurrent urodynamic testing identifies brain structures involved in micturition cycle in patients with multiple sclerosis. J Urol. 2017;197(2):438–44. https://doi.org/10.1016/j.juro.2016.09.077.CrossRefPubMed

36.

Khavari R, Tran K, Helekar SA, et al. Noninvasive, Individualized Cortical Modulation Using Transcranial Rotating Permanent Magnet Stimulator for Voiding Dysfunction in Women with Multiple Sclerosis: A Pilot Trial. J Urol 2021:101097JU0000000000002297. https://doi.org/10.1097/JU.0000000000002297.

37.

Shi Z, Tran K, Karmonik C, Boone T, Khavari R. High spatial correlation in brain connectivity between micturition and resting states within bladder-related networks using 7 T MRI in multiple sclerosis women with voiding dysfunction. World J Urol. 2021;39(9):3525–31. https://doi.org/10.1007/s00345-021-03599-4.CrossRefPubMedPubMedCentral

38.

Tran K, Hubbard L, Karmonik C, Boone TB, Khavari R. Preliminary analysis of brain footprints in multiple sclerosis females with detrusor sphincter dyssynergia: a concurrent urodynamic and functional magnetic resonance imaging study. Int Neurourol J. 2021. https://doi.org/10.5213/inj.2142012.006.CrossRefPubMedPubMedCentral

39.

Tran K, Karmonik C, Boone TB, Khavari R. Are white matter tract integrities different in multiple sclerosis women with voiding dysfunction? Female Pelvic Med Reconstr Surg. 2021;27(1):e101–5. https://doi.org/10.1097/SPV.0000000000000830.CrossRefPubMedPubMedCentral

40.

Tran K, Shi Z, Karmonik C, et al. Therapeutic effects of non-invasive, individualized, transcranial neuromodulation treatment for voiding dysfunction in multiple sclerosis patients: study protocol for a pilot clinical trial. Pilot Feasibility Stud. 2021;7(1):83. https://doi.org/10.1186/s40814-021-00825-z.CrossRefPubMedPubMedCentral

41.

Mawla I, Schrepf A, Ichesco E, et al. Natural bladder filling alters resting brain function at multiple spatial scales: a proof-of-concept MAPP network neuroimaging Study. Sci Rep. 2020;10(1):19901. https://doi.org/10.1038/s41598-020-76857-x.CrossRefPubMedPubMedCentral

42.

Orringer DA, Golby A, Jolesz F. Neuronavigation in the surgical management of brain tumors: current and future trends. Expert Rev Med Devices. 2012;9(5):491–500. https://doi.org/10.1586/erd.12.42.CrossRefPubMedPubMedCentral

43.

Noh TS, Rah YC, Kyong JS, et al. Comparison of treatment outcomes between 10 and 20 EEG electrode location system-guided and neuronavigation-guided repetitive transcranial magnetic stimulation in chronic tinnitus patients and target localization in the Asian brain. Acta Otolaryngol. 2017;137(9):945–51. https://doi.org/10.1080/00016489.2017.1316870.CrossRefPubMed

44.

Sparing R, Hesse MD, Fink GR. Neuronavigation for transcranial magnetic stimulation (TMS): where we are and where we are going. Cortex. 2010;46(1):118–20. https://doi.org/10.1016/j.cortex.2009.02.018.CrossRefPubMed

45.

Theodoroff SM, Stevens AA, McMillan G, Pettersson DR, Woodward W, Folmer RL. MRI verification of a 10–20 targeting protocol used during transcranial magnetic stimulation sessions for tinnitus. Brain Topogr. 2018;31(4):690–9. https://doi.org/10.1007/s10548-018-0636-9.CrossRefPubMedPubMedCentral

46.

Herwig U, Satrapi P, Schonfeldt-Lecuona C. Using the international 10–20 EEG system for positioning of transcranial magnetic stimulation. Brain Topogr. 2003;16(2):95–9. https://doi.org/10.1023/b:brat.0000006333.93597.9d.CrossRefPubMed

47.

De Witte S, Klooster D, Dedoncker J, Duprat R, Remue J, Baeken C. Left prefrontal neuronavigated electrode localization in tDCS: 10–20 EEG system versus MRI-guided neuronavigation. Psychiatry Res Neuroimaging. 2018;274:1–6. https://doi.org/10.1016/j.pscychresns.2018.02.001.CrossRefPubMed

48.

Collins DL, Neelin P, Peters TM, Evans AC. Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J Comput Assist Tomogr. 1994;18(2):192–205 (https://www.ncbi.nlm.nih.gov/pubmed/8126267).CrossRefPubMed

49.

Weissbart SJ, Bhavsar R, Rao H, et al. Specific changes in brain activity during urgency in women with overactive bladder after successful sacral neuromodulation: a functional magnetic resonance imaging study. J Urol. 2018;200(2):382–8. https://doi.org/10.1016/j.juro.2018.03.129.CrossRefPubMed

50.

Ketai LH, Komesu YM, Schrader RM, et al. Mind-body (hypnotherapy) treatment of women with urgency urinary incontinence: changes in brain attentional networks. Am J Obstet Gynecol. 2021;224(5):498 e1–498 e10. https://doi.org/10.1016/j.ajog.2020.10.041.CrossRefPubMed

51.

Lefaucheur JP, Andre-Obadia N, Antal A, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014;125(11):2150–206. https://doi.org/10.1016/j.clinph.2014.05.021.CrossRefPubMed

52.

Aloizou AM, Pateraki G, Anargyros K, et al. Transcranial magnetic stimulation (TMS) and repetitive TMS in multiple sclerosis. Rev Neurosci. 2021;32(7):723–36. https://doi.org/10.1515/revneuro-2020-0140.CrossRefPubMed

53.

Bag AK, Patel BN, Osman S, Roberson GH. Clinico-radiologic profile of spinal cord multiple sclerosis in adults. Neuroradiol J. 2011;24(4):511–8. https://doi.org/10.1177/197140091102400405.CrossRefPubMed

54.

Stankiewicz JM, Neema M, Alsop DC, et al. Spinal cord lesions and clinical status in multiple sclerosis: A 1.5 T and 3 T MRI study. J Neurol Sci. 2009;279(1–2):99–105. https://doi.org/10.1016/j.jns.2008.11.009.CrossRefPubMedPubMedCentral

55.

Galler S, Stellmann JP, Young KL, et al. Improved lesion detection by using axial T2-weighted MRI with full spinal cord coverage in multiple sclerosis. AJNR Am J Neuroradiol. 2016;37(5):963–9. https://doi.org/10.3174/ajnr.A4638.CrossRefPubMedPubMedCentral

56.

Rahnama’i MS. Neuromodulation for functional bladder disorders in patients with multiple sclerosis. Mult Scler. 2020;26(11):1274–80. https://doi.org/10.1177/1352458519894714.CrossRefPubMed

Title: Evaluating noninvasive brain stimulation to treat overactive bladder in individuals with multiple sclerosis: a randomized controlled trial protocol
Authors: Betsy H. Salazar
Kristopher A. Hoffman
John A. Lincoln
Christof Karmonik
Hamida Rajab
Santosh A. Helekar
Rose Khavari
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Repetitive Transcranial Magnetic Stimulation
Multiple Sclerosis
Overactive Bladder
Magnetic Resonance Imaging
Magnetic Resonance Imaging
Nerve Stimulation
Transcranial Magnetic Stimulation
Transcranial Magnetic Stimulation
Published in: BMC Urology / Issue 1/2024
Electronic ISSN: 1471-2490
DOI: https://doi.org/10.1186/s12894-023-01358-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Evaluating noninvasive brain stimulation to treat overactive bladder in individuals with multiple sclerosis: a randomized controlled trial protocol

Abstract

Background

Methods

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2024

Giant peritoneal loose body and its protein composition: a case report

Enhanced clinical decisions for management of benign prostatic hyperplasia using patient-reported outcomes: protocol for a prospective observational study

“Bone in the penis” or fasciitis ossificans of the penis – a first time description of a pseudo-tumor at an extraordinary site

The effect of a fermented soy beverage among patients with localized prostate cancer prior to radical prostatectomy

Neoadjuvant stereotactic ablative body radiotherapy combined with surgical treatment for renal cell carcinoma and inferior vena cava tumor thrombus: a prospective pilot study

Does the contralateral testicular volume decide the need for diagnostic laparoscopy in cases of unilateral impalpable undescended testis?