Naturalistic Bladder Filling Reveals Subtypes in Overactive Bladder Syndrome That Differentially Engages Urinary Urgency-Related Brain Circuits: Results From the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN)

No AccessJournal of UrologyAdult Urology5 Oct 2023Naturalistic Bladder Filling Reveals Subtypes in Overactive Bladder Syndrome That Differentially Engages Urinary Urgency-Related Brain Circuits: Results From the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN)This article is commented on by the following:Editorial Comment Ishtiaq Mawla, Andrew Schrepf, Jason J. Kutch, Margaret E. Helmuth, Abigail R. Smith, Eric Ichesco, Claire C. Yang, Victor P. Andreev, Karl J. Kreder, Catherine S. Bradley, Vincent A. Magnotta, Ziya Kirkali, Richard E. Harris, H. Henry Lai, and Steven E. Harte Ishtiaq MawlaIshtiaq Mawla Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan Co-first authors. More articles by this author , Andrew SchrepfAndrew Schrepf Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan Co-first authors. More articles by this author , Jason J. KutchJason J. Kutch Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, California More articles by this author , Margaret E. HelmuthMargaret E. Helmuth Arbor Research Collaborative for Health, Ann Arbor, Michigan More articles by this author , Abigail R. SmithAbigail R. Smith Arbor Research Collaborative for Health, Ann Arbor, Michigan More articles by this author , Eric IchescoEric Ichesco Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan More articles by this author , Claire C. YangClaire C. Yang Department of Urology, University of Washington, Seattle, Washington More articles by this author , Victor P. AndreevVictor P. Andreev Arbor Research Collaborative for Health, Ann Arbor, Michigan More articles by this author , Karl J. KrederKarl J. Kreder Department of Urology, University of Iowa Carver College of Medicine, Iowa City, Iowa More articles by this author , Catherine S. BradleyCatherine S. Bradley Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, Iowa More articles by this author , Vincent A. MagnottaVincent A. Magnotta Department of Radiology, University of Iowa, Iowa City, Iowa More articles by this author , Ziya KirkaliZiya Kirkali National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland More articles by this author , Richard E. HarrisRichard E. Harris Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan Susan Samueli Integrative Health Institute, School of Medicine, University of California at Irvine, Irvine, California More articles by this author , H. Henry LaiH. Henry Lai Division of Urologic Surgery, Departments of Surgery and Anesthesiology, Washington University in St Louis, St Louis, Missouri Co-senior authors. More articles by this author , and Steven E. HarteSteven E. Harte ‡Correspondence: Division of Urologic Surgery, 4960 Children’s Pl, Campus Box 8242-0022-02, St Louis, MO 63110 E-mail Address: [email protected] Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan Co-senior authors. More articles by this author the LURN Study Group View All Author Informationhttps://doi.org/10.1097/JU.0000000000003699AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookLinked InTwitterEmail Abstract Purpose: Overactive bladder (OAB) may be attributed to dysfunction in supraspinal brain circuits. Overactive bladder participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study reported sensations of urinary urgency during a bladder-filling paradigm while undergoing brain functional MRI to map supraspinal dysfunction. Materials and Methods: OAB participants and controls (CONs) completed 2 resting-state functional MRI scans following consumption of 350 mL water. Scans were conducted at fuller and emptier bladder states, interleaved with voiding. Urgency ratings (0-10) were assessed. Patterns of urgency during bladder filling were investigated using latent class trajectory models. Clusters of participants encompassing each pattern (ie, subtype) were derived from aggregated groups of OAB and CON independent of diagnosis. Results: Two distinct patterns of urgency trajectories were revealed: first subtype with OAB and CON who were unresponsive to bladder filling (OAB-1 and CON-1) and second highly responsive subtype predominantly containing OAB (OAB-2). OAB-2 participants scored significantly higher on urinary symptoms but not pain or psychosocial measures. Neuroimaging analyses showed change in urgency due to both bladder filling and voided volume related to multiple loci of brain network connectivity in OAB-2, and in some cases, different than OAB-1 and/or CON-1. Sensorimotor to dorsomedial/dorsolateral prefrontal connectivity mediated the relationship between stimulus (voided volume) and percept (urgency) in OAB-2. Conclusions: Our results reveal different OAB subtypes with latent class trajectory models of urgency ratings during natural bladder filling. Functional MRI revealed differences in pathophysiology between subtypes, namely sensorimotor-prefrontal connectivity is a key locus in OAB patients with higher urinary symptoms. REFERENCES 1. . The burden of overactive bladder on US public health. Curr Bladder Dysfunct Rep. 2016; 11(1):8-13. Crossref, Medline, Google Scholar 2. Economic costs of overactive bladder in the United States. Urology. 2010; 75(3):526-532.e18. Crossref, Medline, Google Scholar 3. 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. Crossref, Medline, Google Scholar 4. 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. Crossref, Medline, Google Scholar 5. . Neural control of micturition in humans: a working model. Nat Rev Urol. 2015; 12(12):695-705. Crossref, Medline, Google Scholar 6. . Brain control of normal and overactive bladder. J Urol. 2005; 174(5):1862-1867. Link, Google Scholar 7. . Cerebral control of the bladder in normal and urge-incontinent women. Neuroimage. 2007; 37(1):1-7. Crossref, Medline, Google Scholar 8. . Abnormal connections in the supraspinal bladder control network in women with urge urinary incontinence. Neuroimage. 2008; 39(4):1647-1653. Crossref, Medline, Google Scholar 9. . Brain activity measured by functional magnetic resonance imaging is related to patient reported urgency urinary incontinence severity. J Urol. 2010; 183(1):221-228. Link, Google Scholar 10. . Brain activity during bladder filling is related to white matter structural changes in older women with urinary incontinence. Neuroimage. 2010; 51(4):1294-1302. Crossref, Medline, Google Scholar 11. . Brain activity underlying impaired continence control in older women with overactive bladder. Neurourol Urodyn. 2012; 31(5):652-658. Crossref, Medline, Google Scholar 12. . Alterations in connectivity on functional magnetic resonance imaging with provocation of lower urinary tract symptoms: a MAPP research network feasibility study of urological chronic pelvic pain syndromes. J Urol. 2016; 195(3):639-645. Link, Google Scholar 13. The LURN Research Network Neuroimaging and Sensory Testing (NIST) study: design, protocols, and operations. Contemp Clin Trials. 2018; 74:76-87. Crossref, Medline, Google Scholar 14. Experimental pain and auditory sensitivity in overactive bladder syndrome: a symptoms of the lower urinary tract dysfunction research network (LURN) study. J Urol. 2022; 207(1):161-171. Link, Google Scholar 15. Multisite, multimodal neuroimaging of chronic urological pelvic pain: methodology of the MAPP Research Network. NeuroImage Clin. 2016; 12:65-77. Crossref, Medline, Google Scholar 16. Moving towards a comprehensive assessment of lower urinary tract symptoms (LUTS). Neurourol Urodyn. 2012; 31(4):448-454. Crossref, Medline, Google Scholar 17. . Estimation of extended mixed models using latent classes and latent processes: the R package lcmm. J Stat Softw. 2017; 78(2):1-56. Crossref, Google Scholar 18. . Deciding on the number of classes in latent class analysis and growth mixture modeling: a Monte Carlo simulation study. Struct Equ Modeling. 2007; 14(4):535-569. Crossref, Google Scholar 19. . The Brief Pain Inventory: User Guide. MD Anderson Center; 2008. Google Scholar 20. Characterization of whole body pain in urological chronic pelvic pain syndrome at baseline: a MAPP research network study. J Urol. 2017; 198(3):622-631. Link, Google Scholar 21. . Abnormal resting-state brain activity and connectivity of brain-bladder control network in overactive bladder syndrome. Acta Radiol. 2022; 63(12):1695-1702. Crossref, Medline, Google Scholar 22. . The precuneus: a review of its functional anatomy and behavioural correlates. Brain. 2006; 129(3):564-583. Crossref, Medline, Google Scholar 23. Non-invasive characterization of real-time bladder sensation using accelerated hydration and a novel sensation meter: an initial experience. Neurourol Urodyn. 2017; 36(5):1417-1426. Crossref, Medline, Google Scholar 24. Comparison of sensation event descriptors in participants with overactive and normal bladders during non-invasive hydration studies. Arch Nephrol Urol Stud. 2021; 1(1):03. Medline, Google Scholar 25. . Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015; 193(5):1572-1580. Link, Google Scholar Support: This is publication number 35 of the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN). This study is supported by the National Institute of Diabetes and Digestive and Kidney Diseases through cooperative agreements (Grants DK097780, DK097772, DK097779, DK099932, DK100011, DK100017, DK099879). Research reported in this publication was supported at Northwestern University, in part, by the National Institutes of Health’s National Center for Advancing Translational Sciences (Grant UL1TR001422). Ishtiaq Mawla was supported by F99DK126121 (NIH-NIDDK) training grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conflict of Interest Disclosures: All authors have no conflicts of interest with regard to this manuscript. Ethics Statement: This study received Institutional Review Board approval (IRB No. 00007807). Author Contributions: The authors have followed the practice and ethical guidelines set forth by the International Committee of Medical Journal Editors (ICMJE) and meet the 4 criteria for authorship: Substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data for the work; and drafting the work or revising it critically for important intellectual content; and final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Data Availability: The data that support the findings of this study are openly available in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository at https://repository.niddk.nih.gov/; please reference the acronym LURN. Clinical Trial Registration No.: NCT02485808. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of Urology5 Oct 2023Editorial Comment Supplementary Materials Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.Keywordsoveractive bladderbrain imagingpathophysiologyurinary urgencymagnetic resonance imagingAcknowledgmentsWe thank Heather Van Doren, senior medical editor with Arbor Research Collaborative for Health, for editorial assistance on this manuscript. The following individuals were instrumental in the planning and conduct of this study at each of the participating institutions: Duke University, Durham, North Carolina (DK097780): Principal Investigators: Cindy Amundsen, MD; Eric Jelovsek, MD. Co-Investigators: Kathryn Flynn, PhD; Jim Hokanson, PhD; Aaron Lentz, MD; David Page, PhD; Nazema Siddiqui, MD; Lisa Wruck, PhD; Todd Harshbarger, PhD. Study Coordinators: Paige Green; Magaly Guerrero. University of Iowa, Iowa City, Iowa (DK097772): Principal Investigators: Catherine S. Bradley, MD, MSCE; Karl Kreder, MD, MBA. Co-Investigators: Bradley A. Erickson, MD, MS; Daniel Fick, MD; Vince Magnotta, PhD; Philip Polgreen, MD, MPH. Study Coordinators: Sarah Heady; Chelsea Poesch; Jean Walshire. Northwestern University, Chicago, Illinois (DK097779): Principal Investigators: James W. Griffith, PhD; Kimberly Kenton, MD, MS; Brian Helfand, MD, PhD. Co-Investigators: Carol Bretschneider, MD; David Cella, PhD; Sarah Collins, MD; Julia Geynisman-Tan, MD; Alex Glaser, MD; Christina Lewicky-Gaupp, MD; Margaret Mueller, MD; Francesca Farina, PhD; Richard Fantus, MD; Devin Boehm, BS. Study Coordinators: Hosanna An; Andrea Villegas; Melissa Marquez; Malgorzata Antoniak; Pooja Talaty; Sophia Kallas; Jessica Thomas. Dr Helfand and Ms Talaty are at NorthShore University HealthSystem. University of Michigan Health System, Ann Arbor, Michigan (DK099932): Principal Investigator: J. Quentin Clemens, MD, FACS, MSCI. Co-Investigators: John DeLancey, MD; Dee Fenner, MD; Richard E. Harris, PhD; Steve Harte, PhD; Anne P. Cameron, MD; Aruna Sarma, PhD; Giulia Lane, MD; Priyanka Gupta, MD; Whitney Horner, MD; Jannah Thompson, MD. Study Coordinators: Linda Drnek; Greg Mowatt; Sarah Richardson. University of Washington, Seattle, Washington (DK100011): Principal Investigator: Claire Yang, MD; Co-Investigator: Anna Kirby, MD; Study Coordinators: Brenda Vicars, RN; Sreya Gutta. Washington University in St Louis, St Louis, Missouri (DK100017): Principal Investigator: H. Henry Lai, MD. Co-Investigators: Joshua Shimony, MD, PhD; Fuhai Li, PhD. Study Coordinators: Linda Black; Vivien Gardner; Patricia Hayden; Diana Wolff; Aleksandra Klim, RN, MHS, CCRC. Arbor Research Collaborative for Health, Data Coordinating Center (DK099879): Principal Investigator: Robert Merion, MD, FACS. Co-Investigators: Victor Andreev, PhD, DSc; Brenda Gillespie, PhD; Abigail Smith, PhD. Project Manager: Melissa Fava, MPA, PMP; Jessica Durkin, Med, MBA. Clinical Monitor: Melissa Sexton, BA, CCRP. Research Analysts: Margaret Helmuth, MA; Sarah Mansfield, MS. Project Associate: Julia Nashif. National Institute of Diabetes and Digestive and Kidney Diseases, Division of Kidney, Urology, and Hematology, Bethesda, Maryland: Project Scientist: Ziya Kirkali, MD. Project Officer: Christopher Mullins, PhD. Project Advisor: Julie Barthold, MD.Metrics Author Information Ishtiaq Mawla Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan Co-first authors. More articles by this author Andrew Schrepf Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan Co-first authors. More articles by this author Jason J. Kutch Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, California More articles by this author Margaret E. Helmuth Arbor Research Collaborative for Health, Ann Arbor, Michigan More articles by this author Abigail R. Smith Arbor Research Collaborative for Health, Ann Arbor, Michigan More articles by this author Eric Ichesco Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan More articles by this author Claire C. Yang Department of Urology, University of Washington, Seattle, Washington More articles by this author Victor P. Andreev Arbor Research Collaborative for Health, Ann Arbor, Michigan More articles by this author Karl J. Kreder Department of Urology, University of Iowa Carver College of Medicine, Iowa City, Iowa More articles by this author Catherine S. Bradley Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, Iowa More articles by this author Vincent A. Magnotta Department of Radiology, University of Iowa, Iowa City, Iowa More articles by this author Ziya Kirkali National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland More articles by this author Richard E. Harris Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan Susan Samueli Integrative Health Institute, School of Medicine, University of California at Irvine, Irvine, California More articles by this author H. Henry Lai Division of Urologic Surgery, Departments of Surgery and Anesthesiology, Washington University in St Louis, St Louis, Missouri Co-senior authors. More articles by this author Steven E. Harte Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan ‡Correspondence: Division of Urologic Surgery, 4960 Children’s Pl, Campus Box 8242-0022-02, St Louis, MO 63110 E-mail Address: [email protected] Co-senior authors. More articles by this author Expand All Support: This is publication number 35 of the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN). This study is supported by the National Institute of Diabetes and Digestive and Kidney Diseases through cooperative agreements (Grants DK097780, DK097772, DK097779, DK099932, DK100011, DK100017, DK099879). Research reported in this publication was supported at Northwestern University, in part, by the National Institutes of Health’s National Center for Advancing Translational Sciences (Grant UL1TR001422). Ishtiaq Mawla was supported by F99DK126121 (NIH-NIDDK) training grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conflict of Interest Disclosures: All authors have no conflicts of interest with regard to this manuscript. Ethics Statement: This study received Institutional Review Board approval (IRB No. 00007807). Author Contributions: The authors have followed the practice and ethical guidelines set forth by the International Committee of Medical Journal Editors (ICMJE) and meet the 4 criteria for authorship: Substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data for the work; and drafting the work or revising it critically for important intellectual content; and final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Data Availability: The data that support the findings of this study are openly available in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository at https://repository.niddk.nih.gov/; please reference the acronym LURN. Clinical Trial Registration No.: NCT02485808. Advertisement PDF downloadLoading ...