Neurourology and Urodynamics 30:762–765 (2011) How Does Neuromodulation Work Bastian Amend, 1 Klaus E. Matzel, 2, * Paul Abrams, 3 William C. de Groat, 4 and Karl-Dietrich Sievert 1 1 Department of Urology, Eberhard Karl University of Tuebingen, Tuebingen, Germany 2 Department of General Surgery, University Hospital Erlangen, Erlangen, Germany 3 Department of Urology, Bristol Urological Institute, Southmead Hospital, Bristol, UK 4 Departments of Pharmacology and Urology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania Although sacral neuromodulation (SNM) is approved and successfully used for different urological and proctologic func- tional diseases for the long-term treatment, less is known about the working mechanisms underlying SNM. This review highlights SNM clinical application, the current data of LUT neuroanatomy and neurophysiology, SNM techniques and its prospective working mechanisms. Functional imaging techniques have facilitated a more detailed insight into the neural network between the central nervous system (CNS) and the lower urinary tract (LUT). In addition to the well-known factors of the spinal micturition pathway, several pontine (e.g. pontine micturition centre) and suprapon- tine (e.g. cingulate cortex) regions and their interactions have been identified. An attribution of CNS activity levels to different LUT conditions is possible for the first time. Based on this information, different SNM actions could also have been allocated to different ascending/descending pathways and supraspinal regions, whereas acute SNM especially affects regions of learning activity, chronic SNM might result in CNS plasticity even though clinical effectiveness fades after SNM deactivation. Studies to treat fecal incontinence or to prevent detrusor overactivity in complete spinal cord injured patients support the importance of sympathetic pathways for the action of SNM. Despite increasing knowledge about SNM influence on the CNS, the complexity of its underlying working mechanisms is not understood at all. Further investigations with improved functional imaging techniques will enhance our SNM background. Neurourol. Urodynam. 30:762–765, 2011. © 2011 Wiley-Liss, Inc. Key words: central nervous system plasticity; pontine micturition center; functional imaging; idiopathic overactive bladder syndrome; lower urinary tract; sympathetic nervous system INTRODUCTION Although sacral neuromodulation (SNM) has evolved to an effective treatment option for different disorders of the lower genitourinary tract, less is known about the exact mechanism of action. A complex intrapelvic, intraspinal, and supraspinal neural network controls the bowel and the urinary bladder; however, recently, the traditional concept of a single spinal mic- turition reflex pathway has been surpassed with more advanced genitourinary neurophysiology knowledge. New techniques, most notably functional magnetic resonance imaging (fMRI), facilitate investigations to better understand the neuronal coor- dination of the lower urinary tract (LUT) and surrounding pelvic organs. On the occasion of the International Consultation of Inconti- nence Research Society (ICI-RS) in June 2010, the existing data regarding explanations for SNM functioning were collected and the possible explanations of how SNM works have been sum- marized in this review article. CLINICAL APPLICATION SNM is a proven efficacy in the treatment of (partially,) veg- etative and somatic LUT and bowel dysfunctions; in particular, overactive bladder syndrome (OAB), 1,2 non-obstructive urinary retention, constipation, and fecal incontinence. 3 As a result the ICI introduced SNM into their recommended treatment algorithms. 4 After first line treatment failure with antimuscar- incs for OAB, SNM is the recommended grade A treatment for females and grade B for males. 4 Despite different pathophysiologies, SNM demonstrates ther- apeutic potency using the same surgical procedure with regard to electrode(s) positioning in relationship to nerve roots. The therapeutic differences include unilateral or bilateral stimu- lation as well as amplitude and frequency of the impulse generator. An individual patient evaluation is essential in order to evaluate the distinctive settings required, either by periph- eral nerve evaluation with temporary electrodes or by chronic quadripolar electrodes. The patient outcome demonstrates the different underlying LUT patho-mechanisms in correlation to the peripheral and central nervous system (CNS). NEUROPHYSIOLOGY OF THE LOWER URINARY TRACT The LUT is characterized by two conditions: first, the micturi- tion phase with voluntary relaxation of the striated external urinary sphincter and contraction of the smooth detrusor mus- cle (5--8 times a day) and second, the collecting phase (urinary continence) with a tonic active striated external urinary sphinc- ter and a non-contracted compliant smooth detrusor muscle for about 99.7% of the 24hr. Previously published textbooks refer only to a spinal micturition pathway responsible for both urine collection and controlled micturition, but more recent Conflict of interest: Nothing to declare Dirk de Ridder led the review process. * Correspondence to: Prof. Dr. Klaus E. Matzel M.D., Department of Urology, Eber- hard Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany. E-mail: karl.sievert@med.uni-tuebingen.de Received 7 February 2011; Accepted 9 February 2011 Published online 15 June 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.21096 © 2011 Wiley-Liss, Inc.