Does electrical stimulation in the lower urinary tract increase urine production? A randomised comparative proof-of-concept study in healthy volunteers

Trial design During electrical stimulation in the lower urinary tract for the purpose of current perception threshold and sensory evoked potential recording, we observed that bladder volume increased rapidly. The aim of this prospective randomised comparative proof-of-concept study was to quantify urine production per time during stimulation of the lower urinary tract using different stimulation frequencies. Methods Ninety healthy subjects (18 to 36 years old) were included. Forty females and 50 males were randomly assigned to one of the following study groups: dome, trigone or proximal, membranous (males only) or distal urethra. Starting from 60mL prefilling, stimulation was performed at two separate visits with a 14 French custom-made catheter using randomly applied frequencies of 0.5Hz, 1.1Hz, 1.6Hz (each with 500 stimuli). After each stimulation cycle per frequency, urine production was assessed. Main outcome measures represented urine production during stimulation, daily life and their ratio. Results Lower urinary tract electrical stimulation increased urine production per time compared to bladder diary baseline values. Linear mixed model showed that frequency (p<0.001), stimulation order (p = 0.003), intensity (p = 0.042), and gender (p = 0.047) had a significant influence on urine production. Location, visit and age had no significant influence. Conclusions Urine production is increased during electrical stimulation with a bigger impact of higher frequencies. This might be relevant for methodological aspects in the assessment of lower urinary tract afferent function and for patients with impaired renal urine output. Inhibition of renal sympathetic nerve activity by vagal afferents may be the underlying mechanism.


BACKGROUND AND OBJECTIVE OF THE STUDY
Lower urinary tract symptoms (LUTS) as urinary urgency, frequency, and incontinence have great impact on the health-related quality of life, including impairments in sexuality, emotional well-being and productivity at home and at work [1,2]. The estimated worldwide prevalence of LUTS is high with 45% having at least one LUTS [3]. Consequently, there is an enormous economic burden for every health care system [4,5]. A large proportion of LUTS (i.e. overactive bladder (OAB)) affects the storage phase and is attributed to aberrant sensory function of the LUT [1,3,6,7]. However, in many cases the exact causes and pathologic mechanisms responsible for LUTS are unknown, which might be partly due to a lack of accurate and specific diagnostic tools. There is currently no objective and reliable clinical assessment tool of human bladder and urethral afferent nerve function and integrity available. Such an assessment tool would enable a greater understanding of the role of sensory nerves in LUTS. So far, clinical assessment of bladder sensations relies on filling cystometry (FC). During this urodynamic examination, patients usually indicate a first sensation of filling (FSF), a first desire to void (FDV) and a strong desire to void (SDV), and in pathologic cases urgency. Although this gives important information about the character of bladder sensations, it is not an objective measurement because it relies on the compliance, alertness, and subjective feelings of the patient. Thus, the objectivity and reliability of FC is discussed controversial: There are studies questioning the reliability of FC, in which only few urodynamic parameters show excellent reliability, others in turn affirm it [8][9][10][11]. Committee No. 25 of the International Consultation on Incontinence (ICI) states that there is limited and inadequate information regarding the reproducibility, accuracy, sensitivity, specificity, and the predictive value of urodynamic tests [12]. Therefore, there is an ongoing quest for an objective and reliable method to improve evaluation of bladder sensations in humans. Committee No. 7 of the ICI strongly recommends such an improvement of diagnostic performance with regard to its objectivity and reproducibility [13]. In addition, FC does only reflect sensory information from the bladder but not from the urethra. To improve sensory assessment of the LUT several groups have investigated current perception threshold (CPT) testing at different sites of the LUT including the urethra. First reports on LUT CPTs go back to 1899 using quite invasive setups with monopolar stimulation [14]. Recent studies used mainly bipolar stimulation to provide more organ specific CPTs as bipolar stimulation enables a more localized current that limits the stimulation to the bladder afferent nerves [15]. In patients with neurogenic lesions or diseases (i.e. diabetic neuropathy, Parkinson's disease, multiple sclerosis, spinal cord lesion) expectedly higher bladder CPTs were observed compared to healthy subjects [16][17][18]. Generally, higher values have been reported for bladder CPTs than for urethral CPTs [19][20][21][22][23] and ageing seems to be associated with higher urethral CPTs [22,24]. Pelvic surgery has been reported to increase bladder [22] and urethral CPTs [25,26]. However, some results are conflicting regarding urethral CPTs following pelvic surgery [22,25,26], which might be attributed to the type and radicalness of surgery. Urgency urinary incontinence patients demonstrated significantly higher urethral CPTs compared to controls [24], which could be partly "normalized" by oral antimuscarinics [27]. Conflicting results have been reported in non-neurogenic OAB (NNOAB) patients, with significantly lower bladder CPTs [28] but also equal bladder CPTs compared to non-OAB/healthy subjects [15,24].
In patients with neurogenic DO (NDO) [29] and NNOAB [30] it was demonstrated that antimuscarinic treatment significantly elevated CPTs which was interpreted as evidence that antimuscarinic drugs affect LUT sensory function, which is in line with animal studies and previous clinical studies in humans [31][32][33]. Elaboration on methodological aspects revealed that next to pulse frequency and duration, electrode position and bladder volume have a significant effect on the CPT results (sensitivity of the bladder can be increased by filling the bladder) and should thus be mentioned when reporting CPT outcomes from the LUT and standardized if possible [34]. However, only few studies report on these important aspects and a huge variety of CPT parameters and techniques have been used which makes a valid comparison difficult. Several, more recent studies started to use a commercially available automated CPT measurement system called "Neurometer®" (Neurotron Inc., Baltimore, USA) that is claimed to be able to page 4 of 21 differentiate between CPTs of C-fibers, A-delta fibers, and A-beta fibers using sine wave frequencies of 5Hz, 250Hz, and 2000Hz, presumably capable of selective activation of each of these fiber types respectively [16,21,24]. Although the principle of frequency-related neuroselectivity due to the different fiber specific refractory periods in relation to their fiber diameter appears theoretically plausible, there are doubts that this approach is readily transferable to CPT measurements in the human LUT. One of the articles that is frequently cited in Neurometer® studies as proof of neuroselectivity is a neurophysiological study in rats demonstrating a certain selectivity of A-beta, Adelta, and C-fibers in response to 2000Hz, 250Hz, and 5Hz stimulation respectively [35]. However, only 2000Hz was demonstrated to be purely A-beta fiber specific, but 250Hz and 5Hz activated both, A-delta and A-beta fibers, and C-fibers and A-delta fibers, respectively [35]. Thus it remains still necessary to clarify how specific and sensitive neuroselective CPT measurements can be performed in the LUT. The skepticism is supported by a study investigating LUT CPTs using the Neurometer® in patients with idiopathic DO, lacking to demonstrate a significant difference in 5Hz CPTs before and after resiniferatoxin instillation into the bladder [36], although resiniferatoxin is known to desensitize bladder afferent C-fibers [7,36]. Another issue that needs further clarification is the presence of A-beta fibers in the LUT. Studies using the Neurometer® for LUT CPT measurement persistently present CPT values after 2000Hz stimulation of the bladder mucosa which would indicate the presence of Abeta fibers in the LUT [16,21,24,30]. However, A-beta fibers have never been described in the LUT [37]. Although CPTs are believed to reflect the level of responsiveness of the afferent nerves, this method still remains semi-objective and no correlation between urinary symptoms, cystometric filling sensations and LUT CPTs could be found neither with square nor sine wave stimulation [21,38], whereas sine wave stimulations seems to result in less reliable CPTs compared to square waves [15]. Other, somewhat older studies investigated the possibility to record sensory evoked potentials (SEPs) following LUT electrical stimulation. The clinical utility of SEPs is based on their ability to reveal abnormal sensory function, when findings from previous investigations (i.e. history, neurologic examination, urodynamic examination) are equivocal [39]. Through analysis of latencies and amplitudes, SEPs provide objective information of nerve fiber integrity and in relation to the conduction velocity also on the fiber type. The previous studies presented first feasibility results of SEP recording from the LUT following electrical stimulation of the vesico-urethral junction and the posterior urethra in healthy subjects [40][41][42]67] and patients [43][44][45][46]. In these studies, mainly bipolar stimulation was used, as monopolar stimulation is less LUT specific due to the high probability to impinge on several electrically excitable structures between the cathode (intravesical) and anode (on the surface of thigh or abdomen). Although most stimulations were performed with 2Hz at similar sites, the heterogeneous study populations and inconsistencies of some important measurement settings (i.e. bladder volume, stimulation strength and recording filter parameters) hamper a meaningful comparison of those studies and resulted in varying SEP shapes and latencies. Unfortunately, this approach was not systematically followed up until now and there is a lack on studies investigating the reliability of this method, providing normative data and data from other LUT sites (i.e. trigone, bladder dome), and exploring methodological standards. There is a lack of an objective marker for LUT afferent function and a subtle instrument to distinguish between true neurogenic LUT dysfunction and non-neurogenic, end organ related (i.e. urothelial derived OAB) LUT dysfunction. Based on our previous study, LUT SEPs have the potential to be such an objective marker [67]. We now aim to validate our method as an objective marker for clinical diagnostics that allows the evaluation of pathological LUT conditions and its distinction from healthy LUT neurophysiology and function. Furthermore, data from the LUT SEP can readily be compared to urodynamic findings and common SEP data from the legs and pudendal somatosensory afferents. This will allow a detailed neurophysiological workup of each patient to classify expected changes in the LUT afferent system. In addition, we aim to evaluate the use of LUT SEPs as an instrument to objectively assess the effect of LUT therapies targeting its afferents (i.e. botulinum toxin, antimuscarinics, sacral neuromodulation). LUT SEPs might essentially contribute to a better understanding of the mechanism of action of those LUT therapies.

Objectives:
 To advance the evaluation of viscerosensory afferent pathways in healthy subjects and patients with lower urinary tract symptoms (LUTS) or dysfunctions using SEPs to promote the understanding of afferent alterations leading to LUT symptoms and to advance a more precise assessment of LUT function.  To refine the methodology of LUT SEPs  To investigate the differences in LUT sensory perception between healthy subjects and patients with LUT dysfunction  To investigate the effect of established and approved therapies * *LUTS therapies will be applied completely independent from the study and their application relies solely on the decision of the currently treating physician, e.g. urologist/gynaecologist, who is not involved in this study.

QUESTIONS, TRIAL POPULATION
The study consists of two parts with different main focus/questions and study population.
Part I: a) What is the influence of different stimulation parameters (e.g. stimulation frequency) on the reliability, shape, latency, amplitude, and topographical distribution of SEPs recorded during electrical stimulation of the LUT? b) Is there any potential effect of subject age and sex on LUT SEPs? c) Does the desire to void and corresponding bladder filling volume have an impact on the latencies and amplitudes of LUT SEPs? d) Is there a correlation between LUT SEPs and outcome parameters from other neurophysiological, e.g. tibial, pudendal, and S3 dermatome sensory evoked potentials (SSEPs) and contact heat evoked potentials (CHEPS), and neuro-urological, e.g. urodynamics, assessments.
Trial population: Healthy adult volunteers (n = at least 120, females and males, age >18 years).
Part II: a) Does the assessment of LUT SEPs provide reliable markers for LUTS? b) Is there any relation between LUT SEP measures and the symptom severity (recorded with standardized questionnaires) or urodynamic outcomes in patients with LUTS? c) Do SEP measures allow assessment of potential treatment effects of established and approved LUTS therapies? d) Is there a correlation between LUT SEPs and outcome parameters from other neurophysiological, e.g. tibial, pudendal, and S3 dermatome SSEPs and CHEPS, and neuro-urological, e.g. urodynamics, assessments.

Part I:
 Effectiveness of the stimulation frequency, to obtain an SEP will be related to the prevailing afferent conduction velocity due to fiber composition at the stimulation localization and it can be increased up to the reciprocal value corresponding to this conduction velocity without compromising SEP recording.  Higher frequencies decrease SEP return rates due to fiber refractoriness  Aging will increase current perception thresholds (CPTs) and decrease latencies of LUT SEPs.

Part II:
 Patients with LUTS will show significantly decreased latencies and pathological LUT SEPs compared to healthy subjects.  LUT SEPs recorded at SDV will show shorter latencies due to a facilitating effect of bladder distention.
 LUT SEP latencies will correlate negatively with urgency severity and maximum cystometric capacity.  Treatment for LUTS will significantly decrease LUT sensory thresholds and LUT SEPs amplitudes but not latencies. The project will consist of two parts:

TARGETED PRIMARY AND SECONDARY ENDPOINTS
Part I: LUT SEP measurements in healthy subjects ( Figure 1 and 2). Part I consists of 3 visits, screening (Visit 1), study measurement one (Visit 2), and study measurement two (Visit 3).

Study measurement 1 and 2 (Visits 2 and 3, each 3 hours):
Prior to each measurement, urine will be analyzed to exclude pregnancy or urinary tract infection. Each session consists of a resting EEG measurement followed by recordings of cortical evoked potentials elicited by transurethral electrical LUT stimulation (LUT SEPs) and transcutaneous electrical (SSEPs) and heat stimulations (CHEPS) at different body sites. A detailed sequence of measurements during visits 2 and 3 is summarized in Figure 2. Each EEG session comprises several neurophysiological standard assessments, including recordings of the electrooculogram (left and right eye), electrocardiogram, electromyogram andelectroencephalogram (EEG) using a 64 Ag/AgCl surface electrodes system comprising a capbased extended international 10-20 montage (Easy cap, Easy cap GmbH, Munich, Germany). Electrode impedances will be constantly kept below 20kΩ. In addition, six needle electrodes will be placed in the scalp, respectively above the spine and the iliac crest for routine clinical SEP recording for a segmental assessment. Intravesical stimulation will be applied transurethrally using a custom made 14 Ch catheter (Unisensor AG, Attikon, Switzerland) comprising three platinum electrodes and a radiopaque marker, which allows precise catheter positioning under fluoroscopic control.The same catheter allows to control bladder volumes during LUT stimulation. After each intravesical stimulation the bladder will be drained and refilled with the same amount of contrast medium (Ultravist 150, Bayer Schweiz AG, Switzerland) to ensure constant measurement conditions. For intravesical stimulation, electrical pulses will be applied repeatedly at different LUT sites using different stimulation parameters in terms of stimulation frequency (0.1-5Hz), pulse shape (monopolar, bipolar, rectangular and sinusoidal) and pulse width (0.1-1ms). Stimulation intensity will be individually adapted to produce clear but tolerable sensation, which typically is 3-4 times sensory threshold. All LUT stimulations will be performed at low bladder volumes, e.g. 0-100ml, and high bladder volumes, e.g. volume at SDV.
In addition, standard neurophysiological measurements such as tibial, pudendal, and S3 SSEPs and CHEPS will be performed for subsequent comparison with LUT SEPs.
Follow-up: Two to three days after each visit, a follow-up interview via telephone or e-mail questionnaire will be performed to evaluate the general wellbeing of the subjects and to exclude any adverse effects (Figure 1). Concerning the telephone and e-mail follow up we will use a standardized questionnaire (see also separate follow up form). In case of adverse events, subjects will be appointed to an extra visit for further evaluation and treatment if applicable. Part II: LUT SEP measurements in patients with LUTS (Figure 3 and 4). Part II consists of 4 visits, screening (Visit 1), study measurement one (Visit 2), study measurement two (Visit 3) and eventually a third post-treatment measurement (Visit 4) (Figure 3 and 4). 1, 1 hour, Figure 3): First, patients are informed about the entire study, the planned investigations, and the required behavior. After having provided written informed consent, they will be screened for their medical history, current medication, vital signs and their neurological status. Urine will be analyzed to exclude pregnancy or urinary tract infection. Subsequently a neuro-urological examination will be performed. All patients are required to complete a 3-day bladder diary (including pad test), the International Consultation on Incontinence Questionnaires for male or female LUTS (ICIQ-FLUTS/MLUTS), the International Prostate Symptom Score (IPPS) and the International Index of Erectile Function/Female Sexual Function Index (IIEF/FSFI) , the SwissGerman OAB, the ICIQ-LUTSqol, the Qualiveen, the HADS and the MoCA.

Study measurements 1 and 2 (Visits 2 and 3, each 3 hours):
Prior to each measurement, urine will be analyzed to exclude urinary tract infection or pregnancy. In the case that a LUT medication has been stopped at Visit 1 (for instance stopped antimuscarinic treatment, stopped alpha-blocker treatment etc.), a 3-day bladder diary (including pad test), the International Consultation on Incontinence Questionnaires for male or female LUTS (ICIQ-FLUTS/MLUTS), the International Prostate Symptom Score (IPSS), the International Index of Erectile Function/Female Sexual Function Index (IIEF/FSFI), the SwissGerman OAB, the ICIQ-LUTSqol, and the Qualiveen will be completed again 2 weeks after washout of the LUT relevant medication to evaluate any changes in LUTS. The study measurements 1 and 2 of part II are equally structured to the study measurements 1 and 2 (Visit 2 and 3) of part I (Figure 2).  Follow-up: Two to three days after each visit, a follow-up interview via telephone or e-mail questionnaire will be performed to evaluate the general wellbeing of the subjects and to exclude any adverse effects (Figure 1). Concerning the telephone and e-mail follow up we will use a standardized questionnaire (see also separate follow up form). In case of adverse events, patients will be appointed to an extra visit for further evaluation and treatment if applicable.

MEASURE TO MINIMIZE BIAS
Taking into account circadian fluctuations in the EEG, for each individual, the time of the day will be approximately held constant for all EEG measurements. Patients and healthy volunteers will be age matched to minimize an age effect on data interpretation. The EEG analysis will be conducted on the model of cluster as well as individual analysis to adjudge, if the cluster results depend on individuals or on all measurements.

RECRUITMENT
Healthy subjects will be recruited via announcements at the University of Zürich and in local print and online media (i.e. www.marktplatz.ch). Patients will be recruited via announcements in local print and online media and via patient consultations in the Spinal Cord Injury Center at Balgrist University Hospital, and the Departments of Urology, Gynecology, and Neurology at the University Hospital Zürich. All subjects and patients will be provided with the study information and informed consent form and given sufficient time to ask questions and to consider all of the information provided and the risks associated with participation.

EFFECTIVENESS PARAMETERS: MEASURING METHODS AND TIMES
This is a basic research study. Thus, no assessment of effectiveness is implemented.

Safety parameters before measurements:
 Case history regarding any neurological, urological pathology or any regular medication intake  Neuro-urological examination of the patients/healthy volunteers  Urine analysis to exclude UTI. Subjects with a UTI will not undergo the experiment and further microbiological urine analysis will be initiated. If the UTI is symptomatic (fever, dysuria, urgency) empiric oral antibiotic treatment will be started. Otherwise, antibiotic treatment will be applied according to the results of the microbiological urine analysis. The subject can be reassigned to the study, if the microbiological urine analysis shows no evidence of an UTI or the UTI has been successfully treated.  Pregnancy test. In case of pregnancy, the subject will be excluded from the study and referred to a gynaecologist.

Safety parameters during measurements:
 The research team performing the investigation/measurement and the responsible physician are consistently in interaction with the subjects monitoring vital signs and comfort of the subjects. There is always the opportunity to stop the measurements immediately Safety parameters after measurements:  Follow-up by telephone interview or e-mail two days after each measurement to assess general well-being and potential side effects such as dysuria, hematuria, urinary urgency, fever (see also separate follow-up form)

FOLLOW -UP OBSERVATION FOR STUDY SUBJECTS WITH ADVERSE EVENTS
All adverse events will be followed until they have abated, or until the initial state has been reached or until a stable situation has been reached. Depending on the event, follow-up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist. Covariables: The impact of subject age, gender, and body height on responder rate / latency and amplitude will be evaluated using multivariate analysis as appropriate.

PLANNED NUMBER OF TRIAL SUBJECTS WITH CLEARLY STATED JUSTIFICATION
We are planning to include at least 120 healthy subjects (study part I) and 100 patients with LUTS (study part II) to realize a meaningful random effects and subgroup analysis. This is an exploratory basic research study with a pure diagnostic purpose. A power analysis is not applicable. Data will be evaluated on the basis of a case-by-case analysis as well as on cluster analysis.

DESCRIPTION OF THE STATISTICAL METHODS FORESEEN AND THE PLANNED INTERMEDIATE ASSESSMENTS
We plan to summarize interval scaled variates with medians; means and standard deviations (SD) where appropriate. Dichotomous variates will be described as ratios and percentages. a) Univariate analysis We will use t-tests to compare mean between groups and chi-square/Fisher's exact tests to compare dichotomous variables.

b) Multivariate analysis
To adjust for unequal distribution of parameters at baseline we will perform multivariate regression models, linear models in case of an interval scaled outcome and logistic regression in case of a dichotomous outcome.

c) Interim analysis
We plan no interim analysis. In the case that the independent study monitoring board advises to suspend or stop the study, an interim analysis will be performed.

HANDLING OF MISSING DATA OR OF DATA IN THE CASE OF SUBJECTS HALTING THE TRIAL PREMATURELY
In the case subjects halting the study prematurely, all recorded data will be used as far as meaningful for the evaluation and answering of our study questions. In case of missing or lost data, completion or recovery of data is pursued and eventually healthy volunteers or patients are invited for an extra visit to repeat or make up for the missing data. If amount of missing data is corrupting a meaningful statistical analysis new healthy volunteers or/and patients will be recruited.

DEFINITION OF THE EVALUATION GROUPS
Healthy volunteers and patients with LUTS are enrolled according to the inclusion/exclusion criteria.

PREVENTIVE MEASURES AND DUTIES:
For study part I and II: No consumption of caffeine, nicotine, alcohol, hallucinogens or use of hair styling products prior to Visits 2-3 (Part I) or 2-4 (Part II).

FINAL EXAMINATION
A follow-up telephone or e-mail interview will be performed with all subjects/patients 2 days after each measurement or in case of premature study termination to assess general well-being and potential adverse events or symptoms (see also separate follow up form). In case of adverse events, subjects will be appointed to an extra visit for further evaluation and treatment if applicable.

CONFIRMATION
This study is conducted in compliance with the current study protocol, according to the principles of the Declaration of Helsinki (www.wma.net/en/20activities/10ethics/10helsinki/index.html), according to the guidelines on Good Clinical Practices (www.bag.admin.ch/themen/medizin/00701/00702/00703/index.html?lang=de), and according to Research with Human Subjects published by the Swiss Academy of Medical Sciences (www.samw.ch/en/News/News.html).
The investigators are aware of the GCP Guidelines, the effective legal regulations and accept them.

REPORTING OF SEVERE ADVERSE REACTIONS AND CHANGES TO THE PROTOCOL
All serious adverse events will be reported to the ethic committee within 15 days after the investigator has first knowledge of the serious adverse reactions. Serious adverse events that result in death or are life threatening will be reported expedited. The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse reaction. This is for a preliminary report with another 8 days for completion of the full report. Any change to the protocol and final reports will be submitted to the according ethical commission (KEK Zürich) in a timely manner.

OFFICIAL STATEMENT REGARDING DAMAGE COVERAGE OR ADDITIONAL COSTS
Participation in this study will not cause any additional costs for the patients or healthy volunteers. The costs of the study measurements and the examination are all covered by a research fund. Study related damages to patients or healthy subjects are covered by an insurance that fulfills the legal requirements in Switzerland (Axa Winterthur, insurance policy number 14.050.565).

EVALUATION OF THE RISK-BENEFIT RATIO
Due to the low risk profile of this study, the benefit clearly outweighs the risk. Healthy subjects and especially patients can benefit from the advanced diagnostic measures that will be used in this study without being exposed to health hazards. Previous studies showed no significant adverse events and only rare cases of self-limited dysuria. The used devices and techniques are safe and have been frequently and safely used for investigations in humans either in several previous studies or during daily clinical routine. This study can significantly contribute to a better understanding of LUT neurophysiology in healthy and pathological conditions, which certainly will help to improve future LUT diagnostics and to make treatment evaluation and development more effective.
In detail, our study on LUT SEPs has great potential to improve such investigation and provide normative data to make it more accessible for the clinical diagnostic use. That in turn would be beneficial for patients with LUTS in regard to a better functional and neurophysiological LUT diagnostic and consequently treatment selection.

HANDLING, ARCHIVING, AND DESTRUCTION OF DATA AND SAMPLES
Data entry, analysis, and archiving are handled strictly confidential. The data are anonymized using a serial subject number. Only the informed consent form allows the allocation of the subject number with the true subject identity. The informed consent form exists as hard copy only. All other hard copy data (e.g. CRF, ICIQ-FLUTS/MLUTS, IPSS, and IIEF/FSFI questionnaires, bladder diary, SwissGerman OAB, ICIQ-LUTSqol, Qualiveen, HADS, MoCA) and electronic data (e.g. SEP latencies and amplitudes) are only identifiably by the serial subject number. The informed consent forms will be separately stored from the other documents in a separate study folder to guarantee anonymity. The other hard copy data will be stored in the according study folders in the neuro-urology research office at the Balgrist University Hospital.
The electronic data are saved on the wissnet-server of the Paralab at the Balgrist University Hospital. Following completion of the study, all data will be archived for 10 years. Thereafter, hard copy data will be shredded and electronic data deleted.

DESCRIPTION OF THE DATA TO BE ENTERED DIRECTLY INTO THE CASE REPORT FORMS
The CRF includes data on: -Body weight, body height -Current and past medical history, concomitant medication, neurological status -Result summary of urine analysis, pregnancy test, neuro-urological examination, and urodynamics -Current perception and pain thresholds of SEPs and CHEPS, subjective subject response on electrical or contact heat stimulation -Adverse events during measurements