Protocol for a prospective, randomized study on neurophysiological assessment of lower urinary tract function in a healthy cohort
Lely et al. BMC Urology
Protocol for a prospective, randomized study on neurophysiological assessment of lower urinary tract function in a healthy cohort
Stéphanie van der Lely 0 3
Martina Stefanovic 0 3
Melanie R. Schmidhalter 0 3
Marta Pittavino 2
Reinhard Furrer 2
Martina D. Liechti 0 3
Martin Schubert 1
Thomas M. Kessler 0 3
Ulrich Mehnert 0 3
0 Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich, Balgrist University Hospital , Forchstrasse 340, 8008 Zürich , Switzerland
1 Neurophysiology, Spinal Cord Injury Center & Research, University of Zürich, Balgrist University Hospital , Forchstrasse 340, 8008 Zürich , Switzerland
2 Institute of Mathematics, University of Zürich , Winterthurerstrasse 190, 8057 Zürich , Switzerland
3 Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich, Balgrist University Hospital , Forchstrasse 340, 8008 Zürich , Switzerland
Background: Lower urinary tract symptoms are highly prevalent and a large proportion of these symptoms are known to be associated with a dysfunction of the afferent pathways. Diagnostic tools for an objective and reproducible assessment of afferent nerve function of the lower urinary tract are missing. Previous studies showed first feasibility results of sensory evoked potential recordings following electrical stimulation of the lower urinary tract in healthy subjects and patients. Nevertheless, a refinement of the methodology is necessary. Methods: This study is a prospective, randomized trial conducted at Balgrist University Hospital, Zürich, Switzerland. Ninety healthy subjects (forty females and fifty males) without lower urinary tract symptoms are planned to be included in the study. All subjects will undergo a screening visit (including standardized questionnaires, 3-day bladder diary, urinalysis, medical history taking, vital signs, physical examination, neuro-urological examination) followed by two measurement visits separated by an interval of 3 to 4 weeks. Electrical stimulations (0.5Hz-5Hz, bipolar, square wave, pulse width 1 ms) will be applied using a custom-made transurethral catheter at different locations of the lower urinary tract including bladder dome, trigone, proximal urethra, membranous urethra and distal urethra. Every subject will be randomly stimulated at one specific site of the lower urinary tract. Sensory evoked potentials (SEP) will be recorded using a 64-channel EEG cap. For an SEP segmental work-up we will place additional electrodes on the scalp (Cpz) and above the spine (C2 and L1). Visit two and three will be conducted identically for reliability assessment. Discussion: The measurement of lower urinary tract SEPs elicited by electrical stimulation at different locations of the lower urinary tract has the potential to serve as a neurophysiological biomarker for lower urinary tract afferent nerve function in patients with lower urinary tract symptoms or disorders. For implementation of such a diagnostic tool into clinical practice, an optimized setup with efficient and reliable measurements and data acquisition is crucial. In addition, normative data from a larger cohort of healthy subjects would provide information on variability, potential confounding factors and cut-off values for investigations in patients with lower urinary tract dysfunction/symptoms. Trial registration: Clinicaltrials.gov; Identifier: NCT02272309.
Sensory evoked potential; Electroencephalography; Lower urinary tract; Urinary bladder; Urethra; Randomized; Lower urinary tract dysfunction; Current perception threshold; A-delta afferent fibers; Electrical stimulation
Lower urinary tract symptoms (LUTS) such as urinary
urgency, frequency and incontinence, imply a massive
impairment of quality of life [1, 2].
LUTS are highly prevalent and a large proportion of
LUTS are found to be associated with afferent nerve
dysfunction [1, 3–5]. Assessment of afferent pathways in
patients with LUTS is however a challenge. Specific
diagnostic tools for an objective and reproducible
measurement of bladder and urethral afferent nerve function
are missing. Yet, filling cystometry (FC) is the standard
method used in clinical practice for the assessment of
bladder sensations [6–10]. Nevertheless, FC largely
depends on the subjective perceptions and collaboration of
the patient and is hence not an objective measurement
of bladder sensations. In addition, the reliability of the
FC is questionable and its variability and outcome
resolution is too large to detect differences smaller than
100 mL [11, 12]. Moreover, FC only covers sensory
information from the bladder but not from the urethra.
Current perception threshold (CPT) testing is another
method of assessing sensations from the lower urinary
tract (LUT). CPT testing is performed by asking the
subject to indicate the onset of sensation when an
increasing electrical stimulus is applied . It was shown that
this method is safe and well tolerated by healthy subjects
and patients, but still, it provides only semi-quantitative
information on sensations of the LUT [14–16]. In
addition, local factors such as distance of electrodes to
the mucosa and the mucosal condition itself can
significantly affect CPTs [14, 17, 18].
A more objective and qualitative assessment of
afferent nerve function are sensory evoked potentials (SEP)
that are routinely used in neurophysiology to detect
afferent nerve conduction qualities and integrity from
different parts of the human body. By analysing the
latencies and amplitudes of the SEPs (Fig. 1),
information on nerve fiber integrity, conduction velocity and
fiber type can be obtained [19, 20]. SEPs from the LUT
would be useful not only for an assessment of LUT
sensory function, to amend findings from previous
investigations (i.e. history, neurologic examination, urodynamic
examination), but also as a surrogate marker and
outcome measure for treatments targeting afferent LUT
pathways . However, SEP measurements stimulating
the LUT are more challenging than SEP measurements
for cutaneous sites due to less direct control of electrode
placement and potential changes of bladder volume with
time, which can influence the SEP measurement.
Furthermore, bladder SEPs may be less synchronized as they
are likely mediated by poorly or non-myelinated fibres
leading to less distinct summation of sensory potentials.
Nevertheless, previous studies reported first feasibility
results of SEP recordings from the LUT following
Fig. 1 Example of a cortical LUT SEP recorded at Cz with the
markers of the P1, N1 and P2 peaks and the corresponding latencies
and peak-to-peak amplitudes
electrical stimulation in healthy subjects [22–26] and
patients [20, 27–29]. However, due to heterogeneous
measurement settings and study populations, a clear
conclusion cannot be drawn from these data. Currently,
there is no standard for SEP measurements for the LUT.
Hence, optimal stimulation and recording procedures as
well as parameters still need to be determined.
In this study we would like to advance the evaluation
of viscero-sensory afferent pathways of the LUT and to
refine the methodology of LUT SEPs in healthy subjects.
We aim to get more knowledge on the impact 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. In a first step it is our goal to
find a frequency that allows a faster acquisition of
reliable SEPs than the previously used 0.5 Hz [25, 26] and
to obtain normative LUT SEP data for the different
localizations in the LUT from different gender groups. In
a second step we aim to implement the optimized
methodology into clinical practice to use it as an objective
marker of pathological LUT conditions and to show
distinction of healthy LUT neurophysiology and function.
Methods and design
This study is a prospective, randomized trial conducted
as a single center study at the Spinal Cord Injury Center
& Research Lab, Balgrist University Hospital, University
of Zürich, Zürich, Switzerland. The study comprises
three visits of which the first will be a screening visit
followed by two measurement visits separated by an
interval of 3–4 weeks (Fig. 2). The site of stimulation
will be indicated by random group assignment (in
females and males: dome, trigone, proximal urethra, distal
urethra; in males additionally: membranous urethra).
Consequently, ten females and ten males will be
allocated to one localization. In addition, the frequencies
used for the stimulation of the LUT and thereafter the
SSEP measurements will be randomly applied.
Study population and recruitment
The volunteers will be recruited via announcements at
the University of Zürich, internet platforms (i.e.
www.marktplatz.uzh.ch, www.tutti.ch, www.ronorp.net)
and personal contacts. According to the inclusion- and
exclusion criteria (Table 1), healthy female and male
subjects without any LUTS will be included. Health is
defined as the absence of any health troubles, as assessed
by a complete medical history, standardized
questionnaires, physical, neurological and neuro-urological
examinations (Table 2). The absence of LUTS will be
determined by uroflowmetry, a 3-day bladder diary and
standardized urological questionnaires (FLUTS 
/MLUTS ; Qualiveen ; IPSS ; Swiss German
OAB ) (Table 2).
Investigations and procedures
Screening (visit one)
The content and purpose of the study will be explained
in written and oral form to all recruited subjects. Those
subjects providing written informed consent will be
screened for in- and exclusion criteria by using the tests,
questionnaires, and examinations listed in Table 2.
Subjects who are eligible for study participation according
to the in- and exclusion criteria (Table 1) will be invited
for visit two and three (Fig. 2).
Measurement visits (visit two and three)
Prior to each measurement, the urine of the volunteers
is analyzed to exclude signs suggestive for asymptomatic
bacteriuria, microhaematuria, and (in women only)
pregnancy. Both measurements consist of a resting
electroencephalogram (EEG) measurement followed by
recordings of SEPs elicited by transurethral electrical
stimulation at a specific LUT site indicated by the group
assignment. Each measurement includes recordings of
the electrooculogram (left and right eye),
electrocardiogram, and electroencephalogram using a 64 Ag/AgCl
surface electrodes system comprising a cap-based
extended international 10–20 montage (Easy cap, Easy cap
GmbH, Herrsching, Germany). Electrode impedances
are constantly kept below 20kΩ. Six additional
electrodes are placed at Cpz (reference: Fz), C2 (reference:
Fz) and L1 (reference: iliac crest), respectively, for
segmental assessment. LUT electrical stimulation will be
applied transurethrally with a custom-made 14 Ch
catheter (Unisensor AG, Attikon, Switzerland), using
frequencies between 0.5Hz and 5Hz (bipolar, square wave,
pulse width 1 ms). Stimulation intensities are adapted to
the 3 to 4× CPT, which is determined using the method
of limits prior to each SEP measurement . The
catheter includes platinum electrodes and a radiopaque
marker, which allows precise catheter positioning under
fluoroscopic guidance. After each stimulation, the
bladder will be emptied and filled with 60 mL of contrast
medium (Ultravist® 150TM, Bayer AG, Switzerland). Con
sequent to LUT SEPs, SEPs elicited by transcutaneous
stimulation of the tibial and pudendal nerves will be
recorded in random order. These standard
neurophysiological measurements will serve as comparators to the
Fig. 2 Study design and time schedule
Table 1 Inclusion and exclusion criteria for healthy female and male volunteers
LUT lower urinary tract, SDV strong desire to void, UTI urinary tract infection
aassessed by MoCA and HADS; bexcluded by urine dipstick test; cassessed by history taking; dassessed by 3-day bladder diary; eassessed by neuro-urological
examination fassessed by standardized urological questionnaires (FLUTS, MLUTS, IPSS, Qualiveen, Swiss-German OAB questionnaire); gassessed by uroflowmetry
Good mentala and physical healthc
No regular intake of medicationc
Bladder capacity <150 mL or SDV already at 60mLd, e, g
Number of voids per day <8, number of voids per night <2d, f, c
LUT SEPs. Visits two and three will be performed
identically with an interval of 3 to 4 weeks (Fig. 3).
Two to three days after each measurement visit, a
follow-up interview is performed to evaluate the general
well-being of the volunteers. In case of any side effects,
such as dysuria, the subjects are appointed to an extra
medical visit for further evaluation, investigation and, if
necessary, medical treatment.
During the first visit, all subjects are carefully
screened to exclude subjects with neurological and/or
urological pathology or any regular medication intake.
At the beginning of every visit an urinalysis and
pregnancy test (in females only) is performed to exclude
signs suggestive for asymptomatic bacteriuria,
microhaematuria and pregnancy, respectively. Pregnancy
leads to study exclusion and referral to a gynecologist
for further evaluation. In case of a positive urine
Table 2 Overview of the screening procedure
FSFI  / IIEF 
IPSS  (only for males)
Any neurological or urological pathology e, f, c
Any anatomical anomaly/malignancy of the LUT or genitalia e, c
Any previous pelvic, spine or craniocerebral surgeryc
dipstick test suspicious for asymptomatic bacteriuria
or urinary tract infection (UTI), the measurement will
be postponed until the dipstick test result becomes
negative or UTI has been treated. In case of a
dipstick test indicating microhaematuria, subjects can
choose to repeat the test at a later time-point or to
directly have the result verified by clean
catheterization. If clean catheterization still indicates
microhaematuria, subjects will be excluded from study
participation and referred to their general practitioner
or urologist for further evaluation.
Two or three days after the measurement visits, a
follow-up interview will be conducted to assess general
well-being and document possible adverse events or
symptoms. In case of an adverse event, additional tests
or medical interventions will be initiated as necessary
and subjects might be referred to a general physician or
medical specialist for further investigations and/or
treatment. All responsible authorities will be informed about
any adverse events (AE) or severe adverse events (SAE).
These events will be observed and followed until
complete cure. To decrease the radiation dose during
visits two and three, we will not perform full radiographs
but fluoroscopy with a reduced field of view focusing on
the LUT only. For a protection of the male gonads, men
will wear a gonad shielding.
Endpoints of the study
Primary endpoint: N1 responder rate / latency of N1 – as
the most prominent peak of LUT SEPs.
Secondary endpoints: A) Latencies (P1, P2),
amplitudes (P1, N1, P2, P1N1, N1P2), topographies and
source localizations of LUT SEPs; B) CPTs; C) latencies,
amplitudes, topographies and source localization of
tibial, pudendal SSEPs; D) 3-day bladder diary, scores of
questionnaires (i.e. ICIQ-FLUTS /ICIQ-MLUTS
, IPSS , IIEF  /FSFI , Swiss German OAB
, ICIQ-LUTSqol , Qualiveen , HADS ,
Fig. 3 Flowchart of the measurement visits (visits two and three)
Determination of sample size
Based on data from a previous study , the sample
size was determined using a non-parametric approach
. Non-parametric smoothing estimates (kernel
smooth) were iteratively compared for subsets of
individuals in order to establish the smallest subset (sample
size) in which a significant outcome was observed.
Determined using cross-validation , the smoothing
parameter was set to 20. From the smoothed curves, the
empirical second derivatives (as an expression of the
'information', i.e. latency, amplitude and dispersion,
contained therein) were used, the estimates of which were
computed and standardized by the absolute value of
their mean. The difference between the two frequencies
(0.5Hz and 3Hz) was taken into account, to allow for a
standardized vector summary of the curve. Normality
was tested using the Kolmogorov-Smirnov method and
no evidence against was revealed. A t-test based on this
standardized vector was subsequently conducted. Power
analysis was performed using a bootstrapping technique
[42, 43]. For each different sample size combination, the
difference between the two frequencies, contained in the
standardized vector, was analyzed. The bootstrap
simulations were executed at the individual level. All elements
of the standardized vector summary were first
subsampled before results were presented based on the
mean p-values for all possible combinations. To ensure
robustness of the results, four different criteria –
standard deviation, variance, total variance (sum of the
absolute values) and wigglyness (sum of the absolute values
of the second derivatives) – were applied to the
standardized vector. The aforementioned procedure was
repeated for the different study visits and simulation
sites. This resulted in a required sample size of 50 male
and 40 female subjects, taking into account potential
Data management and analysis
All EEG data will be filtered and segmented using Brain
Vision Analyzer 2 (Version 220.127.116.117, Brain Products,
Gilching, Germany). The segments will be averaged and
the P1, N1, P2 latencies as well as the P1N1 and N1P2
amplitudes will be determined.
Study data will be collected and managed using the
Research Electronic Data Capture Tool (REDCap,
Version 6.12.1, Vanderbilt University) electronic data
capture tools hosted at Balgrist University Hospital .
REDCap is a secure, web-based application designed to
support data capture for research studies, providing 1)
an intuitive interface for validated data entry; 2) audit
trails for tracking data manipulation and export
procedures; 3) automated export procedures for seamless data
downloads to common statistical packages; and 4)
procedures for importing data from external sources.
Primarily, all data will be examined using exploratory
data analysis (EDA) methods and described providing
mean and standard deviation (or median and range
where appropriate). ANOVAs or independent sample
ttests (or Kruskal-Wallis test or Mann-Whitney tests
where appropriate) will be performed to compare
participant characteristics between groups or to detect
gender differences. Linear mixed effects models will be used
to compare the two measurement visits. The level of
significance will be 5% (alpha = 0.05). Regression
techniques will be taken into account, if needed. All the
statistical analyses will be performed with the software
RStudio (Version 0.98.1083) .
This clinical trial will investigate the effect of several
stimulation frequencies at different locations of the
LUT. Since it was already shown that SEPs could be
reproducibly recorded from the LUT , we now aim to
optimize the settings to achieve a faster acquisition of
reliable SEPs, which is important for implementation
into clinical diagnostics and to minimize measurement
bias through changes that occur over time such as
The assessment of normative values of LUT SEPs in
healthy male and female subjects will give us more
knowledge on the variability of LUT SEPs, as well as
potential factors that may influence the shape and the
reliability of the SEPs. Cut-offs for amplitude and latency
values can be defined for future investigations in patients
with LUT dysfunction. The advancement of
neurophysiological assessment methods for the LUT will
significantly influence the evaluation of afferent nerve
function in the LUT and has the potential to serve as a
clinical diagnostic tool complementary to standard
urodynamic investigations. After having refined our
methodology, we would like to apply LUT SEPs with the
optimized stimulation frequency in different patient
groups suffering from LUTS, including patients with
spinal cord injury and multiple sclerosis. Established
cut-off amplitudes and latency values from this study
should then be used to relate LUT symptoms and
dysfunction in patients with LUT SEP data, thus amending
FC findings with an objective evaluation of afferent LUT
nerve function in these disorders.
At the time of manuscript submission, first subjects have
been recruited, included and investigated.
AE: Adverse event; CPT: Current perception threshold; EDA: Exploratory data
analysis; EEG: Electroencephalography / electroencephalogram; FC: Filling
cystometry; GCP: Good clinical practice; LUTS: Lower urinary tract symptoms;
OAB: Overactive bladder; SAE: Severe adverse event; SDV: Strong desire to
void; SEP: Sensory evoked potential; UTI: Urinary tract infection
SvdL, UM participated in designing protocol of the study. SvdL, MRS, MP, UM
drafted the manuscript. MSt, RF, MDL, MS, TMK critically revised the
manuscript. MS, TMK, UM obtained the funding of this study. SvdL, MSt, MRS
collect the data of the study. All the authors read and approved the final
Ethics approval and consent to participate
The study was approved by the local ethics committee (Kantonale
Ethikkommission Zürich, KEK-ZH-Nr. 2013-0518) and is performed according
to the (World Medical Association) Declaration of Helsinki , the guidelines
for Good Clinical Practice (GCP) , and the guidelines of the Swiss
Academy of Medical Sciences . Written informed consent is required
for study participation. All personal data are handled according to the
federal law of data protection in Switzerland .
1. Coyne KS , Wein AJ , Tubaro A , Sexton CC , Thompson CL , Kopp ZS , Aiyer LP . The burden of lower urinary tract symptoms: evaluating the effect of LUTS on health-related quality of life, anxiety and depression: EpiLUTS . BJU Int . 2009 ; 103 Suppl 3 : 4 - 11 .
2. Irwin DE , Milsom I , Kopp Z , Abrams P , Cardozo L. Impact of overactive bladder symptoms on employment, social interactions and emotional wellbeing in six European countries . BJU Int . 2006 ; 97 ( 1 ): 96 - 100 .
3. Irwin DE , Kopp ZS , Agatep B , Milsom I , Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction . BJU Int . 2011 ; 108 ( 7 ): 1132 - 8 .
4. Yoshimura N. Lower urinary tract symptoms (LUTS) and bladder afferent activity . Neurourol Urodyn . 2007 ; 26 ( 6 Suppl): 908 - 13 .
5. Fowler CJ . Bladder afferents and their role in the overactive bladder . Urology . 2002 ; 59 ( 5 Suppl 1 ): 37 - 42 .
6 Schafer W , Abrams P , Liao L , Mattiasson A , Pesce F , Spangberg A , Sterling AM , Zinner NR , van Kerrebroeck P , International Continence S. Good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies . Neurourol Urodyn . 2002 ; 21 ( 3 ): 261 - 74 .
7 Heeringa R , van Koeveringe GA , Winkens B , van Kerrebroeck PE , de Wachter SG . Degree of urge, perception of bladder fullness and bladder volumehow are they related ? J Urol . 2011 ; 186 ( 4 ): 1352 - 7 .
8 Erdem E , Akbay E , Doruk E , Cayan S , Acar D , Ulusoy E. How reliable are bladder perceptions during cystometry? Neurourol Urodyn . 2004 ; 23 ( 4 ): 306 - 9 .
9 De Wachter S , Van Meel TD , Wnydaele JJ . Can a faked cystometry deceive patients in their perception of filling sensations? A study on the reliability of spontaneously reported cystometric filling sensations in patients with nonneurogenic lower urinary tract dysfunction . Neurourol Urodyn . 2008 ; 27 ( 5 ): 395 - 8 .
10 Groen J , Pannek J , Castro Diaz D , Del Popolo G , Gross T , Hamid R , Karsenty G , Kessler TM , Schneider M , t Hoen L , et al. Summary of European Association of Urology (EAU) guidelines on Neuro-Urology. Eur Urol . 2016 ; 69 ( 2 ): 324 - 33 .
11 Virseda M , Salinas J , Esteban M , Mendez S. Reliability of ambulatory urodynamics in patients with spinal cord injuries . Neurourol Urodyn . 2013 ; 32 ( 4 ): 387 - 92 .
12 Bellucci CH , Wollner J , Gregorini F , Birnbock D , Kozomara M , Mehnert U , Kessler TM . Neurogenic lower urinary tract dysfunction-do we need same session repeat urodynamic investigations ? J Urol . 2012 ; 187 ( 4 ): 1318 - 23 .
13 Yarnitsky D. Quantitative sensory testing . Muscle Nerve . 1997 ; 20 ( 2 ): 198 - 204 .
14 De Wachter S , Wyndaele JJ. Quest for standardisation of electrical sensory testing in the lower urinary tract: the influence of technique related factors on bladder electrical thresholds . Neurourol Urodyn . 2003 ; 22 ( 2 ): 118 - 22 .
15 De Laet K , De Wachter S , Wyndaele JJ. Current perception thresholds in the lower urinary tract: Sine- and square-wave currents studied in young healthy volunteers . Neurourol Urodyn . 2005 ; 24 ( 3 ): 261 - 6 .
16 Ulrich Mehnert, André Reitz , Maya Ziegler , Peter A. Knapp , Brigitte Schurch . Does Tolterodine Extended Release Affect the Bladder Electrical Perception Threshold? A Placebo Controlled, Double-Blind Study With 4 and 8 mg in Healthy Volunteers . The Journal of Urology . 2007 ; 178 ( 6 ): 2495 - 2500 .
Ukimura O , Ushijima S , Honjo H , Iwata T , Suzuki K , Hirahara N , Okihara K , Mizutani Y , Kawauchi A , Miki T. Neuroselective current perception threshold evaluation of bladder mucosal sensory function . Eur Urol . 2004 ; 45 ( 1 ): 70 - 6 .
Sensory function assessment of the human male lower urinary tract using current perception thresholds . Neurourol Urodyn . 2016 [ Epub ahead of print] .
Cruccu G , Aminoff MJ , Curio G , Guerit JM , Kakigi R , Mauguiere F , Rossini PM , Treede RD , Garcia-Larrea L. Recommendations for the clinical use of somatosensory-evoked potentials . Clin Neurophysiol . 2008 ; 119 ( 8 ): 1705 - 19 .
Deltenre PF , Thiry AJ . Urinary bladder cortical evoked potentials in man: suitable stimulation techniques . Br J Urol . 1989 ; 64 ( 4 ): 381 - 4 .
Chiappa KH , Ropper AH . Evoked potentials in clinical medicine (first of two parts) . N Engl J Med . 1982 ; 306 ( 19 ): 1140 - 50 .
Ganzer H , Madersbacher H , Rumpl E. Cortical evoked potentials by stimulation of the vesicourethral junction: clinical value and neurophysiological considerations . J Urol . 1991 ; 146 ( 1 ): 118 - 23 .
Hansen MV , Ertekin C , Larsson LE . Cerebral evoked potentials after stimulation of the posterior urethra in man . Electroencephalogr Clin Neurophysiol . 1990 ; 77 ( 1 ): 52 - 8 .
Sarica Y , Karacan I , Thornby JI , Hirshkowitz M. Cerebral responses evoked by stimulation of vesico-urethral junction in man: methodological evaluation of monopolar stimulation . Electroencephalogr Clin Neurophysiol . 1986 ; 65 ( 2 ): 130 - 5 .
Flavia Gregorini , Stephanie C. Knüpfer , Martina D. Liechti , Martin Schubert , Armin Curt , Thomas M. Kessler , Ulrich Mehnert . Sensory evoked potentials of the bladder and urethra in middle-aged women: the effect of age . BJU International . 2015 ; 115 : 18 - 25 .
Electroencephalogr Clin Neurophysiol . 1996 ; 100 ( 1 ): 55 - 61 .
Electroencephalogr Clin Neurophysiol . 1982 ; 54 ( 5 ): 494 - 8 .
Hansen MV , Ertekin C , Larsson LE , Pedersen K. A neurophysiological study of patients undergoing radical prostatectomy . Scand J Urol Nephrol . 1989 ; 23 ( 4 ): 267 - 73 .
Am J Obstet Gynecol . 2004 ; 191 ( 1 ): 73 - 82 .
Scoring the short form ICSmaleSF questionnaire . International Continence Society. J Urol . 2000 ; 164 ( 6 ): 1948 - 55 .
Barry MJ , Fowler Jr FJ , O'Leary MP , Bruskewitz RC , Holtgrewe HL , Mebust WK , Cockett AT . The American Urological Association symptom index for benign prostatic hyperplasia . The measurement committee of the American Urological Association . J Urol . 1992 ; 148 ( 5 ): 1549 - 57 . discussion 1564.
Neurourol Urodyn . 2015 ; 34 ( 3 ): 255 - 63 .
Rosen RC , Riley A , Wagner G , Osterloh IH , Kirkpatrick J , Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction . Urology . 1997 ; 49 ( 6 ): 822 - 30 .
Rosen R , Brown C , Heiman J , Leiblum S , Meston C , Shabsigh R , Ferguson D , D'Agostino Jr R. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function . J Sex Marital Ther . 2000 ; 26 ( 2 ): 191 - 208 .
Kelleher CJ , Cardozo LD , Khullar V , Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women . Br J Obstet Gynaecol . 1997 ; 104 ( 12 ): 1374 - 9 .
38 Zigmond AS , Snaith RP . The hospital anxiety and depression scale . Acta Psychiatr Scand . 1983 ; 67 ( 6 ): 361 - 70 .
39 Nasreddine ZS , Phillips N , Chertkow H. Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample . Neurology . 2012 ; 78 ( 10 ): 765 - 6 . author reply 766.
40 Silverman BW . Some aspects of the spline smoothing approach to nonparametric regression curve fitting . J R Stat Soc B Methodol . 1985 ; 47 ( 1 ): 1 - 52 .
41 Abraham B , Ledolter J. Introduction To Regression Modeling . 2006 .
42 Davidson AC , Hinkley DV . Bootstrap Methods and Their Application . Cambridge University Press . 1997 ; 48 .
43 Efron B. Bootstrap methods: another look at the jackknife . Annals of Statistics . 1979 ; 7 ( 1 ): 1 - 26 .
44 Harris PA , Taylor R , Thielke R , Payne J , Gonzalez N , Conde JG . Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support . J Biomed Inform . 2009 ; 42 ( 2 ): 377 - 81 .
45 R Development Core Team . R. A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing ; 2015 .
46 World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects . JAMA . 2013 ; 310 ( 20 ): 2191 - 4 .
47 International conference on harmonisation . Good clinical practice guideline . http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html.
48 Swiss Academy of Medical Sciences. Guideline-concerning scientific research involving human beings . 2009 :http://www.samw.ch/de/ Publikationen/Leitfaden-fuer-die-Praxis .html. Accessed 22 Nov 2016 .
49 The Federal Authorities of the Swiss Confederation . Bundesgesetz über den Datenschutz (DSG) vom 19. Juni 1992 , Stand. 01.01. 2014 . 1992 : https://www. admin.ch/opc/de/classified-compliation/19920153/index.html#app1. Accessed 22 Nov 2016 .