Overactive bladder and voiding dysfunction are highly prevalent and often associated with malfunction of the bladder afferent pathways. Appropriate diagnostic tools for an objective assessment of afferent nerve function of the human bladder are currently missing. One promising possibility is the assessment of sensory evoked potentials (SEP) during repetitive electrical bladder stimulation, which proved feasible in healthy subjects. For an implementation into clinical practice, however, further refinements for efficient and reliable data acquisition are crucial. The aim of this randomized study was to find the optimal measurement settings regarding stimulation frequency, repetition number, and data acquisition. Forty healthy subjects underwent two visits of SEP (Cz-Fz) assessments using repetitive (500 stimuli) electrical stimulation of 0.5 Hz, 1.1 Hz, and 1.6 Hz and pulse width of 1 ms at the bladder dome or trigone. SEP analyses revealed higher amplitudes and better signal-to-noise ratio (SNR) with lower stimulation frequencies, while latencies remained unchanged. Decreasing amplitudes and SNR were observed with continuing stimulation accompanied by decreasing responder rate (RR). When applying stimuli at a frequency of 0.5 Hz, averaging across 200 stimuli revealed optimal reliability with best SNR, RR and sufficiently high amplitudes. This constitutes an optimal compromise between the duration of the assessment and SEP peak-to-peak amplitudes.

BackgroundLower 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.MethodsThis 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.DiscussionThe 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 registrationClinicaltrials.gov; Identifier: NCT02272309.

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.