Low-Frequency Tibial Neuromodulation Increases Voiding Activity - a Human Pilot Study and Computational Model

Despite widespread clinical adoption for disorders of incontinence such as overactive bladder, there remain unknowns surrounding the mechanism that underpins Tibial Nerve Stimulation (TNS). Current understanding suggests that TNS counteracts incontinence by the inhibition of brainstem and spinal cord activity. How this inhibition alters bladder function is not fully understood. We hypothesize that the supraspinal components of the system act as a high-pass filter, allowing voiding signals to proceed only when bladder filling reaches a critical level. Testing this hypothesis may explain how TNS is able to induce both an inhibitory and a little-explored excitatory effect on bladder activity in response to high-frequency (20 Hz) and low-frequency (1 Hz) stimulation, respectively. We performed a single-blinded trial in healthy human participants administered high and low-frequency Transcutaneous TNS. We also developed a computational model of the lower-urinary tract and control circuit to study the frequency-dependent effects of TNS. For the first time, we report a frequency-dependent effect of TNS via the ability to alter urge perception and up-regulate and down-regulate bladder activity, corroborating model predictions. These results provide a foundation for the development of targeted and effective TNS therapies, benefiting from in silico models. We hope that future clinical research will determine the efficacy of low-frequency TNS as a non-invasive treatment option for urinary retention. Significance StatementThis work describes an experimental study supported by a novel computational model that for the first time captures the frequency-dependent effects of tibial neuromodulation on the urinary control system in humans. The findings of the work provide critically important evidence for the role of the brainstem as a filter, which may explain the little-explored excitatory effect of tibial neuromodulation on bladder activity. These results have considerable clinical implications in the treatment of urinary retention, a condition for which there are at present very few non-invasive treatment options available.