Low-frequency tibial neuromodulation excites bladder activity in humans

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 upregulate and downregulate 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.