Ramped kilohertz-frequency signals produce nerve conduction block without onset response

<i>Objective.</i>Reversible block of peripheral nerve conduction using kilohertz-frequency (KHF) electrical signals has substantial potential for treating diseases. However, onset response, i.e. KHF-induced excitation en route to producing nerve block, is an undesired outcome of neural block protocols. Previous studies of KHF nerve block observed increased onset responses when KHF signal amplitude was linearly ramped for up to 60 s at frequencies up to 30 kHz. Here, we evaluated the onset response across a broad range of ramp durations and frequencies.<i>Approach</i>. In experiments on the rat tibial nerve and biophysical axon models, we quantified nerve responses to linearly ramped KHF signals applied for durations from 16 to 512 s and at frequencies from 10 to 83.3 kHz. We also investigated the role of slow inactivation on onset response during linear ramps by using lacosamide to enhance slow inactivation pharmacologically and by introducing a slow inactivation gating variable in computational models.<i>Main results</i>. In experiments, sufficiently high frequencies (⩾20.8 kHz) with amplitudes that were ramped sufficiently slowly (4.4-570<i>μ</i>A s^-1) generated conduction block without onset response, and increasing frequency enabled shorter ramps to block without onset response. Experimental use of lacosamide to enhance slow inactivation also eliminated onset response. In computational models, the effects of ramp duration/ramp rate on onset response only occurred after introducing a slow inactivation gating variable, and the models did not account for frequency effects.<i>Significance</i>. The results reveal, for the first time, the ability to use charge-balanced linearly ramped KHF signals to block without onset response. This novel approach enhances the precision of neural blocking protocols and enables coordinated neural control to restore organ function, such as in urinary control after spinal cord injury.