Model based analysis of the orderly size-wise activation observed with sinusoidal low frequency alternating current stimulation of peripheral nerves

Extracellular sinusoidal low frequency alternating current (LFAC) stimulation of peripheral motor nerves has been observed to induce size wise activation of nerve fibers, unlike the inverse recruitment order typically seen in extracellular pulsed stimulation. This study aims to explore potential biophysical mechanisms responsible for this phenomenon using computational modeling. Volume conductor model was utilized with a bipolar cuff electrode encasing a single rat-sized fascicle. The extracellular potentials generated by LFAC and pulse stimulation were projected onto the McIntyre-Richardson-Grill models of myelinated motor nerve fibers to examine the activation of fibers ranging from 5.7 to 16m in diameter. Intracellular and extracellular stimulation were compared for strength-frequency relationships with LFAC (1-20Hz) and strength-duration curves for pulse stimulation. The threshold tracking technique was used to study membrane electrotonus and threshold electrotonus of different fibers to examine subthreshold accommodation in response to LFAC and prolonged pulse stimulation. The simulations revealed that the inverse order of fiber recruitment is an inherent characteristic of extracellular stimulation and is theoretically independent of the stimulation waveform. LFAC showed an inverse strength-frequency relationship (higher frequency, lower threshold current), similar to the inverse strength-duration relationship for pulsed stimulation. Analysis of subthreshold accommodation showed that larger fibers exhibit greater accommodation than smaller fibers, leading to increased activation thresholds as fast Na+ activation factor m3h decreases while slow K+ activation increases, supporting accommodation as a contributor to orderly recruitment. With increasing LFAC frequency (up to 20Hz), these accommodation characteristics were reduced and large-fiber state dynamics shifted toward those of smaller fibers. LFAC was also found to induce subthreshold oscillations that promoted spike initiation during slow depolarization. These findings suggest that LFAC provides a controlled and optimized method for achieving orderly recruitment without the need for complex selective blocking protocols. By leveraging intrinsic membrane properties, LFAC offers a neuromodulation strategy that preserves physiological recruitment order, with direct implications for selective nerve stimulation in clinical and neuroprosthetic applications. Author summaryElectrical stimulation is widely used to activate peripheral nerves in motor rehabilitation and neuroprosthetic devices, but conventional pulse stimulation activates larger nerve fibers first (with lower current intensity), which can induce rapid muscle fatigue and pain. We used well-established and validated computational models of motor nerve fibers (axons) to explore how sinusoidal low frequency alternating current (LFAC) stimulation can produce a more physiological, size-wise recruitment order. We simulated myelinated motor nerve fibers of different diameters individually inside a bipolar cuff electrode and analyzed how the membrane and ion channels changed during stimulation levels that are below thresholds for action potential firing. We found that larger fibers adapt (accommodate) more strongly during the slow depolarization of LFAC: their sodium channels become less open, while potassium activation increases, raising the current required to induce an action potential. Smaller fibers were less affected by this accommodation effect and could reach firing at lower current intensities. We also found that these effects depend on stimulation frequency; at lower frequencies, the accommodation characteristics were more defined (for all fibers), while at higher frequencies they were reduced (for large fibers) and all fiber responses became more similar. Our results suggest that the responses of intrinsic membrane dynamics to LFAC lead fiber recruitment toward a more physiological order, which facilitates the design of safer and more selective nerve stimulation strategies with LFAC.