Characterizing Peripheral Motor Nerve Activation Using Sinusoidal Low Frequency Alternating Current Stimulation

Peripheral nerve stimulation using implantable cuff electrodes and sinusoidal Low Frequency Alternating Currents (LFAC) is a novel approach being explored for neuromodulation. This dissertation has investigated the characteristics and mechanisms of motor nerve stimulation using LFAC across different stimulation paradigms. Our findings provide a foundational understanding of LFAC stimulation as a potential alternative to traditional pulsed stimulation in neuromodulation, specifically for vagus nerve stimulation and functional electrical stimulation applications. The first study showed the fundamental properties of LFAC stimulation using bipolar cuff electrodes, indicating the existence of inverse relationships between LFAC activation thresholds and both frequency and electrode pitch. The study provided the first evidence of orderly fibers recruitment with LFAC, both in-silico (utilizing volume conductor models and the McIntyre-Richardson-Grill, MRG, models of myelinated motor nerve fibers) and in acute in-vivo experiments (N = 34, isoflurane-anaesthetized rats). The results suggested that LFAC stimulation can maintain physiological recruitment patterns under certain conditions, and bipolar cuff electrode geometry influences nerve excitation thresholds. The second study investigated the underlying mechanisms of LFAC-induced activation through in-silico studies. The findings suggested a possible role of nerve membrane accommodation during LFAC stimulation and sodium channel dynamics in facilitating orderly recruitment with the influence of subthreshold oscillations. The study identified the fiber-frequency-dependent nature of LFAC activation and divergence from conventional pulse-based extracellular stimulation. The third study explored the influence of different cuff electrode configurations: unipolar, monopolar, bipolar, and tripolar on LFAC activation thresholds through in-silico studies. The results demonstrated that electrode geometry affects recruitment selectivity, activation efficiency, and threshold variability. Unipolar and monopolar configurations resulted in lower activation thresholds; however, their selectivity was reduced as frequency increased. On the other hand, bipolar and tripolar configurations provided more controlled activation as contact separation and cuff edge distance have interconnected influences. The findings suggest the importance of optimizing electrode design and/or configuration to maximize the advantage of LFAC stimulation. In the fourth study, an initial comparison of muscle fatigue induced by LFAC versus traditional rectangular pulse stimulation was conducted in-vivo (N = 3, isoflurane-anaesthetized rats). The preliminary results suggest that LFAC may increase fatigue resistance compared to pulsed stimulation, potentially offering advantages for mitigating FES rapid muscle fatigue and that LFAC frequency is a critical factor. Collectively, these studies established a foundation for sinusoidal LFAC motor nerve stimulation that could be optimized for targeted therapeutic and rehabilitative neuromodulation applications.