Fibers in smaller fascicles have lower activation thresholds with cuff electrodes due to thinner perineurium and smaller cross-sectional area.

. In nerve stimulation therapies, fibers in larger fascicles generally have higher activation thresholds, but the mechanisms are not well understood. We implemented and analyzed computational models to uncover the effects of morphological parameters on activation thresholds.. We implemented finite element models of human vagus nerve stimulation to quantify the effects of morphological parameters on thresholds in realistic nerves. We also implemented simplified models to isolate effects of perineurium thickness, endoneurium diameter, fiber diameter, and fascicle location on current density, potential distributions (), and activation thresholds across cuff geometries and stimulation waveforms. Usingfrom each finite element model, we simulated activation thresholds in biophysical cable models of mammalian axons.. Perineurium thickness increases with fascicle diameter, and both thicker perineurium and larger endoneurial diameter contributed to higher activation thresholds via lower peak and broader longitudinal potentials. Thicker perineurium caused less current to enter the fascicle transversely, decreasing peak. Thicker perineurium also inhibited current from leaving the fascicle, causing more constant longitudinal current density, broadening. With increasing endoneurial diameter, intrafascicular volume increased faster than surface area, thereby decreasing intrafascicular current density and peak. Additionally, larger fascicles have greater cross-sectional area, thereby facilitating longitudinal intrafascicular current flow and broadening. A large neighboring fascicle could increase activation thresholds, and for a given fascicle, fiber diameter had the greatest effect on thresholds, followed by fascicle diameter, and lastly, fascicle location within the epineurium. The circumneural cuff elicited robust activation across the nerve, whereas a bipolar transverse cuff with small contacts delivering a pseudo-monophasic waveform enabled more selective activation across fiber diameters and locations.. Our computational studies provide mechanistic understanding of neural responses across relevant morphological parameters of peripheral nerves, thereby informing rational design of effective therapies.