Bifurcation of neural firing patterns driven by potassium dynamics and neuron-electrode geometry during high-frequency stimulation.

Abstract

High-frequency stimulation (HFS), the basis of deep brain stimulation, elicits diverse neuronal responses, yet the mechanisms remain unclear. Classical conduction block theories cite sodium channel inactivation and axonal failure but cannot explain the abrupt, reproducible firing transitions observed in vivo. Here, we combine single-unit recordings from rat CA1 neurons with a biophysically detailed multi-compartment model to examine how HFS shapes axonal excitability. The results show that neuronal responses are governed by two coupled factors: the electrode-axon geometry and peri-axonal extracellular potassium ([K⁺]o) dynamics. Small changes in either parameter reliably triggered bifurcation-like transitions between tonic, clustered, and low-rate regular firing. Conduction block preceded initiation failure with increasing electrode-axon distance, whereas elevated [K⁺]o shifted membranes between excitable and non-excitable states. This unified bifurcation framework extends the conduction block hypothesis, recasts axons as nonlinear elements, and provides mechanistic insights to optimize electrode placement, stimulation tuning, and closed-loop neuromodulation strategies.