Effects of Extracellular Resistance on Neuronal Sensitivity Under Weak Alternating Electric Field Stimulation: A Computational Study.

Weak alternating electric fields are widely used in neuromodulation techniques such as transcranial alternating current stimulation (tACS), yet the precise biophysical mechanisms underlying neuronal responses remain incompletely understood. Current computational models often neglect the electrical properties of the extracellular microenvironment, limiting their predictive accuracy. Motivated by experimentally observed frequency-dependent modulation of neuronal activity, we developed a two-compartment model of hippocampal CA3 pyramidal neurons in which extracellular resistance is explicitly parameterized and systematically examined as a key factor influencing neuronal response properties under external electric fields. Within a dual-compartment Hodgkin-Huxley framework, the neuron is divided into a "soma-basal dendrite unit" and an "apical dendrite unit," accounting for voltage polarization induced by external fields. Using phase-locking ratio curves and three-dimensional parameter response surface, we systematically characterized neuronal sensitivity to field parameters and examined how potassium equilibrium potential (VK) and extracellular resistance (Rout) modulate these responses. Our results demonstrate that increasing Rout enhances neuronal responsiveness to external fields, while VK variations primarily regulate intrinsic excitability. These findings provide mechanistic insights into the frequency-dependent modulation of neuronal responses under weak electric fields, consistent with phenomena observed in biological neural systems, and provide a mechanistic and theoretical framework for understanding the joint effects of electric field amplitude and frequency on neuronal sensitivity to weak electric fields, which may help inform future neuromodulation strategies.