The role of sodium channels in direct current stimulation—axonal perspective

Transcranial neurostimulation methods are utilized as therapies for various neuropsychiatric disorders. Primarily, they entail the delivery of weak subthreshold currents across the brain, which modulate neuronal excitability. However, it is still a puzzle how such weak electrical fields actuate their effects. Previous studies showed that axons are the most sensitive subcellular compartment for direct current stimulation, and maximal polarization is achieved at their terminals. Nonetheless, polarization of axon terminals according to models was predicted to be weak, and the mechanism for substantial axon terminals polarization was obscure. Here, we show that a weak subthreshold electrical field modifies the conductance of voltage-dependent sodium channels in axon terminals, subsequently amplifying their membrane polarization. Moreover, we show that this amplification has substantial effects on synaptic functioning. Finally, we employ analytical modeling to explain how sodium currents modifications enhance axon terminal polarization. These findings relate to the mechanistic aspects of any neurostimulation technique.