Accommodation to hyperpolarization of human axons assessed in the frequency domain

Human axons in vivo were subjected to subthreshold currents with a threshold impedance amplitude profile to allow the use of frequency domain techniques to determine the propensity for resonant behavior and to clarify the relative contributions of different ion channels to their low-frequency responsiveness. Twenty-four studies were performed on the motor and sensory axons of the median nerve in six subjects. The response to oscillatory currents was tested between direct current (DC) and 16 Hz. A resonant peak at ∼2-2.5 Hz was found in the response of hyperpolarized axons, but there was only a small broad response in axons at resting membrane potential (RMP). A mathematical model of axonal excitability developed using DC pulses provided a good fit to the frequency response for human axons and indicated that the hyperpolarization-activated current Ih and the slow potassium current IKs are principally responsible for the resonance. However, the results indicate that if axons are hyperpolarized by more than -60% of resting threshold, the only conductances that are appreciably active are Ih and the leak conductance, i.e., that the activity of these conductances can be studied in vivo virtually in isolation at hyperpolarized membrane potentials. Given that the leak conductance dampens resonance, it is suggested that the -60% hyperpolarization used here is optimal for Ih As expected, differences between the frequency responses of motor and sensory axons were present and best explained by reduced slow potassium conductance GKs, up-modulation of Ih, and increased persistent Na(+) current INaP (due to depolarization of RMP) in sensory axons.