The assertion that large-diameter nerve fibers have low thresholds and small-diameter fibers have high thresholds in response to electrical stimulation has been held in a nearly axiomatic regard in the field of neuromodulation and neuroprosthetics. In contrast to the short pulses used to evoke action potentials, long-duration ionic direct current has been shown to block neural activity. We propose that the main determinant of the neural sensitivity to direct current block is not the size of the axon but the types of voltage-gated sodium channels prevalent in its neural membrane. On the basis of the variants of voltage-gated sodium channels expressed in different types of neurons in the peripheral nerves, we hypothesized that the small-diameter nociceptive fibers could be preferentially blocked. We show the results of a computational model and in vivo neurophysiology experiments that offer experimental validation of this novel phenomenon.
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