Evolution of peripheral nerve function in humans: novel insights from motor nerve excitability

Abstract

While substantial alterations in myelination and axonal growth have been described during maturation, their interactions with the configuration and activity of axonal membrane ion channels to achieve impulse conduction have not been fully elucidated. The present study utilized axonal excitability techniques to compare the changes in nerve function across healthy infants, children, adolescents and adults. Multiple excitability indices (stimulus-response curve, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle) combined with conventional neurophysiological measures were investigated in 57 subjects (22 males, 35 females; age range 0.46-24 years), stimulating the median motor nerve at the wrist. Maturational changes in conduction velocity were paralleled by significant alterations in multiple excitability parameters, similarly reaching steady values in adolescence. Maturation was accompanied by reductions in threshold (P < 0.005) and rheobase (P = 0.001); depolarizing and hyperpolarizing electrotonus progressively reduced (P < 0.001), or 'fanned-in'; resting current-threshold slope increased (P < 0.0001); accommodation to depolarizing currents prolonged (P < 0.0001); while greater threshold changes in refractoriness (P = 0.001) and subexcitability (P < 0.01) emerged. Taken together, the present findings suggest that passive membrane conductances and the activity of K(+) conductances decrease with formation of the axo-glial junction and myelination. In turn, these functional alterations serve to enhance the efficiency and speed of impulse conduction concurrent with the acquisition of motor skills during childhood, and provide unique insight into the evolution of postnatal human peripheral nerve function. Significantly, these findings bring the dynamics of axonal development to the clinical domain and serve to further illuminate pathophysiological mechanisms that occur during development.

Figure 1

Median nerve motor conduction velocity changes with age

Figure 2

Mean stimulus–response relations for healthy subjects grouped by chronological age

Figure 3. Comparison of TE measures with age

A, depolarizing TE curves for healthy subjects grouped by age. B, hyperpolarizing TE curves for healthy subjects grouped by age. C, hyperpolarizing changes at 10–20 ms (TE_h(10–20 ms)) reduced with age, P < 0.0001. D, depolarizing changes at 10–20 ms (TE_d(10–20 ms)) reduced with age, P < 0.0001. E, accommodation half-time increased with age, P < 0.0001. F, the ratio of TE_d(10–20) to TE_h(10–20) increased with age, P < 0.0001.

Figure 4

Comparison of current–threshold relationship for healthy subjects grouped by chronological age

Figure 5. Comparison of recovery cycle of excitability measures with age

A, recovery cycle of excitability curves. B, mean group data illustrating that refractoriness at 2.5 ms significantly increased with age; refractoriness was not present for the youngest group as a mean threshold reduction was observed.

Figure 6. The relationships between axonal excitability parameters and motor conduction velocity

A, threshold changes to subthreshold 40% hyperpolarizing currents at 10–20 ms (TE_h(10–20 ms)). B, threshold changes to subthreshold 40% hyperpolarizing currents at 90–100 ms (TE_h(90–100 ms)). C, accommodation half-time.

Figure 7. Simulation of the excitability changes in clinical nerve excitability with maturation using the mathematical model

Grey lines represent the model generated by the young adulthood group. Green lines were generated by the model by increasing GBB from 33.9 to 48.2 units and GKfi from 100 to 309 units, which reduced the discrepancy in late infancy and early childhood by 83.1%. Red lines were generated by the model by increasing GBB from 33.9 to 40.4 units and GKfi from 100 to 218 units, which reduced the discrepancy in late childhood by 79.6%. A, recovery cycles. B, charge–duration plot based on stimuli of 0.2 ms and 1 ms duration, with the negative intercept on the x-axis equating to T_SD, and the slope equal to the rheobase. C, TE for 100 ms polarizing currents ±40% of the resting threshold. D, current–threshold relationship.