Changes in excitability of human motor axons underlying post-ischaemic fasciculations: evidence for two stable states

1. We have investigated the origin of post-ischaemic ectopic discharges in human nerve by recording changes in electrical excitability following periods of ischaemia (15-20 min) sufficient to induce spontaneous motor fasciculations. The ulnar nerve was stimulated beneath a pressure cuff on the upper arm, and compound motor action potentials recorded from abductor digiti minimi. 2. On releasing the cuff after 15 min of ischaemia, thresholds to short current pulses increased in two distinct phases: a slow phase followed by a rapid rise to a peak threshold. The rapid rise was too fast to track (i.e. 100% threshold increase in less than 4 s), and was sometimes followed after 30-40 s by an equally rapid fall. Small polarizing currents affected the timing of the rapid threshold increase, as if it was occurring at a particular membrane potential. 3. By recording complete stimulus-response curves every few seconds, we found that the rapid threshold changes were associated with a bimodal distribution of thresholds. Most fibres were found in either a high-threshold or low-threshold state, and these two states converged over a period of about 10 min. 4. Spontaneous motor fasciculations were only recorded after the rapid rise in threshold and when the fibres existed in two threshold states. The spontaneous activity was not responsible for inducing the two states, since they could also be recorded in its absence. 5. A computer model of a human motor axon node and internode was constructed, incorporating channel types demonstrated in other axons, and channel densities adjusted to match the responses of human axons to depolarizing and hyperpolarizing current pulses. An increase in extracellular potassium concentration produced a region of negative slope conductance in the current-voltage relationship of the model, and the appearance of two stable states with enhanced activity of the electrogenic sodium pump. 6. Transitions between the two stable states of the model could account qualitatively for the rapid threshold changes recorded from post-ischaemic axons. In the model, spontaneous action potentials occurred following some transitions from the high potential state to the low potential state. We suggest that post-ischaemic motor fasciculations in man also involve transitions between two equilibrium states, occurring in axons with high extracellular potassium and high electrogenic pump activity.