Excitability and the safety margin in human axons during hyperthermia

Key points center dot In six healthy subjects, the excitability of both motor and sensory axons was altered during hyperthermia, lowering their safety margin. center dot The results suggest that slow K+ channels play a significant role in these changes in axonal excitability during hyperthermia. center dot Inward rectification was reduced during hyperthermia, and the modelling suggests that the hyperpolarization-activated cation current, Ih, was reduced, thus hampering its ability to counter activity-dependent hyperpolarization. center dot Hyperthermia lowers the safety margin for action potential generation and propagation. Differences in their responses to hyperthermia suggest that motor axons undergo conduction block more readily than sensory axons during fever, particularly when the safety margin is already impaired. Abstract Hyperthermia challenges the nervous system's ability to transmit action potentials faithfully. Neuromuscular diseases, particularly those involving demyelination have an impaired safety margin for action potential generation and propagation, and symptoms are commonly accentuated by increases in temperature. The aim of this study was to examine the mechanisms responsible for reduced excitability during hyperthermia. Additionally, we sought to determine if motor and sensory axons differ in their propensity for conduction block during hyperthermia. Recordings of axonal excitability were performed at normal temperatures and during focal hyperthermia for motor and sensory axons in six healthy subjects. There were clear changes in excitability during hyperthermia, with reduced superexcitability following an action potential, faster accommodation to long-lasting depolarization and reduced accommodation to hyperpolarization. A verified model of human motor and sensory axons was used to clarify the effects of hyperthermia. The hyperthermia-induced changes in excitability could be accounted for by increasing the modelled temperature by 6 degrees C (and adjusting the maximum conductances and activation kinetics according to their Q10 values; producing a 2 mV hyperpolarization of resting membrane potential), further hyperpolarizing the voltage dependence of Ih (motor, 11 mV; sensory, 7 mV) and adding a small depolarizing current at the internode (motor, 20 pA; sensory, 30 pA). The modelling suggested that slow K+ channels play a significant role in reducing axonal excitability during hyperthermia. The further hyperpolarization of the activation of Ih would limit its ability to counter the hyperpolarization produced by activity, thereby allowing conduction block to occur during hyperthermia.