Biophysical Determinants of the Behaviour of Human Myelinated Axons

Abstract

This thesis investigates the role of the hyperpolarization-activated current, Ih, on the excitability of human axons. It exploits the unique characteristics of the underlying hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels to improve existing and create new techniques for studying Ih. An isolated amplifier with low-noise and high common-mode rejection was developed, and threshold tracking techniques were modified to allow the measurement of the excitability of low-threshold sensory axons and of cutaneous afferents close to their receptors. These developments open up the possibility of studying changes in polyneuropathies, where symptoms and possibly the underlying pathology are more apparent distally in the limbs. Strong and long-lasting hyperpolarization was used to open more HCN channels and to examine their contribution to the excitability of motor and sensory axons. A mathematical model of myelinated motor axons was adapted to account for the response to strong and long-lasting hyperpolarization. Without structural changes the model was then modified to fit the observed excitability of sensory axons. Changes in the excitability and safety margin during focal hyperthermia were studied in both motor and sensory axons of the median nerve, and the underlying mechanisms were explored using the new mathematical model. Finally, the involvement of Ih in the frequency preference of oscillation in human axons was investigated by developing resonance techniques that have hitherto never been used to study axonal function.