Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels are found on central neurones and peripheral nerves, including cardiac nerve fibres. They are responsible for the inwardly rectifying IH current and are the only channels activated by hyperpolarisation. As such, they are in a unique position to influence nerve excitability. We have explored differences in the function of HCN channels in upper and lower limb and facial nerves using nerve excitability measures as developed by Bostock and colleagues over the past 20 years. Facial nerve studies in healthy individuals. Compared the median nerve, the facial nerve showed significantly less inward rectification in response to hyperpolarizing currents (p<0.0005), an indication of reduced Ih current, and also a significant reduction in the superexcitability at 7ms (p=0.018) seen in the recovery cycle an indication of Increased K+ activation at the paranode. Both these changes may underlie the pathophysiology of hemifacial spasm where structural irritation to the facial nerve is believed to play a predominant role (compare this to carpal tunnel syndrome when muscle spasms are rarely if ever reported). Tibial nerve studies in healthy individuals. The change in excitability measures during hyperthermia (+6 degrees centigrade) was investigated in median and tibial nerves. Significant differences between recovery cycle superexcitability, accommodation to small depolarising currents and alterations in late stages of the strong hyperpolarising currents of threshold electrotonus were observed in the lower limbs during hyperthermia. The differences between upper and lower limb late hyperpolarising phases (S3) indicates functional differences in HCN channel function/expression in the lower limbs. Indeed, a higher slow HCN isoform expression in the lower limb may be expected as a result of the high and prolonged axon firing rates as a mechanism to counteract activity dependent hyperpolarisation. It is proposed that these physiological differences may account for the generation of neuropathological symptoms in distal neuropathies, particularly those associated with heat.