Estimation of intraepidermal fiber density by the detection rate of nociceptive laser stimuli in normal and pathological conditions

The variability of warm and heat pain sensitivity between body regions is usually ascribed to differences in intraepidermal nerve fiber (IENF) density. However, although crucial to assess the function of the thermo-nociceptive system, especially in the context of small fiber neuropathies, the relationship between psychophysical performance and IENF density is poorly understood. Here, we examine the hypothesis according to which the nociceptive system must receive a critical amount of afferent information to generate a conscious percept and/or a behavioral response. The amount of nociceptive information is defined by the stimulus, but also by the state of the nervous system encoding, transmitting and processing the afferent input. Furthermore, this amount may be expected to depend on the number of activated IENF, itself dependent on the size of the stimulated surface area as well as the density of IENF. By characterizing the relationship between psychophysical responses to nociceptive stimuli, size of the stimulated surface area and IENF density estimated using skin biopsies in healthy subjects as well as experimental and pathological conditions of reduced IENF density, we were able to estimate the number of nociceptive afferents required to elicit a conscious percept. Convergent results were obtained across the different experiments, indicating that the detection rate to brief small-diameter CO(2) laser pulses could be used to estimate IENF density and, hence, to diagnose and quantify denervation in small fiber neuropathies.