Altered excitability of small cutaneous nerve fibers during cooling assessed with the perception threshold tracking technique

Abstract

Background There is a need for new approaches to increase the knowledge of the membrane excitability of small nerve fibers both in healthy subjects, as well as during pathological conditions. Our research group has previously developed the perception threshold tracking technique to indirectly assess the membrane properties of peripheral small nerve fibers. In the current study, a new approach for studying membrane excitability by cooling small fibers, simultaneously with applying a slowly increasing electrical stimulation current, is evaluated. The first objective was to examine whether altered excitability during cooling could be detected by the perception threshold tracking technique. The second objective was to computationally model the underlying ionic current that could be responsible for cold induced alteration of small fiber excitability. The third objective was to evaluate whether computational modelling of cooling and electrical simulation can be used to generate hypotheses of ionic current changes in small fiber neuropathy. Results The excitability of the small fibers was assessed by the perception threshold tracking technique for the two temperature conditions, 20 °C and 32 °C. A detailed multi-compartment model was developed, including the ionic currents: Na TTXs , Na TTXr , Na P , K Dr , K M , K Leak , K A , and Na/K-ATPase. The perception thresholds for the two long duration pulses (50 and 100 ms) were reduced when the skin temperature was lowered from 32 to 20 °C (p < 0.001). However, no significant effects were observed for the shorter durations (1 ms, p = 0.116; 5 ms p = 0.079, rmANOVA, Sidak). The computational model predicted that the reduction in the perception thresholds related to long duration pulses may originate from a reduction of the K Leak channel and the Na/K-ATPase. For short durations, the effect cancels out due to a reduction of the transient TTX resistant sodium current (Na v 1.8). Additionally, the result from the computational model indicated that cooling simultaneously with electrical stimulation, may increase the knowledge regarding pathological alterations of ionic currents. Conclusion Cooling may alter the ionic current during electrical stimulation and thereby provide additional information regarding membrane excitability of small fibers in healthy subjects and potentially also during pathological conditions.

Increased preferential activation of small cutaneous nerve fibers by optimization of electrode design parameters

“…These electrodes have been shown to elicit pinprick-like sensations, related to Aδ-fiber activation [1]- [4], [30]. This corresponds well with the findings of the present study for which it was likewise observed that smaller cathode areas produced higher electrical potentials in the epidermal skin layers and resulted in lower activation thresholds of the Aδ-fiber model.…”

Human pain ratings to electrical sinusoids increase with cooling through a cold-induced increase in C-fibre excitability

“…Notably, and consistent with a general reduction in excitability with cooling, nonpainful perception thresholds determined in response to 50-millisecond and 100-millisecond-long, exponential, shark fin–shaped, electrical current profiles decreased when skin temperature was lowered from 32°C to 20°C. 27…”

Nerve growth factor sensitizes nociceptors to C‐fibre selective supra‐threshold electrical stimuli in human skin

“…Interestingly, mechanical impact pain was not reduced during A‐fibre block, which might be linked to the endings activated by this strong mechanical stimulus being at a deeper location and thus somewhat warmer than the skin. It will be of interest to investigate systematically the influence of skin surface temperature on pain responses caused by sinusoidal currents, particularly in light of recent findings demonstrating that lower temperatures increase the excitability of unmyelinated nerve fibres ex vivo (Hugosdottir et al., 2019).…”