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Small-surface-area electrodes have successfully been used to preferentially activate cutaneous nociceptors, unlike conventional large area-electrodes, which preferentially activate large non-nociceptor fibers. Assessments of the strength-duration relationship, threshold electrotonus, and slowly increasing pulse forms have displayed different perception thresholds between large and small surface electrodes, which may indicate different excitability properties of the activated cutaneous nerves. In this study, the origin of the differences in perception thresholds between the two electrodes was investigated. It was hypothesized that different perception thresholds could be explained by the varying distributions of voltage-gated ion channels and by morphological differences between peripheral nerve endings of small and large fibers. A two-part computational model was developed to study activation of peripheral nerve fibers by different cutaneous electrodes. The first part of the model was a finite-element model, which calculated the extracellular field delivered by the cutaneous electrodes. The second part of the model was a detailed multicompartment model of an Aδ-axon as well as an Aβ-axon. The axon models included a wide range of voltage-gated ion channels: Na(TTXs), Na(TTXr), Na(p), K(dr), K(M), K(A), and HCN channel. The computational model reproduced the experimentally assessed perception thresholds for the three protocols, the strength-duration relationship, the threshold electrotonus, and the slowly increasing pulse forms. The results support the hypothesis that voltage-gated ion channel distributions and morphology differences between small and large fibers were sufficient to explain the difference in perception thresholds between the two electrodes. In conclusion, assessments of perception thresholds using the three protocols may be an indirect measurement of the membrane excitability, and computational models may have the possibility to link voltage-gated ion channel activation to perception threshold measurements.

Objective. Electrical preferential activation of small nociceptive fibers may be achieved with the use of specialized small area electrodes, however, the existing electrodes are limited to low stimulation intensities. As existing electrodes have been developed empirically, the present study aimed to use computational modeling and optimization techniques to investigate if changes in electrode design parameters could improve the preferential activation of small fibers. Approach. Two finite element models; one of a planar concentric and one of an intra-epidermal electrode were combined with two multi-compartmental nerve fiber models of an Aδ-fiber and an Aβ-fiber. These two-step hybrid models were used for the optimization of four electrode parameters; anode area, anode–cathode distance, cathode area, and cathode protrusion. Optimization was performed using a gradient-free bounded Nelder–Mead algorithm, to maximize the current activation threshold ratio between the Aβ-fiber model and the Aδ-fiber model. Main results. All electrode parameters were optimal at their lower bound, except the cathode protrusion, which was optimal a few micrometers above the location of the Aδ-fiber model. A small cathode area is essential for producing a high current density in the epidermal skin layer enabling activation of small fibers, while a small anode area and anode–cathode distance are important for the minimization of current spread to deeper tissues, making it less likely to activate large fibers. Combining each of the optimized electrode parameters improved the preferential activation of small fibers in comparison to existing electrodes, by increasing the activation threshold ratio between the two nerve fiber types. The maximum increase in the activation threshold ratio was 289% and 595% for the intra-epidermal and planar concentric design, respectively. Significance. The present study showed that electrical preferential small fiber activation can be improved by electrode design. Additionally, the results may be used for the production of an electrode that could potentially be used for clinical assessment of small fiber neuropathy.

The excitability of large nerve fibers is reduced when their membrane potential is slowly depolarizing, i.e., the fibers display accommodation. The aim of this study was to assess accommodation in small (mainly Aδ) and large (Aβ) cutaneous sensory nerve fibers using the perception threshold tracking (PTT) technique. Linearly increasing ramp currents (1 ms-200 ms) were used to assess the excitability of the nerve fibers by cutaneous electrical stimulation. To investigate the PPT technique’s ability to preferentially activate different fiber types, topical application of lidocaine/prilocaine (EMLA) or a placebo cream was applied. By means of computational modeling, the underlying mechanisms governing the perception threshold in the two fiber types was studied. The axon models included the voltage-gated ion channels: transient TTX-sensitive sodium current, transient TTX-resistant sodium current (Na TTXr), persistent sodium current, delayed rectifier potassium channel (K Dr), slow potassium channel, and hyperpolarization-activated current. Large fibers displayed accommodation, whereas small fibers did not display accommodation (P < 0.05). For the pin electrode, a significant interaction was observed between cream (EMLA or placebo) and pulse duration (P< 0.05); for the patch electrode, there was no significant interaction between cream and duration, which supports the pin electrode’s preferential activation of small fibers. The results from the computational model suggested that differences in accommodation between the two fiber types may originate from selective expression of voltage-gated ion channels, particularly the transient Na TTXr and/or K Dr. The PTT technique could assess the excitability changes during accommodation in different nerve fibers. Therefore, the PTT technique may be a useful tool for studying excitability in nerve fibers in both healthy and pathological conditions. NEW & NOTEWORTHY When large nerve fibers are stimulated by long, slowly increasing electrical pulses, interactive mechanisms counteract the stimulation, which is called accommodation. The perception threshold tracking technique was able to assess accommodation in both small and large fibers. The novelty of this study is that large fibers displayed accommodation, whereas small fibers did not. Additionally, the difference in accommodation between the fiber could be linked to expression of voltage-gated ion channels by means of computational modeling.

OBJECTIVE: Over the recent years, several small area electrodes have been introduced as tools for preferential stimulation of small cutaneous nerve fibers. However, the performance of the electrodes is highly debated and have not previously been systematically compared. The electrodes have been developed empirically and little is known about the electrical potential they produce in the skin, and how this influences the nerve fiber activation. The objective of the present study was to develop and validate a computational model to compare the preferential stimulation of small fibers for electrodes of different designs.APPROACH: A finite element model of the skin was developed and coupled with an Aβ-fiber and an Aδ-fiber multi-compartmental nerve fiber model, to describe the current spread and consequent nerve fiber activation produced by five different surface electrodes; intra-epidermal, planar concentric, pin, planar array, and patch. The model was validated through experimental assessments of the strength-duration relationship, impedance, and reaction times.MAIN RESULTS: The computational model predicted the intra-epidermal electrode to be the most preferential for small fiber activation. The intra-epidermal electrode was, however, also found to be the most sensitive to positioning relative to nerve fiber location, which may limit the practical use of the electrode.SIGNIFICANCE: The present study highlights the influence of different electrode design features on the current spread and resulting activation of cutaneous nerve fibers. Additionally, the computational model may be used for the optimization of electrode design towards even better preferential stimulation of small fibers.

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 v1.8). 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.

Introduction: Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear. Methods: Patients scheduled for adjuvant oxaliplatin for colorectal cancer were examined with quantitative sensory testing and nerve excitability tests at baseline and after the second or third oxaliplatin cycle at different skin temperatures. Results: Seven patients were eligible for examination. All patients felt evoked pain and tingling when touching something cold after oxaliplatin infusion. Oxaliplatin decreased motor nerve superexcitability (P