BackgroundThere 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.ResultsThe 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: NaTTXs, NaTTXr, NaP, KDr, KM, KLeak, KA, 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 KLeak channel and the Na/K-ATPase. For short durations, the effect cancels out due to a reduction of the transient TTX resistant sodium current (Nav1.8). Additionally, the result from the computational model indicated that cooling simultaneously with electrical stimulation, may increase the knowledge regarding pathological alterations of ionic currents.ConclusionCooling 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.

中文翻译：

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使用感知阈值跟踪技术评估冷却过程中小皮神经纤维的兴奋性改变

背景需要新的方法来增加对健康受试者以及病理状态下小神经纤维膜兴奋性的了解。我们的研究小组之前开发了感知阈值跟踪技术来间接评估周围小神经纤维的膜特性。在当前的研究中，评估了一种通过冷却小纤维并同时应用缓慢增加的电刺激电流来研究膜兴奋性的新方法。第一个目标是检查感知阈值跟踪技术是否可以检测到冷却过程中兴奋性的改变。第二个目标是对可能导致冷诱导小纤维兴奋性改变的潜在离子电流进行计算建模。第三个目标是评估冷却和电模拟的计算模型是否可用于生成小纤维神经病变中离子电流变化的假设。结果通过感知阈值跟踪技术评估了两种温度条件下小纤维的兴奋性，20 °C 和 32 °C。开发了详细的多室模型，包括离子电流：NaTTX、NaTTXr、NaP、KDr、KM、KLeak、KA 和 Na/K-ATPase。当皮肤温度从 32°C 降低到 20°C 时，两个长持续时间脉冲（50 和 100 ms）的感知阈值降低（p < 0.001）。然而，在较短的持续时间内没有观察到显着影响（1 毫秒，p = 0.116；5 毫秒，p = 0.079，rmANOVA，Sidak）。计算模型预测，与长持续时间脉冲相关的感知阈值的降低可能源于 KLeak 通道和 Na/K-ATPase 的减少。在短时间内，由于瞬态 TTX 抗钠电流 (Nav1.8) 的减少，效果会抵消。此外，计算模型的结果表明，在电刺激的同时冷却，可能会增加有关离子电流病理改变的知识。结论冷却可能会改变电刺激过程中的离子电流，从而提供有关健康受试者小纤维膜兴奋性的额外信息并且可能也在病理条件下。在短时间内，由于瞬态 TTX 抗钠电流 (Nav1.8) 的减少，效果会抵消。此外，计算模型的结果表明，在电刺激的同时冷却，可能会增加有关离子电流病理改变的知识。结论冷却可能会改变电刺激过程中的离子电流，从而提供有关健康受试者小纤维膜兴奋性的额外信息并且可能也在病理条件下。在短时间内，由于瞬态 TTX 抗钠电流 (Nav1.8) 的减少，效果会抵消。此外，计算模型的结果表明，在电刺激的同时冷却，可能会增加有关离子电流病理改变的知识。结论冷却可能会改变电刺激过程中的离子电流，从而提供有关健康受试者小纤维膜兴奋性的额外信息并且可能也在病理条件下。