Aims Selective activation of nociceptive fibers is difficult using electrical stimulation as the activation threshold is higher than for non-nociceptive fibers. It remains unclear to what extent accommodation of non-nociceptive fibers during slowly rising electrical pulses can be utilized to reverse this activation order. The aim of this study was to evaluate the ability of different pulse forms to activate nociceptive fibers with minimal co-activation of non-nociceptive fibers by comparing subjective perception thresholds (PT). Methods Electrical pulses were applied on the volar forearm of 25 subjects with (1) small diameter pin electrodes providing high current density in the skin epidermis, where primarily nociceptive fibers terminate and (2) standard patch electrodes (2.63 cm2). PTs were obtained for exponential current increase, linear current increase, increasing form of exponential current decay (ED), and standard rectangular current pulses. All pulse forms were tested at two relatively long durations (5 and 50 ms). The PT ratio between patch- and pin electrode was calculated as an estimate of the ability of a pulse form to preferentially activate nociceptive fibers. The short form McGill pain questionnaire (SF-MPQ) was used to assess perceived quality of pain for all pulse forms. Results For the pin electrode, PT tended to decrease with increasing pulse area. Patch electrode PT tended to increase for increasing pulse area for non-rectangular 50 ms pulses, in contrast to 5 ms pulses, indicating accommodation of non-nociceptive fibers. Largest PT ratio was obtained for the 50 ms ED. SF-MPQ scores were higher for the pin- compared to the patch electrode. Pin electrode pain qualities were mainly described as stabbing and sharp. SF-MPQ scores did not differ between pulse forms. Conclusions Long duration ED pulses seem to activate nociceptive fibers better than regular, short duration pulses; most likely reflecting accommodation of non-nociceptive fibers.

Background Electrical stimulation is widely used in experimental pain research but it lacks selectivity towards small nociceptive fibers. When using standard surface patch electrodes and rectangular pulses, large fibers are activated at a lower threshold than small fibers. Pin electrodes have been designed for overcoming this problem by providing a higher current density in the upper epidermis where the small nociceptive fibers mainly terminate. At perception threshold level, pin electrode stimuli are rather selectively activating small nerve fibers and are perceived as painful, but for high current intensity, which is usually needed to evoke sufficient pain levels, large fibers are likely co-activated. Long duration current has been shown to elevate the threshold of large fibers by the mechanism of accommodation. However, it remains unclear whether the mechanism of accommodation in large fibers can be utilized to activate small fibers even more selectively by combining pin electrode stimulation with a long duration pulse. Results In this study, perception thresholds were determined for a patch- and a pin electrode for different pulse shapes of long duration. The perception threshold ratio between the two different electrodes was calculated to estimate the ability of the pulse shapes to preferentially activate small fibers. The perception threshold ratios were compared between stimulation pulses of 5- and 50 ms durations and shapes of: exponential increase, linear increase, bounded exponential, and rectangular. Qualitative pain perception was evaluated for all pulse shapes delivered at 10 times perception threshold. The results showed a higher perception threshold ratio for long duration 50 ms pulses than for 5 ms pulses. The highest perception threshold ratio was found for the 50 ms, bounded exponential pulse shape. Results furthermore revealed different strength-duration relation between the bounded exponential- and rectangular pulse shapes. Pin electrode stimulation at high intensity was mainly described as “stabbing”, “shooting”, and “sharp”. Conclusion These results indicate that long duration pulses with a bounded exponential increase preferentially activate the small nociceptive fibers with a pin electrode and concurrently cause elevated threshold of large non-nociceptive fibers with patch electrodes.

Electrical stimulation is widely used in pain research and profiling, but current technologies lack selectivity toward small sensory fibers. Pin electrodes deliver high current density in upper skin layers, and it has been proposed that slowly rising exponential pulses can elevate large-fiber activation threshold and thereby increase preferential small-fiber activation. Optimal stimulation parameters for the combined pin electrode and exponential pulse stimulation have so far not been established, which is the aim of this study. Perception thresholds were compared between pin and patch electrodes using single 1- to 100-ms exponential and rectangular pulses. Stimulus-response functions were evaluated for both pulse shapes delivered as single pulses and pulse trains of 10 Hz using intensities from 0.1 to 20 times perception threshold. Perception thresholds (mA) decreased when duration was increased for both electrodes with rectangular pulses and the pin electrode with exponential pulses. For the patch electrode, perception thresholds for exponential pulses decreased for durations ≤10 ms but increased for durations ≥15 ms, indicating accommodation of large fibers. Stimulus-response curves for single pulses were similar for the two pulse shapes. For pulse trains, the slope of the curve was higher for rectangular pulses. Maximal large-fiber accommodation to exponential pulses was observed for 100-ms pulses, indicating that 100-ms exponential pulses should be applied for preferential small-fiber activation. Intensity of 10 times perception threshold was sufficient to cause maximal pain ratings. The developed methodology may open new opportunities for using electrical stimulation paradigms for small-fiber stimulation and diagnostics. NEW & NOTEWORTHY Selective activation of small cutaneous nerve fibers is pivotal for investigations of the pain system. The present study demonstrated that patch electrode perception thresholds increase with increased duration of exponential currents from 20 to 100 ms. This is likely caused by large-fiber accommodation, which can be utilized to activate small fibers preferentially through small-diameter pin electrodes. This finding may be utilized in studies of fundamental pain mechanisms and, for example, in small-fiber neuropathy.

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.

Individuals with high-level amputation have a great need for functional prostheses because of their vast functional deficits. Conventional techniques are considered inappropriate for high-level amputees due to the lack of physiologically appropriate muscles. This study investigates how accurate phantom movements (PMs) can be classified from physiologically inappropriate muscles. The study involves a case study of a 42-year-old transhumeral amputee. Suitable PMs and best electrode configuration were identified using the sequential forward selection method and brute-force technique. Using linear discriminant analysis, the best PMs (elbow extension/flexion, wrist supination/pronation) and rest were classified with error ranging from 3% to 0.18% when using 3 to 8 EMG channels respectively. A completion rate of 93 % was obtained during a targeted achievement control test in a virtual reality environment. This case indicates that a proximal transhumeral amputee can generate muscle activation patterns related to distinct PMs; and these PMs can be decoded from physiologically inappropriate muscles.