The stability of perception threshold tracking for long session evaluation of Aß- and Aδ-fiber function.

INTRODUCTION/AIMS: Research has proven that epidermal and transcutaneous stimulation can identify the function of Aß and Aδ fibers (i.e., in diabetes) individually using different electrodes. In this study we aimed to determine the stability of perception thresholds when using such electrodes. METHODS: Twenty healthy volunteers participated in this study. The perception threshold of Aß fibers (patch electrode) and Aδ fibers (pin electrode) was estimated 30 times during a period of 60 minutes. A threshold was established every other minute, alternating between the two electrodes. The stimulus duration was 1 millisecond and the interstimulus interval was 1.5 to 2.5 seconds. Linear regressions of the perception threshold as a function of time were performed. The slopes were used as an estimate of habituation and were compared between the electrodes. RESULTS: The slope was significantly larger when assessed by the pin electrode (median: 0.020 [0.009 to 0.030] mA/trial) than when assessed by the patch electrode (median: 0.005 [0.001 to 0.018] mA/trial) (P = .017, paired t test). During the session, total increases in perception threshold of approximately 55% and 1% were seen for the pin and patch electrodes, respectively. DISCUSSION: The two fiber types assessed showed significant perception threshold increases. The higher slope of the pin electrode indicated that the Aδ fibers were more prone to habituation than the Aß fibers, and that habituation should be considered during prolonged experiments. This assessment is valuable for future research on nerve fiber function using the technique for long session experiments.

Oxaliplatin causes increased offset analgesia during chemotherapy - a feasibility study.

OBJECTIVES: Offset analgesia (OA) is the phenomenon where the perceived pain intensity to heat stimulation disproportionally decreases after a slight decrease in stimulation temperature. The neural mechanisms of OA are not fully understood, but it appears that both peripheral and central temporal filtering properties are involved. Chemotherapy with oxaliplatin often causes acute peripheral sensory neuropathy, and manifests primarily as a cold induced allodynia. The aim of this exploratory patient study was to investigate if OA was affected by the neurotoxic effects of adjuvant oxaliplatin treatment. METHODS: OA was assessed in 17 colon cancer patients during 12 cycles of adjuvant oxaliplatin treatment. The OA response was estimated as the decrease in pain intensity caused by a temperature decrease from 46 °C to 45 °C. Changes in the OA during the treatment period was estimated using a mixed linear model and corrected for multiple comparisons by Sidak's test. RESULTS: OA was increased significantly when assessed before the 2nd, 3rd, 5th, 6th, 9th, and 10th treatment cycle compared to the first (baseline) treatment (p<0.05). CONCLUSIONS: OA is generally decreased in persons suffering from chronic pain or peripheral neuropathy as compared to healthy controls. But in the present study, OA increased during chemotherapy with oxaliplatin. The underlying mechanism of this unexpected increase should be further explored.

Optimizing examination time and diagnostic performance of the histamine-induced axon-reflex flare response in diabetes.

INTRODUCTION/AIMS: The axon-reflex flare response is a reliable method for functional assessment of small fibers in diabetic peripheral neuropathy (DPN), but broad adoption is limited by the time requirement. The aims of this study were to (1) assess diagnostic performance and optimize time required for assessing the histamine-induced flare response and (2) associate with established parameters. METHODS: A total of 60 participants with type 1 diabetes with (n = 33) or without (n = 27) DPN participated. The participants underwent quantitative sensory testing (QST), corneal confocal microscopy (CCM), and flare intensity and area size assessments by laser-Doppler imaging (FLPI) following an epidermal skin-prick application of histamine. The flare parameters were evaluated each minute for 15 min, and the diagnostic performance compared to QST and CCM were assessed using area under the curve (AUC). Minimum time-requirements until differentiation and to achieve results comparable with a full examination were assessed. RESULTS: Flare area size had better diagnostic performance compared with CCM (AUC 0.88 vs. 0.77, p < 0.01) and QST (AUC 0.91 vs. 0.81, p = 0.02) than mean flare intensity, and could distinguish people with and without DPN after 4 min compared to after 6 min (both p < 0.01). Flare area size achieved a diagnostic performance comparable to a full examination after 6 and 7 min (CCM and QST respectively, p > 0.05), while mean flare intensity achieved it after 5 and 8 min (CCM and QST respectively, p > 0.05). DISCUSSION: The flare area size can be evaluated 6-7 min after histamine-application, which increases diagnostic performance compared to mean flare intensity.

On determining the mechanical nociceptive threshold in pigs: a reliability study.

Background: A pressure algometer is a valuable tool for assessing the mechanical nociceptive threshold (MNT) in clinical pain studies. Recent research has turned to large animal models of pain because of the closer anatomy and physiology to humans. Although the reliability and usefulness of the MNT have been extensively validated in humans, similar data from large animals is still sparse. Objective: Therefore, the aim of the current study was to evaluate the reliability (within- and between-session) of MNT in the forelimb of pigs using a pressure algometer. Methods: Nine animals were used (23-40 kg), and MNTs were measured at both the right and left limbs at three different sessions, with three repetitions per session. The intraclass correlation coefficient (ICC) was used as a metric for relative reliability. The standard error of measurement (SEM) and coefficient of variation (CV) was used to assess absolute reliability. Systematic bias was also evaluated. Results: The average ICC was found to be 0.71 and 0.45 for the between-session and within-session, respectively. CV ranged from 17.9% to 20.5%, with a grand average of 19.1%. The grand average SEM was 249.5 kPa (16.6%). No systematic differences were found for the MNT between sessions, which suggests that there was no habituation to the stimulus. Conclusion: The reliability indices obtained in this study are comparable to results obtained in other species or anatomical regions and substantiate the use of the pressure algometer as a valuable tool to investigate the nociceptive system in pigs and translation to the human nociceptive withdrawal reflex.

The co-existence of sensory and autonomic neuropathy in type 1 diabetes with and without pain.

AIMS: To investigate the co-existence of diabetic peripheral neuropathy (DPN), painful diabetic peripheral neuropathy (PDPN), and cardiac autonomic neuropathy (CAN) and to establish a model to predict CAN based on peripheral measurements. METHODS: Eighty participants (20 type 1 diabetes (T1DM) + PDPN, 20 T1DM + DPN, 20 T1DM-DPN (without DPN), and 20 healthy controls (HC)) underwent quantitative sensory testing, cardiac autonomic reflex tests (CARTs), and conventional nerve conduction. CAN was defined as ≥ 2 abnormal CARTs. After the initial analysis, the participants with diabetes were re-grouped based on the presence or absence of small (SFN) and large fibre neuropathy (LFN), respectively. A prediction model for CAN was made using logistic regression with backward elimination. RESULTS: CAN was most prevalent in T1DM + PDPN (50%), followed by T1DM + DPN (25%) and T1DM-DPN and HC (0%). The differences in prevalence of CAN between T1DM + PDPN and T1DM-DPN/HC were significant (p < 0.001). When re-grouping, 58% had CAN in the SFN group and 55% in the LFN group, while no participants without either SFN or LFN had CAN. The prediction model had a sensitivity of 64%, a specificity of 67%, a positive predictive value of 30%, and a negative predictive value of 90%. CONCLUSION: This study suggests that CAN predominantly co-exists with concomitant DPN.

Diagnostic Accuracy of Perception Threshold Tracking in the Detection of Small Fiber Damage in Type 1 Diabetes.

AIM: An objective assessment of small nerve fibers is key to the early detection of diabetic peripheral neuropathy (DPN). This study investigates the diagnostic accuracy of a novel perception threshold tracking technique in detecting small nerve fiber damage. METHODS: Participants with type 1 diabetes (T1DM) without DPN (n = 20), with DPN (n = 20), with painful DPN (n = 20) and 20 healthy controls (HCs) underwent perception threshold tracking on the foot and corneal confocal microscopy. Diagnostic accuracy of perception threshold tracking compared to corneal confocal microscopy was analyzed using logistic regression. RESULTS: The rheobase, corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) (all P < .001) differed between groups. The diagnostic accuracy of perception threshold tracking (rheobase) was excellent for identifying small nerve fiber damage, especially for CNFL with a sensitivity of 94%, specificity 94%, positive predictive value 97%, and negative predictive value 89%. There was a significant correlation between rheobase with CNFD, CNBD, CNFL, and Michigan Neuropathy Screening Instrument (all P < .001). CONCLUSION: Perception threshold tracking had a very high diagnostic agreement with corneal confocal microscopy for detecting small nerve fiber loss and may have clinical utility for assessing small nerve fiber damage and hence early DPN. CLINICAL TRIALS: NCT04078516.

Perception threshold tracking: validating a novel method for assessing function of large and small sensory nerve fibers in diabetic peripheral neuropathy with and without pain.

ABSTRACT: It remains unknown why some people with diabetes develop painful neuropathies while others experience no pain. This study aimed to validate a novel method for assessing the function of small sensory nerves in diabetes to further elucidate this phenomenon. The function of large and small nerves was assessed using a novel perception threshold tracking technique in 3 well-characterized groups (n = 60) with type 1 diabetes, namely, (1) painful diabetic peripheral neuropathy (T1DM + PDPN), (2) painless diabetic peripheral neuropathy (T1DM + DPN), and (3) no neuropathy (T1DM - DPN), and healthy controls (n = 20). Electrical currents with different shapes, duration, and intensities were applied by 2 different skin electrodes activating large and small fibers, respectively. The minimal current needed to activate the fibers were analyzed as the rheobase of the stimulus-response function. Nerve fiber selectivity was measured by accommodation properties of stimulated nerves. The rheobase of both fiber types were highest for T1DM + PDPN, followed by T1DM + DPN, T1DM - DPN, and healthy controls, indicating that the nerve properties are specific in individuals with diabetes and pain. There was an overall significant difference between the groups ( P < 0.01). The accommodation properties of stimulated fibers were different between the 2 electrodes ( P < 0.05) apart from in the group with T1DM + PDPN, where both electrodes stimulated nerves displaying properties similar to large fibers. Perception threshold tracking reveals differences in large and small nerve fiber function between the groups with and without diabetes, DPN, and pain. This indicates that the methods have potential applications in screening DPN and explore further the features differentiating painful from nonpainful DPN.

Influence of tapentadol and oxycodone on the spinal cord and brain using electrophysiology: a randomized, placebo-controlled trial.

AIMS: The aim of this study was to investigate the effects of tapentadol and oxycodone using the nociceptive withdrawal reflex and sensory evoked potentials. METHODS: Twenty-one healthy volunteers completed a cross-over trial with oxycodone (10 mg), tapentadol (50 mg) extended-release tablets, or placebo treatment administered orally BID for 14 days. Electrical stimulations were delivered on the plantar side of the foot to evoke a nociceptive withdrawal reflex at baseline and post-interventions. Electromyography, recorded at tibialis anterior, and electroencephalography were recorded for analysis of: number of reflexes, latencies, and area under the curve of the nociceptive withdrawal reflex as well as latencies, amplitudes and dipole sources of the sensory-evoked potential. RESULTS: Tapentadol decreased the odds ratio of eliciting nociceptive withdrawal reflex by -0.89 (P = .001, 95% confidence interval [CI] -1.46, -0.32), whereas oxycodone increased the latency of the N1 component of the sensory-evoked potential at the vertex by 12.5 ms (P = .003, 95% CI 3.35, 21.69). Dipole sources revealed that the anterior cingulate component moved caudally for all three interventions (all P < .02), and the insula components moved caudally in both the oxycodone and tapentadol arms (all P < .03). CONCLUSION: A decrease in the number of nociceptive withdrawal reflex was observed during tapentadol treatment, possibly relating to the noradrenaline reuptake inhibition effects on the spinal cord. Both oxycodone and tapentadol affected cortical measures possible due to µ-opioid receptor agonistic effects evident in the dipole sources, with the strongest effect being mediated by oxycodone. These findings could support the dual effect analgesic mechanisms of tapentadol in humans as previously shown in preclinical studies.

The Histamine-Induced Axon-Reflex Response in People With Type 1 Diabetes With and Without Peripheral Neuropathy and Pain: A Clinical, Observational Study.

Small nerve fibres are important when studying diabetic peripheral neuropathy (DPN) as they could be first affected. However, assessing their integrity and function adequately remains a major challenge. The aim of this study was to investigate the association between different degrees of DPN, the presence of neuropathic pain, and the intensity of the axon-reflex flare response provoked by epidermal histamine. Eighty adults were included and divided into 4 groups of 20 with type 1 diabetes and: painful DPN (T1DM+PDPN), non-painful DPN (T1DM+DPN), no DPN and no pain (T1DM-DPN), and 20 persons without diabetes or pain (HC). The vasomotor responses were captured by a Full-field Laser Speckle Perfusion Imager. The response was lowest in T1DM+DPN, followed by T1DM+PDPN, T1DM-DPN and HC. The response was significantly reduced in DPN (T1DM+DPN, T1DM+PDPN) compared with people without (T1DM-DPN, HC) (P < .001). The response was also attenuated in diabetes irrespective of the degree of DPN (T1DM+PDPN, T1DM+DPN, T1DM-DPN) (P < .001). There were no differences in the response between painful neuropathy (T1DM+PDPN) and painless DPN (T1DM+DPN) (P = .189). The method can distinguish between groups with and without diabetes and with and without DPN but cannot distinguish between groups with and without painful DPN. PERSPECTIVE: This study describes how diabetes attenuates the axon-reflex response, and how it is affected by neuropathy and pain clarifying previous findings. Furthermore, the study is the first to utilize histamine when evoking the response, thus providing a new and fast alternative for future studies into the pathophysiology of neuropathic pain.

Priming of central and peripheral mechanisms with heat and cutaneous capsaicin facilitates secondary hyperalgesia to high-frequency electrical stimulation.

Heat/capsaicin sensitization and electrical high-frequency stimulation (HFS) are well-known models of secondary hyperalgesia, a phenomenon related to chronic pain conditions. This study investigated whether priming with heat/capsaicin would facilitate hyperalgesia to HFS in healthy subjects. Heat/capsaicin priming consisted of a 45°C heat stimulation for 5 min followed by a topical capsaicin patch (4 × 4 cm) for 30 min on the volar forearm of 20 subjects. HFS (100 Hz, 5 times 1 s, minimum 1.5 mA) was subsequently delivered through a transcutaneous pin electrode approximately 1.5 cm proximal to the heat/capsaicin application. Two sessions were applied in a crossover design; traditional HFS (HFS) and heat/capsaicin sensitization followed by HFS (HFS + HEAT/CAPS). Heat pain threshold (HPT), mechanical pain sensitivity (MPS), and superficial blood perfusion were assessed at baseline, after capsaicin removal, and up to 40 min after HFS. MPS was assessed with pin-prick stimulation (128 mN and 256 mN) in the area adjacent to both HFS and heat/capsaicin, distal but adjacent to heat/capsaicin and in a distal control area. HPT was assessed in the area of heat/capsaicin. Higher sensitivity to 128 mN pin-prick stimulation (difference from baseline and control area) was observed in the HFS + HEAT/CAPS session than in the HFS session 20 and 30 min after HFS. Furthermore, sensitivity was increased after HFS + HEAT/CAPS compared with after heat/capsaicin in the area adjacent to both paradigms, but not in the area distal to heat/capsaicin. Results indicate that heat/capsaicin causes priming of the central and peripheral nervous system, which facilitates secondary mechanical hyperalgesia to HFS.NEW & NOTEWORTHY High-frequency electrical stimulation (HFS) and heat/capsaicin sensitization are well-known models of secondary hyperalgesia. The results from the current study indicate that increased sensitivity to 128 mN pin-prick stimulation can be obtained when HFS is delivered following an already established heightened central hyperexcitability provoked by heat/capsaicin sensitization.

Novel surface electrode design for preferential activation of cutaneous nociceptors.

Objective.Small area electrodes enable preferential activation of nociceptive fibers. It is debated, however, whether co-activation of large fibers still occurs for the existing electrode designs. Moreover, existing electrodes are limited to low stimulation intensities, for which behavioral and physiological responses may be considered less reliable. A recent optimization study showed that there is a potential for improving electrode performance and increase the range of possible stimulation intensities. Based on those results, the present study introduces and tests a novel planar concentric array electrode design for small fiber activation in healthy volunteers.Approach.Volunteers received electrical stimulation with the planar concentric array electrode and a regular patch electrode. Perception thresholds (PT) were estimated at the beginning and the end of the experiment. Evoked cortical potentials were recorded in blocks of 30 stimuli. For the patch, stimulation current intensity was set to two times PT, while three intensities, two, five, and ten times PT, were applied with the planar concentric array electrode. Sensation quality, numerical-rating scores, and reaction times were obtained for each PT estimation and during each block of evoked potential recordings.Main results.Stimulation with the patch electrode was characterized as dull, while stimulation with the planar concentric array electrode was characterized as sharp, with increased sharpness for increasing stimulus current intensity. Likewise, scores of the numerical rating scale were higher for the planar concentric array electrode compared to the patch and increased with increasing stimulation current intensity. Reaction times and ERP latencies were longer for the planar concentric array electrode compared to the patch.Significance.The presented novel planar concentric array electrode is a small, non-invasive, and single-use electrode that has the potential to investigate small fiber neuropathy and pain mechanisms, as it is small fiber preferential for a wide range of stimulation intensities.

A peculiar experience- everyday life with chronic sensory disturbances after oxaliplatin treatment for colorectal cancer - a phenomenological study.

Purpose: To deepen the understanding of how survivors' experience and give meaning to the embodied phenomenon of chronic sensory disturbances in everyday life after oxaliplatin treatment for colorectal cancer.Methods: Data was generated by means of a semi-structured interview guide and drawings with the aim to explore eight survivors' lifeworld experiences. Data was analyzed through a phenomenological approach.Results: The essential meaning of sensory disturbances emerged in two main themes and four sub-themes. Theme A: 'A peculiar experience that is difficult to logically understand' with the subthemes; 'An ambiguous perception in hands and feet' and 'Being alienated from one's own body'. Theme B: Losing touch with the world' with the subthemes: 'A lack of sensory contact with physical surfaces' and 'Breakdown of sensitivity in hands hampers fine motor skills and social contact'.Conclusion: Sensory disturbances contributed to an ambiguous and discordant perception of an alienated body that was difficult to describe and affected the ability to act and connect to things and other people. Metaphors and drawings were valuable as means to verbalize and illustrate the changed body perception where the 'I can' changed into 'I cannot'. To support the embodied connection to the world new usage patterns were required.

Diabetic Neuropathy Influences Control of Spinal Mechanisms.

PURPOSE: Comprehensive evaluation of the upstream sensory processing in diabetic symmetrical polyneuropathy (DSPN) is sparse. The authors investigated the spinal nociceptive withdrawal reflex and the related elicited somatosensory evoked cortical potentials. They hypothesized that DSPN induces alterations in spinal and supraspinal sensory-motor processing compared with age- and gender-matched healthy controls. METHODS: In this study, 48 patients with type 1 diabetes and DSPN were compared with 21 healthy controls. Perception and reflex thresholds were determined and subjects received electrical stimulations on the plantar site of the foot at three stimulation intensities to evoke a nociceptive withdrawal reflex. Electromyogram and EEG were recorded for analysis. RESULTS: Patients with DSPN had higher perception (P < 0.001) and reflex (P = 0.012) thresholds. Fewer patients completed the recording session compared with healthy controls (34/48 vs. 21/21; P = 0.004). Diabetic symmetrical polyneuropathy reduced the odds ratio of a successful elicited nociceptive withdrawal reflex (odds ratio = 0.045; P = 0.014). Diabetic symmetrical polyneuropathy changed the evoked potentials (F = 2.86; P = 0.025), and post hoc test revealed reduction of amplitude (-3.72 mV; P = 0.021) and prolonged latencies (15.1 ms; P = 0.013) of the N1 peak. CONCLUSIONS: The study revealed that patients with type 1 diabetes and DSPN have significantly changed spinal and supraspinal processing of the somatosensory input. This implies that DSPN induces widespread differences in the central nervous system processing of afferent A-δ and A-ß fiber input. These differences in processing may potentially lead to identification of subgroups with different stages of small fiber neuropathy and ultimately differentiated treatments.

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

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 Aß-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 Aß-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.

Diabetic Peripheral Neuropathy: Diagnosis and Treatment.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is traditionally divided into large and small fibre neuropathy (SFN). Damage to the large fibres can be detected using nerve conduction studies (NCS) and often results in a significant reduction in sensitivity and loss of protective sensation, while damage to the small fibres is hard to reliably detect and can be either asymptomatic, associated with insensitivity to noxious stimuli, or often manifests itself as intractable neuropathic pain. OBJECTIVE: To describe the recent advances in both detection, grading, and treatment of DPN as well as the accompanying neuropathic pain. METHODS: A review of relevant, peer-reviewed, English literature from MEDLINE, EMBASE and Cochrane Library between January 1st 1967 and January 1st 2020 was used. RESULTS: We identified more than three hundred studies on methods for detecting and grading DPN, and more than eighty randomised-controlled trials for treating painful diabetic neuropathy. CONCLUSION: NCS remains the method of choice for detecting LFN in people with diabetes, while a gold standard for the detection of SFN is yet to be internationally accepted. In the recent years, several methods with huge potential for detecting and grading this condition have become available including skin biopsies and corneal confocal microscopy, which in the future could represent reliable endpoints for clinical studies. While several newer methods for detecting SFN have been developed, no new drugs have been accepted for treating neuropathic pain in people with diabetes. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors and anticonvulsants remain first line treatment, while newer agents targeting the proposed pathophysiology of DPN are being developed.

Small and large cutaneous fibers display different excitability properties to slowly increasing ramp pulses.

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 (Aß) 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 (NaTTXr), persistent sodium current, delayed rectifier potassium channel (KDr), 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 NaTTXr and/or KDr. 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.

Comparison of existing electrode designs for preferential activation of cutaneous nociceptors.

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 Aß-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.

Preferential activation of small cutaneous fibers through small pin electrode also depends on the shape of a long duration electrical current.

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.

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

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: 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. 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.

Investigating stimulation parameters for preferential small-fiber activation using exponentially rising electrical currents.

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.