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.

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.

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.

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.

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.

From Perception Threshold to Ion Channels-A Computational Study.

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 Aß-axon. The axon models included a wide range of voltage-gated ion channels: NaTTXs, NaTTXr, Nap, Kdr, KM, KA, 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.

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.

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.

Exploration of the conditioning electrical stimulation frequencies for induction of long-term potentiation-like pain amplification in humans.

Spinal nociceptive long-term potentiation (LTP) can be induced by high- or low-frequency conditioning electrical stimulation (CES) in rodent preparations in vitro. However, there is still sparse information on the effect of different conditioning frequencies inducing LTP-like pain amplification in humans. In this study, we tested two other paradigms aiming to explore the CES frequency effect inducing pain amplification in healthy humans. Cutaneous LTP-like pain amplification induced by three different paradigms (10, 100, and 200 Hz CES) was assessed in fifteen volunteers in a crossover design. Perceptual intensity ratings to single electrical stimulation at the conditioned site and to mechanical stimuli (pinprick and light stroking) in the immediate vicinity were recorded; superficial blood flow was also measured. The short form of the McGill Pain Questionnaire (SF-MPQ) was used for characterizing the perception induced by CES. Compared with the control session, pain perception to pinprick stimuli and area of allodynia significantly increased after all three CES paradigms. In the 10 and 200 Hz sessions, the superficial blood flow 10 min after CES was significantly higher than in the control session reaching a plateau after 20 and 10 min, respectively; for the 100 Hz paradigm, a stable level was found without significant differences compared with CES and control sessions. 10 Hz CES caused a lower SF-MPQ score than 100 Hz. High-frequency (200 Hz) and low-frequency (10 Hz) paradigms can induce heterotopic pain amplification similar to the traditional 100 Hz paradigm. The 10 Hz paradigm can be an appealing alternative paradigm in future studies due to its specific association with low-level discharging of C-fibers during inflammation.

Nerve Fiber Activation During Peripheral Nerve Field Stimulation: Importance of Electrode Orientation and Estimation of Area of Paresthesia.

INTRODUCTION AND AIM: Low back pain is one of the indications for using peripheral nerve field stimulation (PNFS). However, the effect of PNFS varies between patients; several stimulation parameters have not been investigated in depth, such as orientation of the nerve fiber in relation to the electrode. While placing the electrode parallel to the nerve fiber may give lower activation thresholds, anodal blocking may occur when the propagating action potential passes an anode. METHODS: A finite element model was used to simulate the extracellular potential during PNFS. This was combined with an active cable model of Aß and Aδ nerve fibers. It was investigated how the angle between the nerve fiber and electrode affected the nerve activation and whether anodal blocking could occur. Finally, the area of paresthesia was estimated and compared with any concomitant Aδ fiber activation. RESULTS: The lowest threshold was found when nerve and electrode were in parallel, and that anodal blocking did not appear to occur during PNFS. The activation of Aß fibers was within therapeutic range (<10V) of PNFS; however, within this range, Aδ fiber activation also may occur. The combined area of activated Aß fibers (paresthesia) was at least two times larger than Aδ fibers for similar stimulation intensities. CONCLUSION: No evidence of anodal blocking was observed in this PNFS model. The thresholds were lowest when the nerves and electrodes were parallel; thus, it may be relevant to investigate the overall position of the target nerve fibers prior to electrode placement.

Muscle Activation During Peripheral Nerve Field Stimulation Occurs Due to Recruitment of Efferent Nerve Fibers, Not Direct Muscle Activation.

BACKGROUND: Peripheral nerve field stimulation (PNFS) is a potential treatment for chronic low-back pain. Pain relief using PNFS is dependent on activation of non-nociceptive Aß-fibers. However, PNFS may also activate muscles, causing twitches and discomfort. In this study, we developed a mathematical model, to investigate the activation of sensory and motor nerves, as well as direct muscle fiber activation. METHODS: The extracellular field was estimated using a finite element model based on the geometry of CT scanned lumbar vertebrae. The electrode was modeled as being implanted to a depth of 10-15 mm. Three implant directions were modeled; horizontally, vertically, and diagonally. Both single electrode and "between-lead" stimulation between contralateral electrodes were modeled. The extracellular field was combined with models of sensory Aß-nerves, motor neurons and muscle fibers to estimate their activation thresholds. RESULTS: The model showed that sensory Aß fibers could be activated with thresholds down to 0.563 V, and the lowest threshold for motor nerve activation was 7.19 V using between-lead stimulation with the cathode located closest to the nerves. All thresholds for direct muscle activation were above 500 V. CONCLUSIONS: The results suggest that direct muscle activation does not occur during PNFS, and concomitant motor and sensory nerve fiber activation are only likely to occur when using between-lead configuration. Thus, it may be relevant to investigate the location of the innervation zone of the low-back muscles prior to electrode implantation to avoid muscle activation.

Mathematical model of nerve fiber activation during low back peripheral nerve field stimulation: analysis of electrode implant depth.

OBJECTIVES: The lower back is the most common location of pain experienced by one-fifth of the European population reporting chronic pain. A peripheral nerve field stimulation system, which involves electrodes implanted subcutaneously in the painful area, has been shown to be efficacious for low back pain. Moreover, the predominant analgesic mechanism of action is thought to be via activation of peripheral Aß fibers. Unfortunately, electrical stimulation also might coactivate Aδ fibers, causing pain or unpleasantness itself. The aim of this study was to investigate at which implant depth Aß-fiber stimulation is maximized, and Aδ-fiber minimized, which in turn should lead to therapy optimization. MATERIALS AND METHODS: A finite element model was used to estimate the electrical potential generated by a bipolar single-lead electrode implanted in the subcutaneous adipose tissue at depths of 5 mm to 30 mm below the skin surface. The model includes low back tissue; the epidermis, dermis, adipose, and muscle layers, and nerve fibers, which were programmed to branch randomly in the model in a fiber type-specific manner. Likewise, activation thresholds were specific to Aß- and Aδ-fiber types and were estimated using a passive cable model. RESULTS: The stimulus-response functions showed that the skin area covered by Aß-fiber activation was larger than the area covered by Aδ-fiber activation at all depths and all intensities. The skin area covered by Aδ-fiber activation was largest when the electrode was modeled to have a superficial location (5 mm below the skin surface), while the skin area covered by Aß-fiber activation was largest at lower depths. CONCLUSIONS: The present mathematical model predicts an optimal implantation depth of 10 to 15 mm below the skin surface to achieve activation of the greatest area of Aß fibers and the smallest area of Aδ fibers. This finding may act as a guide for peripheral nerve field stimulation implant depth to treat low back pain.

Topical capsaicin modulates the two-point discrimination threshold-Modulation depends on stimulation modality and intensity.

BACKGROUND: Spatial acuity concerns the ability to localize and discriminate sensory input and is often tested using the two-point discrimination threshold (2PDT). Sensitization of the pain system can affect the spatial acuity, but it is unclear how 2PDTs of different testing modalities are affected. The aim was to investigate if the 2PDTs for mechanical and heat stimulation at different intensities were modulated by topical capsaicin sensitization. METHODS: 30 healthy subjects were divided into either a capsaicin or a placebo group. The 2PDT was tested using two different modalities, mechanical and thermal (laser) delivered at innocuous and noxious intensities. The 2PDT were determined at baseline and re-assessed 48 h later. In the follow-up session, the subjects either had a capsaicin patch (8%) or placebo patch placed in the testing area for 30 min before re-testing the 2PDT. RESULTS: The 2PDT was highly dependent on stimulation modality and intensity. The lowest 2PDT was found for innocuous mechanical stimuli (40.0 mm, 95% CI 38.1-41.9 mm), and the highest 2PDT was found for innocuous thermal stimuli (81.7 mm, 95% CI 73.9-89.5 mm). Topical capsaicin generally increased the 2PDT, but this was only significant for innocuous mechanical stimuli. The perceived intensity of the stimuli was increased following capsaicin and was generally higher for noxious stimuli than for innocuous stimuli (ANOVA, p < 0.001). CONCLUSIONS: This study showed that capsaicin provoked pain sensitization increased the 2PDT. The 2PDT tested using innocuous mechanical stimuli showed less variable results indicating that this test is most suitable to detect this aspect of spatial acuity. SIGNIFICANCE STATEMENT: This study investigated how the two-point discrimination threshold (2PDT) can be modulated by topical capsaicin. The 2PDT was assessed for two different modalities (thermal and mechanical) and for two different intensities (innocuous and noxious) before and after capsaicin. The results showed that the 2PDT was generally impaired following capsaicin, but this was only significant for mechanical innocuous stimuli. Furthermore, it was shown that mechanical innocuous stimuli assessed the 2PDT with lower variability than other combinations.

Transcranial Direct Current Stimulation Reduces Pressure Pain Sensitivity in Patients with Non-Malignant Chronic Pain.

OBJECTIVES: Non-malignant chronic pain is a clinical challenge because pharmacological treatment often fails to relieve pain. Transcranial direct current stimulation (tDCS) is a treatment that could have the potential for pain relief and improvement in quality of life. However, there is a lack of clinical trials evaluating the effects of tDCS on the pain system. The aim of the present study was to evaluate the effect of 5 days of anodal tDCS treatment on the pain system in chronic non-malignant pain patients using quantitative sensory testing (QST) and quality of life questionnaires: (1) Brief Pain Inventory-short form (BPI-sf), (2) European Organization for Research and Treatment of Life Questionnaire (EORTC-C30), and (3) Hospital Anxiety Depression Scale (HADS). METHODS: Eleven non-malignant chronic pain patients (51±13.6 years old, 5M) participated in the study. Anodal tDCS was applied for five consecutive days, followed by sham stimulation after a washout period of at least two weeks. Pressure pain thresholds (PPT) and pain tolerance thresholds (PTT) were assessed in different body regions on days 1 and 5. RESULTS: Anodal tDCS appeared to maintain PTT at C5 (clavicle) on day 5, but sham stimulation decreased PTT (P=0.007). Additionally, anodal tDCS increased PTT compared to sham at day 5 at Th10 ventral dermatomes (P=0.014). Both anodal and sham tDCS decreased the BPI-sf total and interference scores, and the EORTC-C30 fatigue score, but no interaction effect was observed. DISCUSSION: This study adds to the evidence in the literature that tDCS may be a potential therapeutic tool for the management of non-malignant chronic pain.

Diabetic Peripheral Neuropathy: Emerging Treatments of Neuropathic Pain and Novel Diagnostic Methods.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes, often leading to severe neuropathic pain. Although other diabetes-related complications have witnessed a surge of emerging treatments in recent years, DPN has seen minimal progression. This stagnation stems from various factors, including insensitive diagnostic methods and inadequate treatment options for neuropathic pain. METHODS: In this comprehensive review, we highlight promising novel diagnostic techniques for assessing DPN, elucidating their development, strengths, and limitations, and assessing their potential as future reliable clinical biomarkers and endpoints. In addition, we delve into the most promising emerging pharmacological and mechanistic treatments for managing neuropathic pain, an area currently characterized by inadequate pain relief and a notable burden of side effects. RESULTS: Skin biopsies, corneal confocal microscopy, transcutaneous electrical stimulation, blood-derived biomarkers, and multi-omics emerge as some of the most promising new techniques, while low-dose naltrexone, selective sodium-channel blockers, calcitonin gene-related peptide antibodies, and angiotensin type 2 receptor antagonists emerge as some of the most promising new drug candidates. CONCLUSION: Our review concludes that although several promising diagnostic modalities and emerging treatments exist, an ongoing need persists for the further development of sensitive diagnostic tools and mechanism-based, personalized treatment approaches.

Activation of peripheral nerve fibers by electrical stimulation in the sole of the foot.

BACKGROUND: Human nociceptive withdrawal reflexes (NWR) can be evoked by electrical stimulation applied to the sole of the foot. However, elicitation of NWRs is highly site dependent, and NWRs are especially difficult to elicit at the heel. The aim of the present study was to investigate potential peripheral mechanisms for any site dependent differences in reflex thresholds. RESULTS: The first part of the study investigated the neural innervation in different sites of the sole of the foot using two different staining techniques. 1) Staining for the Nav1.7 antigen (small nociceptive fibers) and 2) the Sihler whole nerve technique (myelinated part of the nerve). No differences in innervation densities were found across the sole of the foot using the two staining techniques: Nav1.7 immunochemistry (small nociceptive fibers (1-way ANOVA, NS)) and the Sihler's method (myelinated nerve fibers (1-way ANOVA, NS)). However, the results indicate that there are no nociceptive intraepidermal nerve fibers (IENFs) innervating the heel.Secondly, mathematical modeling was used to investigate to what degree differences in skin thicknesses affect the activation thresholds of Aδ and Aß fibers in the sole of the foot. The modeling comprised finite element analysis of the volume conduction combined with a passive model of the activation of branching cutaneous nerve fibers. The model included three different sites in the sole of the foot (forefoot, arch and heel) and three different electrode sizes (diameters: 9.1, 12.9, and 18.3 mm). For each of the 9 combinations of site and electrode size, a total of 3000 Aß fibers and 300 Aδ fibers was modeled. The computer simulation of the effects of skin thicknesses and innervation densities on thresholds of modeled Aδ and Aß fibers did not reveal differences in pain and perception thresholds across the foot sole as have been observed experimentally. Instead a lack of IENFs at the heel decreased the electrical activation thresholds compared to models including IENFs. CONCLUSIONS: The nerve staining and modeling results do not explain differences in NWR thresholds across the sole of the foot which may suggest that central mechanisms contribute to variation in NWR excitability across the sole of the foot.

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.

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.

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.