Intra-epidermal Electrical Stimulation Research Articles

Observing nociceptive detection thresholds and evoked potentials in diabetic patients with and without painful neuropathy

Aim: Diabetic polyneuropathy is the most described complication in patients with diabetes mellitus. A significant percentage of these patients experience disabling neuropathic pain (painful diabetic polyneuropathy). Small nerve fibers are primarily responsible for peripheral nociception, but objectively assessing its function is challenging. The primary objective of this study was to explore the task execution and outcomes of intra-epidermal electrical stimulation technique that combines nociceptive detection thresholds (NDT) and evoked potentials (EPs) in patients with diabetes. We compared the results of diabetic patients, both with and without painful diabetic polyneuropathy, with those of healthy controls to explore potential clinically relevant information. Methods: The NDT-EP method was applied to 38 patients with diabetes (18 with and 20 without chronic painful neuropathy) and 38 age- and sex-matched healthy controls. Individual mean NDTs, psychometric slopes, EP amplitudes, and the effect of the stimuli on EP amplitudes were analyzed and compared between groups using linear regression. Results: The findings revealed significantly lower detection rates, higher NDTs, and lower psychometric slopes in patients with painful diabetic polyneuropathy than in healthy controls. Both patient groups significantly exhibited lower mean EP amplitudes than healthy controls, which were not linked to pulse amplitudes but influenced by stimulus detection. Conclusions: This study showed altered NDT-EP outcomes in patients with painful diabetic polyneuropathy. Whereas the task execution, NDTs, and psychometric slopes may provide valuable insights into small fiber dysfunction, pulse amplitudes seemed not differently encoded in neurophysiological responses to intra-epidermal electrical stimulation near the detection threshold compared to controls. Future studies should investigate whether the altered NDT-EP outcomes could quantify small fiber dysfunction in patients with diabetes mellitus. We recommend further exploration of NDT-EP measures in other patient groups with nociceptive dysfunction.

Moderate cryptoxanthin intake correlates with maintenance of a proper PINT index in a general Japanese population

ABSTRACT Introduction Small fibre neuropathy (SFN) is an early manifestation of diabetic polyneuropathy. Although oxidative stress, inflammation and change of intestinal bacterial population are assumed to be their pathogenesis, the effects of dietary nutrition have not been evaluated. The relationship between dietary nutrition intake and pain sensation was evaluated in the Japanese population. Methods We conducted the Iwaki project, a population-based study recruiting 1,028 individuals, in 2018. The relationships between the pain threshold from intraepidermal electrical stimulation (PINT) and the amount of dietary nutrition evaluated by a brief-type self-administered diet history questionnaire were examined. The odds ratio was further explored after categorizing subjects based on low (< 63.7 μg/day), intermediate (63.7-159.2 μg/day), and high cryptoxanthin levels (> 159.2 μg/day). Results Univariate linear regression analyses showed significant correlations between PINT and cryptoxanthin intake even after adjustments for other nutritional intakes (ß = 0.107, p < 0.01). Multivariate logistic regression analysis revealed low and high cryptoxanthin intake as significant risk factors for abnormal PINT (≥ 0.20 mA). Multivariate linear regression analyses showed significant correlations between PINT and cryptoxanthin intake levels after adjustment for other clinically PINT-related factors (ß = 0.09, p < 0.01). Conclusions Adequate intake of cryptoxanthin is recommended to maintain the pain threshold in the Japanese population.

Tryptophan metabolism and small fibre neuropathy: a correlation study.

Small nerve fibres located in the epidermis sense pain. Dysfunction of these fibres decreases the pain threshold known as small fibre neuropathy. Diabetes mellitus is accompanied by metabolic changes other than glucose, synergistically eliciting small fibre neuropathy. These findings suggest that various metabolic changes may be involved in small fibre neuropathy. Herein, we explored the correlation between pain sensation and changes in plasma metabolites in healthy Japanese subjects. The pain threshold evaluated from the intraepidermal electrical stimulation was used to quantify pain sensation in a total of 1021 individuals in the 2017 Iwaki Health Promotion Project. Participants with a pain threshold evaluated from the intraepidermal electrical stimulation index <0.20 mA were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-low group (n = 751); otherwise, they were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-high group (n = 270). Metabolome analysis of plasma was conducted using capillary electrophoresis time-of-flight mass spectrometry. The metabolite set enrichment analysis revealed that the metabolism of tryptophan was significantly correlated with the pain threshold evaluated from the intraepidermal electrical stimulation index in all participants (P < 0.05). The normalized level of tryptophan was significantly decreased in participants with a high pain threshold evaluated from the intraepidermal electrical stimulation index. In addition to univariate linear regression analyses, the correlation between tryptophan concentration and the pain threshold evaluated from the intraepidermal electrical stimulation index remained significant after adjustment for multiple factors (β = -0.07615, P < 0.05). These findings indicate that specific metabolic changes are involved in the deterioration of pain thresholds. Here, we show that abnormal tryptophan metabolism is significantly correlated with an elevated pain threshold evaluated from the intraepidermal electrical stimulation index in the Japanese population. This correlation provides insight into the pathology and clinical application of small fibre neuropathy.

Effects of anesthetics on nociceptive sensory evoked potentials by intraepidermal noxious electrical stimulation of A-δ fibers.

Generation of nociceptive sensory evoked potentials (NEPs) by selective stimulation of nociceptive intraepidermal nerve fibers is a simple technique which could be used as intraoperative nociception monitor. We evaluated the effects of remifentanil, propofol and sevoflurane on NEPs by this technique. Patients undergoing general anesthesia were assigned to groups in two studies. A-δ fiber selective NEPs were recorded. Study 1: NEPs were recorded at control, under anesthetics administration: remifentanil at an effect-site concentration (Ce) of 1.0ng/mL (n = 10), propofol at Ce of 0.5µg/mL (n = 10), or sevoflurane at 0.2 minimum alveolar concentration (MAC) (n = 10), and recovery from the anesthetics. Study 2: NEPs were recorded at control and under administration of higher dose anesthetics: propofol at Ce of 0.5 and 1.0µg/mL (n = 10) or sevoflurane at 0.2 and 0.5 MAC (n = 10). A P-value < 0.016 was considered statistically significant in multiple analyses. Study 1: Remifentanil at Ce of 1.0ng/mL significantly suppressed the amplitude of NEPs (mean amplitude (standard deviation) of control vs. remifentanil administration: 16.8µV (3.8) vs. 10.1µV (2.5), P < 0.001). Propofol and sevoflurane did not suppress the amplitude significantly. Study 2: Propofol at Ce of 0.5 and 1.0µg/mL and sevoflurane at 0.2 and 0.5 MAC did not suppress the amplitude significantly. The amplitude of A-δ fiber selective NEPs was suppressed by remifentanil but not propofol or sevoflurane. NEPs with intraepidermal electrical stimulation can assess the analgesic effect of anesthetics. UMIN000038214 REGISTRY URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000043328.

Exploring Psychophysical and Neurophysiological Responses to Intra-Epidermal Electrical Stimuli in Patients With Persistent Spinal Pain Syndrome Type 2 with a Spinal Cord Stimulator.

There is a lack of measures that provide insights into how spinal cord stimulation (SCS) modulates nociceptive function in patients with persistent spinal pain syndrome type 2 (PSPS-T2). Recently, we observed altered nociceptive detection thresholds (NDTs) in response to intra-epidermal electrical stimulation (IES) on the feet of PSPS-T2 patients when dorsal root ganglion stimulation was turned on. Furthermore, we observed altered NDTs and evoked potentials (EPs) in response to IES on the hands of PSPS-T2 patients. To explore whether EPs were obstructed by SCS artifacts, we applied IES twice to the hands of patients with SCS turned on (SCS-ON/ON group). To explore possible confounding effects of SCS outside the stimulated area, we repeated IES on the hands of these patients, once with SCS turned off and subsequently once with SCS turned on (SCS-OFF/ON group). The results demonstrated that EPs were not obstructed by SCS artifacts. Additionally, NDTs and EPs did not significantly change between measurements in the SCS-ON/ON and the SCS-OFF/ON groups. Therefore, the results suggested that possible confounding effects of SCS outside the nociceptive system did not interfere with the detection task performance. This work warrants further exploration of NDT-EP phenomena in response to IES at the painful feet of patients.Clinical Relevance-This work contributes to developing a clinical tool to explore psychophysical and neurophysiological biomarkers for observing modulating effects of SCS in patients with PSPS-T2.

Assessing the Effects of the Topical Application of L-Menthol on Pain-Related Somatosensory-Evoked Potentials Using Intra-Epidermal Stimulation.

L-menthol is known to activate transient receptor potential melastatin 8 (TRPM8) and induce analgesia to thermal stimuli. However, since thermal stimulation leads to the interaction among the other TRP channels, it was unclear whether L-menthol causes analgesia to stimuli other than thermal stimuli. Therefore, we aimed to investigate whether activating TRPM8 via topical application of 10% menthol solution attenuates pain-related somatosensory-evoked potentials (pSEPs) and affects numerical rating scale (NRS) score using intra-epidermal electrical stimulation (IES). We applied 10% L-menthol or control solution on the dorsum of the right hand of 25 healthy participants. The pSEP and NRS, elicited by IES, and sensory threshold were measured before and after each solution was applied. The results showed that the topical application of 10% L-menthol solution significantly reduced N2-P2 amplitude in pSEPs compared with the control solution. Moreover, the N2 latency was significantly prolonged upon the topical application of L-menthol solution. NRS scores were similar under both conditions. These results suggest that topical application of L-menthol does not alter subjective sensation induced using IES, although it may attenuate afferent signals at free nerve endings even with stimuli that do not directly activate TRP channels.

N°53 – Clinical applicability of intra-epidermal electrical stimulation in patients with degenerative cervical myelopathy

N°53 – Clinical applicability of intra-epidermal electrical stimulation in patients with degenerative cervical myelopathy

Extensive Sensorimotor Training Predetermines Central Pain Changes During the Development of Prolonged Muscle Pain

Repetitive movements (RM) are a main risk factor for musculoskeletal pain, which is partly explained by the overloading of musculoskeletal structures. However, RM may also drive brain plasticity, leading to maladaptive changes in sensorimotor areas and altered pain processing. This study aimed to understand whether individuals performing extensive RM (musicians) exhibit altered brain processing to prolonged experimental muscle pain. Nineteen healthy musicians and 20 healthy nontrained controls attended 3 sessions (Day 1–Day 3–Day 8). In each session, event-related potentials (ERPs) to non-nociceptive superficial and nociceptive intraepidermal electrical stimulation, reaction times, electrical detection thresholds, and pressure pain thresholds (PPTs) were recorded. In all participants, prolonged muscle pain was induced by intramuscular injection of nerve growth factor (NGF) into the right first dorsal interosseous muscle at the end of Day1. Pain intensity was assessed on a numerical rating scale (NRS) and was lower in musicians compared to non-musicians (P < .007). Moreover, in musicians, the higher amount of weekly training was associated with lower NRS pain scores on Day 3 to Day 8 (P < .037). Compared with Day1, NGF reduced PPTs on Day 3 to Day 8 (P < .001) and non-nociceptive P200 and P300 ERP amplitudes on Day 8 (P < .044) in both groups. Musicians compared to controls showed secondary hyperalgesia to electrical stimulation on Day 3 to Day 8 (P < .004) and reduced nociceptive P200 ERP amplitudes on Day 8 (P < .005). Across participants, ERP components correlated with pain detection reaction times, sensitivity (PPTs and electrical detection thresholds), and severity (NRS), (all P < .043). These results show that repetitive sensorimotor training leads to brain changes in the processing of prolonged pain, biasing the cortical response to nociceptive inputs. PerspectiveRepetitive sensorimotor training may increase the responsiveness of nociceptive inputs during the development of prolonged muscle pain. These novel data highlight the role of repetitive sensorimotor practice as a source for interindividual variability in central pain processing.

Selective stimulation of nociceptive small fibers during intraepidermal electrical stimulation: Experiment and computational analysis.

Electrical stimulation of skin nociceptors is gaining attention in pain research and peripheral neuropathy diagnosis. However, the optimal parameters for selective stimulation are still difficult to determine because they require simultaneous characterization of the electrical response of small fibers (Aδ- and C-fibers). In this study, we measured the in vivo electrical threshold responses of small fibers to train-pulse stimulation in humans for the first time. We also examined selective stimulation via a computational model, which combines electrical analysis, and terminal fiber and synaptic models, including the first cutaneous pain C-fiber model. Selective stimulation of small fibers is performed by injecting train-pulse stimulation via coaxial electrodes with an intraepidermal needle tip at varying pulse counts and frequencies. The activation Aδ- or C-fibers was discriminated from the differences in reaction time. Aδ-fiber elicited a pinpricking sensation with a mean reaction time of 0.522 s, and C-fiber elicited a tingling sensation or slight burning itch with a mean reaction time of 1.243 s. The implemented multiscale electrical model investigates synaptic effects while considering stimulation waveform characteristics. Experimental results showed that perception thresholds decreased with the number of consecutive pulses and frequency up to convergence (five pulses or 70 Hz) during the selective stimulation of Aδ- and C-fibers. Considering the synaptic properties, the optimal stimulus conditions for selective stimulation of Aδ- vs. C-fibers were train of at least four pulses and a frequency of 40-70 Hz at a pulse width of 1 ms. The experimental results were modeled with high fidelity by incorporating temporal synaptic effects into the computational model. Numerical analysis revealed terminal axon thickness to be the most important biophysical factor affecting threshold variability. The computational model can be used to estimate perception thresholds while understanding the mechanisms underlying the selective stimulation of small fibers. The parameters derived here are important in exploring selective stimulation between Aδ- and C-fibers for diagnosing neuropathies.

WE-220. Nociceptive specificity with intra-epidermal electrical stimulation?

WE-220. Nociceptive specificity with intra-epidermal electrical stimulation?

The diversity and abundance of gut microbiota are associated with the pain sensation threshold in the Japanese population

Small fibre neuropathy (SFN) is an initial pathology of diabetic polyneuropathy (DPN). Serum lipopolysaccharide binding protein levels are positively correlated with the pain threshold in the foot, suggesting that the abundance of gut Gram-negative bacilli, which are a source of lipopolysaccharides, may be involved in the development of DPN. Furthermore, the abundance of the gut and oral microbiota is assumed to be involved in the pathogenesis of diabetes. Nevertheless, the association between SFN and the microbiota has not been clarified. A total of 1056 individuals were recruited in the 2018 Iwaki Health Promotion Project. Pain sensation was evaluated based on the pain threshold from intraepidermal electrical stimulation (PINT). Patients with PINT scores <0.15 mA were categorized into the low-PINT group (n = 718); otherwise, they were categorized into the high-PINT group (n = 283). Furthermore, each group was divided into the subjects with or without glucose tolerance based on HbA1c levels, fasting blood glucose levels and diabetic history. Principal coordinate analysis and α- and β-diversity of the microbiota were evaluated. The correlation between clinical and microbiota data was examined. Oral microbiota diversity showed no structural differences according to PINT scores, whereas principal coordinate analysis and α- and β-diversity revealed significant structural differences in gut microbiota (p < 0.01, p < 0.05 and p < 0.05, respectively), even after the participants with glucose intolerance were excluded (p < 0.01, p < 0.05 and p < 0.05, respectively). The relative abundance of the genus Bacteroides was significantly lower in high-PINT participants compared with low-PINT participants (10 ± 6.7% vs. 11.3 ± 7.0%, p < 0.01), even after the exclusion of subjects with diabetes and impaired fasting glucose (10.0 ± 6.5% vs. 11.2 ± 6.9%, p < 0.05). In univariate linear regression analyses, PINT was significantly correlated with metabolic syndrome parameters, eGFR, uric acid level and the abundance of Bacteroides. The correlation between Bacteroides and PINT scores remained significant after adjustment for multiple factors (β = −0.07181, p < 0.05). Changes of bacterial diversity and a low abundance of gut Bacteroides were correlated with elevated PINT scores in the Japanese population. This correlation may represent a new therapeutic option for SFN.

466-P: Changes in Oral and Intestinal Bacterial Flora Associated with Pain Thresholds

Small fiber neuropathy (SFN) manifests from the early stages of diabetic polyneuropathy. Changes in the oral and intestinal bacterial flora are known to be associated with the onset and progression of diabetes and its complications. However, correlation between SFN and each bacterial flora has not yet been investigated. In the 2018 Iwaki health promotion project, which is a local health promotion study in Aomori prefecture, 1037 participants (431 males and 6females including 814 non-glucose metabolism disorders, 143 fasting hyperglycemia (IFG) , and 80 type 2 diabetic cases (DM) , were evaluated. SFN was evaluated by the pain threshold evoked by intraepidermal electrical stimulation (PINT) . A PINT value of 0.or less was designated as Pint-L, and otherwise was designated as Pint-H. DNA was isolated from saliva and feces and relative bacterial abundance was determined with a next-generation sequencer. Bacteria that account for 1% or more of all bacteria were examined. PINT was significantly increased in IFG (0.12 ± 0.11mA) and DM (0.15 ± 0.13mA) compared to healthy subjects (0.± 0.08mA) (p&amp;lt;0.vs. IFG, p &amp;lt;0.vs. DM) . No significant difference was found depending on the PINT value in the bacteria flora of oral cavity. There were significant differences of gut bacterial flor in α and β-diversity (p&amp;lt;0.05) and principal component analysis (p &amp;lt;0.01) depending on the PINT value. The genus Bacteroides was significantly higher in PINT-H than in PINT-L (p&amp;lt;0.01) . After IFG and DM cases were excluded, a significant difference was maintained. The amount of bacteroides was significantly correlated with age, abdominal circumference, fasting blood glucose, HbA1c (p&amp;lt;0.001) , BMI and PINT value (p &amp;lt;0.05) . In the multiple regression analysis adjusted for these factors, PINT was significantly correlated with the amount of Bacteroides (β = -0.089, p = 0.026) . Our results suggest that the gut Bacteroides may correlate with SFN. The involvement of deterioration of glucose metabolism may not be high in this correlation. Disclosure K.Kudoh: None. Y.Takeuchi: None. S.Osonoi: None. T.Sasaki: None. S.Ogasawara: None. S.Yagihashi: None. H.Mizukami: None.

Observing Altered Nociceptive Detection Thresholds in Patients With Persistent Spinal Pain Syndrome Type 2 With a Dorsal Root Ganglion Stimulator

ObjectivesThere is a lack of clinically relevant measures for quantification of maladaptive mechanisms of the nociceptive system leading to chronic pain. Recently, we developed a method that tracks nociceptive detection thresholds (NDTs) using intraepidermal electrical stimulation. In this study, we explored the feasibility of using this NDT method in patients with persistent spinal pain syndrome type 2 (PSPS-T2) and its potential to enable observation of altered nociceptive processing induced by dorsal root ganglion (DRG) stimulation. In addition, we compared NDTs with quantitative sensory testing (QST) measurements and numeric rating scale (NRS). Materials and MethodsA total of 12 patients with PSPS-T2 (seven men; 60.4 ± 12.3 years) experiencing chronic unilateral lower limb pain treated with DRG stimulation were included in the study. Both the NDT method and electrical and pressure QST methods were performed twice in the L5 dermatome on both the affected and the unaffected foot, once with the DRG stimulator turned off and, subsequently, once with the DRG stimulator turned on. ResultsThe NDT method can be applied to patients with PSPS-T2. With the DRG stimulator turned off, NDTs on the affected side were significantly higher than on the unaffected side. This difference was no longer present once the DRG stimulator was turned on. Furthermore, DRG stimulation affected QST (electrical and pressure) values and NRS scores. Finally, NDTs showed larger contrasts between the sides than QST measures. ConclusionsThe NDT method permitted observation of altered nociceptive function. The effect of DRG stimulation also was reflected in QST outcomes and NRS scores. The larger contrast between the sides for NDTs suggests that the NDT method might be valuable for future quantification of nociceptive dysfunction in chronic pain.

Intra-epidermal evoked potentials: A promising tool for spinal disorders?

ObjectivesTo test the robustness and signal-to-noise ratio of pain-related evoked potentials following intra-epidermal electrical stimulation (IES) compared to contact heat stimulation in healthy controls, and to explore the feasibility and potential added value of IES in the diagnosis of spinal disorders. MethodsPain-related evoked potentials induced by IES (custom-made, non-invasive, concentric triple pin electrode with steel pins protruding 1 mm from the anode, triangularly separated by 7–10 mm respectively) and contact heat stimulation were compared in 30 healthy subjects. Stimuli were applied to four different body sites. Two IES intensities, i.e., high (individually adapted to contact heat painfulness) and low (1.5 times pain threshold), were used. Additionally, a 40-year-old patient with unilateral dissociated sensory loss due to a multi-segmental syringohydromyelia was assessed comparing IES and contact heat stimulation. ResultsBoth IES and contact heat stimulation led to robust pain-related evoked potentials recorded in all healthy subjects. Low intensity IES evoked potentials (14.1–38.0 µV) had similar amplitudes as contact heat evoked potentials (11.8–32.3 µV), while pain ratings on the numeric rating scale were lower for IES (0.8–2.5, compared to 1.5–3.9 for contact heat stimulation). High intensity IES led to evoked potentials with higher signal-to-noise ratio than low intensity IES and contact heat stimulation. The patient case showed impaired pain-related evoked potentials in segments with hypoalgesia for both IES modes. IES evoked potentials were preserved, with delayed latencies, while contact heat evoked potentials were abolished. ConclusionIES evoked robust pain-related cortical potentials, while being less painful in healthy controls. The improved signal-to-noise ratio supports the use of IES for objective segmental testing of nociceptive processing. This was highlighted in a spinal syndrome case, where IES as well as contact heat stimulation reliably detected impaired segmental nociception.

Exploring Nociceptive Detection Thresholds Combined with Evoked Potentials in Patients with Diabetes Mellitus.

There is a lack of diagnostic tools that can objectively measure small fiber neuropathy (SFN) in patients with diabetes mellitus (DM). Recently, nociceptive nerve function was observed by nociceptive detection thresholds (NDTs) and brain evoked potentials (EPs) during intra-epidermal electrical stimulation (IES) targeting Aδ-fibers. In this proof of principle, we studied whether it is possible to measure NDTs combined with EPs in DM patients with and without neuropathic pain. Furthermore, we explored the sensitivity of NDTs and EPs for polyneuropathy in these patients. Five DM patients diagnosed with painful neuropathy (DMp), five DM patients without painful neuropathy (DM), and five healthy controls (HC) were analyzed. These preliminary results showed that we can accurately measure NDTs and EPs in patients with diabetes. Strikingly, increased NDTs were found in DM and DMp compared to HC, of which the DMp showed the largest NDTs. This suggests that NDTs during IES could be a powerful biomarker for monitoring peripheral dysfunctions. Current EEG data of patients did not show any significant differences. The population needs to be enlarged before we can investigate the sensitivity of these NDTs and EPs to diabetic polyneuropathy and associated changes in nociceptive processing in more detail.Clinical Relevance- This proof of principle in a small group of patients with diabetes mellitus potentially treats the observation of the loss of nociceptive function occurring with small fiber neuropathy. That helps the development of a diagnostic measure to monitor future (early-stage) nociceptive dysfunctions in a clinical environment.

Event-related potentials evoked by skin puncture reflect activation of Aβ fibers: comparison with intraepidermal and transcutaneous electrical stimulations.

BackgroundRecently, event-related potentials (ERPs) evoked by skin puncture, commonly used for blood sampling, have received attention as a pain assessment tool in neonates. However, their latency appears to be far shorter than the latency of ERPs evoked by intraepidermal electrical stimulation (IES), which selectively activates nociceptive Aδ and C fibers. To clarify this important issue, we examined whether ERPs evoked by skin puncture appropriately reflect central nociceptive processing, as is the case with IES.MethodsIn Experiment 1, we recorded evoked potentials to the click sound produced by a lance device (click-only), lance stimulation with the click sound (click+lance), or lance stimulation with white noise (WN+lance) in eight healthy adults to investigate the effect of the click sound on the ERP evoked by skin puncture. In Experiment 2, we tested 18 heathy adults and recorded evoked potentials to shallow lance stimulation (SL) with a blade that did not reach the dermis (0.1 mm insertion depth); normal lance stimulation (CL) (1 mm depth); transcutaneous electrical stimulation (ES), which mainly activates Aβ fibers; and IES, which selectively activates Aδ fibers when low stimulation current intensities are applied. White noise was continuously presented during the experiments. The stimulations were applied to the hand dorsum. In the SL, the lance device did not touch the skin and the blade was inserted to a depth of 0.1 mm into the epidermis, where the free nerve endings of Aδ fibers are located, which minimized the tactile sensation caused by the device touching the skin and the activation of Aβ fibers by the blade reaching the dermis. In the CL, as in clinical use, the lance device touched the skin and the blade reached a depth of 1 mm from the skin surface, i.e., the depth of the dermis at which the Aβ fibers are located.ResultsThe ERP N2 latencies for click-only (122 ± 2.9 ms) and click+lance (121 ± 6.5 ms) were significantly shorter than that for WN+lance (154 ± 7.1 ms). The ERP P2 latency for click-only (191 ± 11.3 ms) was significantly shorter than those for click+lance (249 ± 18.6 ms) and WN+lance (253 ± 11.2 ms). This suggests that the click sound shortens the N2 latency of the ERP evoked by skin puncture. The ERP N2 latencies for SL, CL, ES, and IES were 146 ± 8.3, 149 ± 9.9, 148 ± 13.1, and 197 ± 21.2 ms, respectively. The ERP P2 latencies were 250 ± 18.2, 251 ± 14.1, 237 ± 26.3, and 294 ± 30.0 ms, respectively. The ERP latency for SL was significantly shorter than that for IES and was similar to that for ES. This suggests that the penetration force generated by the blade of the lance device activates the Aβ fibers, consequently shortening the ERP latency.ConclusionsLance ERP may reflect the activation of Aβ fibers rather than Aδ fibers. A pain index that correctly and reliably reflects nociceptive processing must be developed to improve pain assessment and management in neonates.

Small nerve fiber selectivity of laser and intraepidermal electrical stimulation: A comparative study between glabrous and hairy skin

ObjectivesIn clinical neurophysiology practice, various methods of stimulation can be used to activate small-diameter nociceptive cutaneous afferents located in the epidermis. These methods include different types of laser and intraepidermal electrical stimulation techniques. The diffusion of the stimulation in the skin, inside or under the epidermis, depends on laser wavelength and electrode design, in particular. The aim of this study was to compare several of these techniques in their ability to selectively stimulate small nerve fibers. MethodsIn 8 healthy subjects, laser stimulation (using a CO2 or Nd:YAP laser) and intraepidermal electrical stimulation (using a micropatterned, concentric planar, or concentric needle electrode), were applied at increasing energy or intensity on the dorsal or volar aspect of the right hand or foot. The subjects were asked to define the perceived sensation (warm, pinprick, or electric shock sensation, corresponding to the activation of C fibers, Aδ fibers, or Aβ fibers, respectively) after each stimulation. Depending on the difference in the sensations perceived between dorsal (hairy skin with thin stratum corneum) and volar (glabrous skin with thick stratum corneum) stimulations, the diffusion of the stimulation inside or under the epidermis and the nature of the activated afferents were determined. ResultsRegarding laser stimulation, the perceived sensations turned from warm to pinprick with increasing energies of stimulation, in particular with the Nd:YAP laser, of which pulse could penetrate deep in the skin according to its short wavelength. In contrast, CO2 laser stimulation produced only warm sensations and no pricking sensation when applied to the glabrous skin, perhaps due to a thicker stratum corneum and the shallow penetration of the CO2 laser pulse. Regarding intraepidermal electrical stimulation using concentric electrodes, the perceived sensations turned from pinprick to a combination of pinprick and electrical shocks with increasing intensities. Using the concentric planar electrode, the sensations perceived at high stimulation intensity even consisted of electric shocks without concomitant pinprick. In contrast, using the micropatterned electrode, only pinprick sensations were produced by the stimulation of the hairy skin, while the stimulation of the glabrous skin produced no sensation at all within the limits of stimulation intensities used in this study. ConclusionsUsing the CO2 laser or the micropatterned electrode, pinprick sensations were selectively produced by the stimulation of hairy skin, while only warm sensation or no sensation at all were produced by the stimulation of glabrous skin. These two techniques appear to be more selective with a limited diffusion of the stimulation into the skin, restricting the activation of sensory afferents to the most superficial and smallest intraepidermal nerve fibers.

Conditioned Pain Modulation: Comparison of the Effects on Nociceptive and Non-nociceptive Blink Reflex

Although conditioned pain modulation (CPM) is considered to represent descending pain inhibitory mechanisms triggered by noxious stimuli applied to a remote area, there have been no previous studies comparing CPM between pain and tactile systems. In this study, we compared CPM between the two systems objectively using blink reflexes. Intra-epidermal electrical stimulation (IES) and transcutaneous electrical stimulation (TS) were applied to the right skin area over the supraorbital foramen to evoke a nociceptive or a non-nociceptive blink reflex, respectively, in 15 healthy males. In the test session, IES or TS were applied six times and subjects reported the intensity of each stimulus on a numerical rating scale (NRS). Blink reflexes were measured using electromyography (R2). The first and second sessions were control sessions, while in the third session, the left hand was immersed in cold water at 10 °C as a conditioning stimulus. The magnitude of the R2 blink and NRS scores were compared among the sessions by 2-way ANOVA. Both the NRS score and nociceptive R2 were significantly decreased in the third session for IES, with a significant correlation between the two variables; whereas, TS-induced non-nociceptive R2 did not change among the sessions. Although the conditioning stimulus decreased the NRS score for TS, the CPM effect was significantly smaller than that for IES (p = 0.002). The present findings suggest the presence of a pain-specific CPM effect to a heterotopic noxious stimulus.

Intravenous lidocaine and magnesium on responses of A-δ and A-β nerve fibers at non-affected and affected areas in three cases of neuralgias

Intravenous magnesium and lidocaine have been used for the management of intractable pain individually or in combination. A study reported on the positive effects when used in combination on neuralgia when antiepileptic drugs failed, but nobody has clarified how the combination works. The aim of the present case report is to see how a combination of intravenous magnesium and lidocaine influenced electrically-evoked responses of peripheral A-δ and A-β nerve fibers at non-affected and affected areas in three patients with neuralgia. For nociceptive stimulation, a method of intraepidermal electrical stimulation (IES) was used for the selective activation of cutaneous A-δ fibers, using a stainless steel concentric bipolar needle electrode. For tactile stimulation, similar cutaneous sites were stimulated for cutaneous A-β fibers using the same electrode. Three patients with intractable trigeminal neuralgia or intercostal neuralgia were treated using an intravenous infusion of a combination of 1.2g of magnesium and 100mg of lidocaine for one hour. Although all patients experienced sound pain relief after the combined intravenous infusion therapy, the combination had a different effect on electrically-evoked responses of peripheral A-δ and A-β nerve fibers at non-affected and affected areas in each patient.

Increased Oxidative Stress Underlies Abnormal Pain Threshold in a Normoglycemic Japanese Population.

Normal-high HbA1c levels are a risk factor for attenuated pain sensation in normoglycemic subjects. It is unclear, however, what mechanisms underlie the pathogenesis of attenuated pain sensation in such a population. We, therefore, explored the relationship between oxidative stress (OS) and pain sensation in a rural Japanese population. A population-based study of 894 individuals (average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold induced by intraepidermal electrical stimulation (PINT) and clinico-hematological parameters associated with OS were evaluated. Univariate linear regression analyses revealed age, BMI, HbA1c, the OS biomarker urine 8-hydroxy-2′-deoxyguanosine (8-OHdG), systolic blood pressure, and decreased Achilles tendon reflex on the PINT scores. Adjustments for age, gender, and multiple clinical measures confirmed a positive correlation between PINT scores and urine 8-OHdG (β = 0.09, p < 0.01). Urine 8-OHdG correlated positively with higher HbA1c levels and age in the normoglycemic population. Unlike in the normoglycemic population, both inflammation and OS were correlated with elevated PINT scores in IFG subjects. OS may be a major contributing factor to elevated PINT scores in a healthy Japanese population.