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

Background Recently, 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. Methods In 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. Results The 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. Conclusions Lance 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.

Innocuous pressure sensation requires A-type afferents but not functional ΡΙΕΖΟ2 channels in humans

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aβ fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aβ afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection.

Can Event-Related Potentials Evoked by Heel Lance Assess Pain Processing in Neonates? A Systematic Review

To clarify the possibility of event-related potential (ERP) evoked by heel lance in neonates as an index of pain assessment, knowledge acquired by and problems of the methods used in studies on ERP evoked by heel lance in neonates were systematically reviewed, including knowledge about Aδ and C fibers responding to noxious stimuli and Aβ fibers responding to non-noxious stimuli. Of the 863 reports searched, 19 were selected for the final analysis. The following points were identified as problems for ERP evoked by heel lance in neonates to serve as a pain assessment index: (1) It is possible that the ERP evoked by heel lance reflected the activation of Aβ fibers responding to non-noxious stimuli and not the activation of Aδ or C fibers responding to noxious stimulation; (2) Sample size calculation was presented in few studies, and the number of stimulation trials to obtain an averaged ERP was small. Accordingly, to establish ERP evoked by heel lance as a pain assessment in neonates, it is necessary to perform a study to clarify ERP evoked by Aδ- and C-fiber stimulations accompanied by heel lance in neonates.

A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior

A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP+) and show that specific ablation or silencing of AAV-NpyP+ SDH interneurons converted touch-sensing Aβ fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP+ neurons received excitatory inputs from Aβ fibers and transmitted inhibitory GABA signals to lamina I neurons projecting to the brain. In a model of neuropathic pain developed by peripheral nerve injury, AAV-NpyP+ neurons exhibited deeper resting membrane potentials, and their excitation by Aβ fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP+ neurons in nerve-injured rats reversed Aβ fiber-derived neuropathic pain-like behavior that was shown to be morphine-resistant and reduced pathological neuronal activation of superficial SDH including lamina I. These findings suggest that identified inhibitory SDH interneurons that act as a critical brake on conversion of touch-sensing Aβ fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.

Mathematical model shows how sleep may affect amyloid β fibrillization

Deposition of amyloid β (Aβ) fibers in extra-cellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer’s disease (AD). While many of the biological aspects that contribute to the formation of Aβ plaques are well addressed at the intra- and inter-cellular level in short timescales, an understanding of how Aβ fibrillization usually starts to dominate at a longer timescale in spite of the presence of mechanisms dedicated to Aβ clearance, is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in sleep-wake cycle. In this study, we develop a minimal model of Aβ fibrillization to investigate the onset of AD over a long time-scale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble Aβ (sAβ) to fibrillar Aβ (fAβ) domination upon surpassing a threshold in the production rate of soluble Aβ. By incorporating the circadian rhythm into our model, we reveal that fAβ accumulation is crucially dependent on the regulation of sleep-wake cycle, thereby indicating the importance of a good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fAβ accumulation in the brain by modification of the critical sAβ production rate.

Analysis of compound action potentials elicited with specific current stimulating pulses in an isolated rat sciatic nerve

The ability to selectively stimulate Aα, Aβ-fibers and Aδ-fibers in an isolated rat sciatic nerve (SNR) was assessed. The stimulus used was a current, biphasic pulse with a quasitrapezoidal cathodic phase and rectangular anodic phase where parameters were systematically varied: intensity of the cathodic phase (i

Sickle Cell Disease Patients Show Sensitization of Myelinated Sensory Nerve Fibers

There is increasing evidence that many patients with sickle cell disease (SCD) develop chronic pain in addition to experiencing acute pain secondary to vaso-occlusive episodes (VOE). Those patients who develop chronic pain often exhibit features suggestive of neuropathic processes such as allodynia and pain "shooting" or "tingling" in character. Using electrophysiologic techniques in ex-vivo nerve-skin preparations and nocifensive behavior studies in sickle cell mouse models, we and others have shown that SCD is associated with sensitization of light touch cutaneous sensory fibers, and decreased threshold in response to 2000Hz and 250 Hz electrical sine wave stimulation. These findings are indicative of Aβ and Ad fibers sensitization and in turn compatible with neuropathic process. We hypothesized that the same phenomena of nerve fiber sensitization in the mouse model would be observed in SCD patients. This hypothesis was tested using an experimental paradigm with sine-wave electrical stimulation delivered at three different frequencies: 2000, 250, and 5 Hz, which preferentially stimulate Aβ, Ad, and C fibers, respectively. Thermal and mechanical sensory testing was also performed. After IRB approval, SCD subjects with high (≥ than 3 ER visits or admissions for VOEs per year) or low (< 2 ER visits or admissions per year) pain frequency, and age- and sex-matched African-American healthy controls were recruited at baseline states during routine clinic visits. After informed consent (and/or assent) was obtained, patients underwent quantitative sensory testing (QST) that included heat and cold perception and tolerance (with a TSA II-Sensory Analyzer), mechanical (using a Wagner FDIX Force One) and current perception and pain tolerance thresholds (using the Neurometer). We enrolled 19 SCD subjects with high and 4 with low pain frequency (total 23 SCD participants), and 11 African-American non-SCD subjects who tolerated and completed all QSTs. As there was no difference between QST responses in patients with high and low pain frequency, these two groups were combined as the SCD group. We found that SCD subjects had significantly decreased cold tolerance threshold (p=0.034) and a trend towards lower thresholds for cold perception and heat tolerance, which is in concert with previously reported findings. Expanding upon these findings, SCD patients had a significantly reduced pain tolerance threshold in response to 2000 Hz stimulation (p=0.005), which preferentially stimulates Aβ fibers (see figure). These results suggest that adolescents with SCD have sensitization of myelinated Aβ fibers. Interrogation of the Ad and C fibers with 250 and 5 Hz stimulation, respectively, revealed no significant differences in tolerance thresholds among the groups, however SCD patients showed a trend toward lower thresholds in both frequencies (see figure). Combined, these findings support the use of sine-wave stimulation on the evaluation of pain phenotype in SCD and the notion that SCD subjects may have neuropathic processes contributing to their pain phenotype.TableDemographics, thermal and mechanical sensory testing in SCD and control subjects.VariableSCD (n=23)Control (n=11)Age (years)16 (15-18.8)19 (14-21)Male (%)3 (30%)11 (48%)Cold Perception (°C)29.8 (28.5-30.5)30.4 (29.9-30.9)Cold Tolerance (°C)8.5 (2.0-17.0) *0.9 (0.0-6.9)Heat Perception (°C)34.4 (33.5-35.2) *33.6 (33.2-34.1)Heat Tolerance (°C)48.9 (47.5-49.8)50.0 (45.3-50.1)Mechanical Tolerance (lbF)7.7 (5.9-9.7)9.5 (7.7-10.8)*p < 0.05. Values are shown as median and interquartile range. SCD subjects reached cold tolerance and heat perception at significantly higher temperatures as compared to controls; p=0.034 and p= 0.035, respectively. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.