Nociceptive Withdrawal Reflex Research Articles

The effect of methylphenidate on anaesthesia recovery: An experimental study in pigs.

Due to the lack of specific antagonists for general anaesthetics, the pharmacological stimulation of the arousal pathways might contribute to reduce recovery time. We aimed at assessing the effect of methylphenidate on physiological parameters, nociceptive withdrawal reflex thresholds, electroencephalographic variables and time of reappearance of reflexes in pigs undergoing propofol anaesthesia. Two experiments have been performed. Five (experiment 1) and sixteen (experiment 2) healthy juvenile pigs were anaesthetised with propofol. In experiment 1, saline, methylphenidate 10 mg/kg or methylphenidate 20 mg/kg was administered intravenously at the end of propofol administration, using a cross-over design. In experiment 2, saline (n = 8) or methylphenidate 20 mg/kg (n = 8) was administered immediately after extubation. In both experiments, physiological parameters, nociceptive withdrawal reflex thresholds, electroencephalographic variables and time of reappearance of reflexes were assessed. Comparison among groups was performed using either the two-way repeated measures ANOVA followed by Bonferroni-Test or the t-test in case of parametric data, and either the Kruskal-Wallis test or the Mann-Whitney Rank Sum test in case of non-parametric data. A p value < 0.05 was considered statistically significant. No clinically relevant changes were observed in both experiments for physiological parameters, nociceptive withdrawal reflex thresholds and electroencephalographic variables. Methylphenidate does not shorten or modify anaesthesia recovery in pigs, when the sole propofol is administered.

How Is the Nociceptive Withdrawal Reflex Influenced by Increasing Doses of Propofol in Pigs?

The nociceptive withdrawal reflex (NWR) is a physiological, polysynaptic spinal reflex occurring in response to noxious stimulations. Continuous NWR threshold (NWRt) tracking has been shown to be possibly useful in the depth of anesthesia assessment. The primary aim of this study was to describe how propofol modulates the NWRt over time in pigs. Five juvenile pigs (anesthetized three times) were included. An intravenous (IV) infusion of propofol (20 mg/kg/h) was started, and boli were administered to effect until intubation. Afterwards, the infusion was increased every ten minutes by 6 mg/kg/h, together with an IV bolus of 0.5 mg/kg, until reaching an electroencephalographic suppression ratio (SR) of between 10% and 30%. The NWRt was continuously monitored. For data analysis, the time span between 15 min following intubation and the end of propofol infusion was considered. Individual durations of propofol administration were divided into five equal time intervals for each pig (TI1-TI5). A linear regression between NWRt and TI was performed for each pig. Moreover, the baseline NWRt and slopes of the linear regression (b1) were compared among days using a Friedman Repeated Measures Analysis of Variance on Ranks. The NWRt always increased with the propofol dose (b1 = 4.71 ± 3.23; mean ± standard deviation). No significant differences were found between the baseline NWRt and the b1 values. Our results suggest that the NWRt may complement the depth of anesthesia assessment in pigs receiving propofol.

Effects of transcutaneous auricular vagus nerve stimulation at left cymba concha on experimental pain as assessed with the nociceptive withdrawal reflex, and correlation with parasympathetic activity.

The aim of this study was to clarify the effects of transcutaneous auricular vagus nerve stimulation (taVNS) to the left cymba concha on the pain perception using nociceptive withdrawal reflex (NWR), which is known to be associated with chronic pain, and to investigate whether there is a relationship between taVNS-induced suppression of the NWR and parasympathetic activation. We applied either 3.0mA, 100 Hz taVNS for 120 s on the left cymba concha (taVNS condition) or the left earlobe (Sham condition) for 20 healthy adults. NWR threshold was measured before (Baseline), immediately after (Post 0), 10min (Post 10) and 30 min after (Post 30) stimulation. The NWR threshold was obtained from biceps femoris muscle by applying electrical stimulation to the sural nerve. During taVNS, electrocardiogram was recorded, and changes in autonomic nervous activity measured by heart rate variability (HRV) were analyzed. We found that the NWR thresholds at Post 10 and Post 30 increased compared with baseline in the taVNS group (10min after: p = .008, 30 min after: p = .008). In addition, increased parasympathetic activity by taVNS correlated with a greater increase in NWR threshold at Post 10 and Post 30 (Post 10: p = .003; Post 30: p = .001). The present results of this single-blinded study demonstrate the pain-suppressing effect of taVNS on NWR threshold and suggest that the degree of parasympathetic activation during taVNS may predict the pain-suppressing effect of taVNS after its application.

Healthy women show more experimentally induced central sensitization compared with men.

Women more often experience chronic pain conditions than men. Central sensitization (CS) is one key mechanism in chronic pain that can differ between the sexes. It is unknown whether CS processes are already more pronounced in healthy women than in men. In 66 subjects (33 women), a thermal CS induction protocol was applied to the dorsum of one foot and a sham protocol to the other. Spatial extent [cm 2 ] of secondary mechanical hyperalgesia (SMH) and dynamic mechanical allodynia were assessed as subjective CS proxy measures, relying on verbal feedback. Changes in nociceptive withdrawal reflex magnitude (NWR-M) and response rate (NWR-RR) recorded through surface electromyography at the biceps and rectus femoris muscles were used as objective CS proxies. The effect of the CS induction protocol on SMH was higher in women than in men (effect size 2.11 vs 1.68). Nociceptive withdrawal reflex magnitude results were statistically meaningful for women (effect size 0.31-0.36) but not for men (effect size 0.12-0.29). Differences between men and women were not meaningful. Nociceptive withdrawal reflex response rate at the rectus femoris increased in women after CS induction and was statistically different from NWR-RR in men (median differences of 13.7 and 8.4% for 120 and 140% reflex threshold current). The objective CS proxy differences indicate that dorsal horn CS processes are more pronounced in healthy women. The even larger sex differences in subjective CS proxies potentially reflect greater supraspinal influence in women. This study shows that sex differences are present in experimentally induced CS in healthy subjects, which might contribute to women's vulnerability for chronic pain.

Nociceptive withdrawal reflexes of the trunk muscles in chronic low back pain.

Individuals with chronic low back pain (CLBP) move their spine differently. Changes in brain motor areas have been observed and suggested as a mechanism underlying spine movement alteration. Nociceptive withdrawal reflex (NWR) might be used to test spinal networks involved in trunk protection and to highlight reorganization. This study aimed to determine whether the organization and excitability of the trunk NWR are modified in CLBP. We hypothesized that individuals with CLBP would have modified NWR patterns and lower NWR thresholds. Noxious electrical stimuli were delivered over S1, L3 and T12, and the 8th Rib to elicit NWR in 12 individuals with and 13 individuals without CLBP. EMG amplitude and occurrence of lumbar multifidus (LM), thoracic erector spinae, rectus abdominus, obliquus internus and obliquus externus motor responses were recorded using surface electrodes. Two different patterns of responses to noxious stimuli were identified in CLBP compared to controls: (i) abdominal muscle NWR responses were generally more frequent following 8th rib stimulation and (ii) occurrence of erector spinae NWR was less frequent. In addition, we observed a subgroup of participants with very high NWR threshold in conjunction with the larger abdominal muscle responses. These results suggest sensitization of NWR is not present in all individuals with CLBP, and a modified organization in the spinal networks controlling the trunk muscles that might explain some changes in spine motor control observed in CLBP.

A Bio-Plausible Approach to Realizing Heat-Evoked Nociceptive Withdrawal Reflex on the Upper Limb of a Humanoid Robot

In this letter, we present a method for realizing the heat-evoked nociceptive withdrawal reflex (NWR) in the upper limb of a humanoid robot so that it can avoid the potential damage caused by noxious heat. We use a spiking neural network whose structure, encoding scheme, and form of information transmission mimic the reflex arc in humans to improve bio-plausibility. The proper synaptic strengths between the sensory neurons and the interneurons in the first two layers are learned using the bio-plausible reward-modulated spike timing-dependent plasticity learning algorithm. By monitoring the spikes from the motor neuron in the third layer, a reflex matching the intensity of the stimulation can be evoked. Experimental evaluations show that noxious heat stimulation can be detected online and evoke the NWR. The experiments on a full-size humanoid robot show that the method enables robots to avoid potential damage robustly with proper NWR, depending on the site and intensity of the stimulation. We also verify that the method takes advantage of the intrinsic characteristics of its neuromorphic encoding scheme to reproduce essential features of the NWR, e.g., spatial summation effect and temporal summation effect in humans. The improved bio-plausibility and the capability to reproduce the human-like feature.

Sustained and potent analgesia with negligible side effects enabled by adaptive individualized granular stimulation in rat brainstem

Objectives. To clarify if an adaptive current stimulation protocol, in which current amplitude is modulated during continuous stimulation, provides better efficacy than constant current stimulation protocol with respect to analgesia caused by individualized stimulation in rat periaqueductal gray matter (PAG) /dorsal raphe nuclei (DRN). Approach. Ultrathin microelectrodes adapted for recording (n = 6) and stimulation (n = 16) were implanted in rat primary somatosensory cortex and PAG/DRN, respectively. In each animal included (n = 12), a subset of PAG/DRN microelectrodes (n = 1–3 per animal) was selected that on simultaneous stimulation blocked nociceptive withdrawal reflexes in awake unrestrained animals without noticeable side effects. Analgesic effects were subsequently assessed from both nociceptive withdrawal reflexes and intracortical pain-related responses on CO2 laser hind paw stimulation. The analgesic effects of adaptive current PAG/DRN stimulation comprising incremental increases of 5 μA/microelectrode (initial median current 30 μA/microelectrode) when effects declined were compared to the effects of constant current stimulation. Behavioral effects and brain state related changes were analyzed using quantitative movement analysis and electrocorticography (recorded on top of the dura mater), respectively. Tissue reactions and probe placement in PAG/DRN were assessed with immunohistochemistry. Main results. Powerful and sustained (4 h) analgesia was achieved with the adaptive current protocol within a rather wide area of PAG/DRN. Analgesic after-effects were seen for up to 30 min. Behavioral and brain state related side effects were minimal. Moreover, 6 weeks after implantation, there were no traces of bleedings, only small glial reactions and small but not statistically significant loss of neurons nearby indicating that the microelectrode stimulation employed is biocompatible. Significance. The results indicate that sustained and powerful analgesia with minimal side effects can be achieved by granular and individualized stimulation in PAG/DRN using an adaptive current stimulation protocol. This microelectrode technology and stimulation paradigm thus has the potential of providing a highly efficient and safe pain therapy.

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

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. 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. 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. 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. 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.

Noxious radiant heat evokes bi-component nociceptive withdrawal reflexes in spinal cord injured humans-A clinical tool to study neuroplastic changes of spinal neural circuits.

Investigating nocifensive withdrawal reflexes as potential surrogate marker for the spinal excitation level may widen the understanding of maladaptive nociceptive processing after spinal cord injury (SCI). The aim of this prospective, explorative cross-sectional observational study was to investigate the response behavior of individuals with SCI to noxious radiant heat (laser) stimuli and to assess its relation to spasticity and neuropathic pain, two clinical consequences of spinal hyperexcitability/spinal disinhibition. Laser stimuli were applied at the sole and dorsum of the foot and below the fibula head. Corresponding reflexes were electromyography (EMG) recorded ipsilateral. Motor responses to laser stimuli were analyzed and related to clinical readouts (severity of injury/spasticity/pain), using established clinical assessment tools. Twenty-seven participants, 15 with SCI (age 18-63; 6.5 years post-injury; AIS-A through D) and 12 non-disabled controls, [non-disabled controls (NDC); age 19-63] were included. The percentage of individuals with SCI responding to stimuli (70-77%; p < 0.001), their response rates (16-21%; p < 0.05) and their reflex magnitude (p < 0.05) were significantly higher compared to NDC. SCI-related reflexes clustered in two time-windows, indicating involvement of both A-delta- and C-fibers. Spasticity was associated with facilitated reflexes in SCI (Kendall-tau-b p ≤ 0.05) and inversely associated with the occurrence/severity of neuropathic pain (Fisher's exact p < 0.05; Eta-coefficient p < 0.05). However, neuropathic pain was not related to reflex behavior. Altogether, we found a bi-component motor hyperresponsiveness of SCI to noxious heat, which correlated with spasticity, but not neuropathic pain. Laser-evoked withdrawal reflexes may become a suitable outcome parameter to explore maladaptive spinal circuitries in SCI and to assess the effect of targeted treatment strategies. Registration: https://drks.de/search/de/trial/DRKS00006779.

Investigations into an overlooked early component of painful nociceptive withdrawal reflex responses in humans.

The role of pain as a warning system necessitates a rapid transmission of information from the periphery for the execution of appropriate motor responses. The nociceptive withdrawal reflex (NWR) is a physiological response to protect the limb from a painful stimulus and is often considered an objective measure of spinal nociceptive excitability. The NWR is commonly defined by its latency in the presumed Aδ-fiber range consistent with the canonical view that "fast pain" is signaled by Aδ nociceptors. We recently demonstrated that human skin is equipped with ultrafast (Aβ range) nociceptors. Here, we investigated the short-latency component of the reflex and explored the relationship between reflex latency and pain perception. We revisited our earlier work on NWR measurements in which, following convention, only reflex responses in the presumed Aδ range were considered. In our current analysis, we expanded the time window to search for shorter latency responses and compared those with pain ratings. In both cohorts, we found an abundance of recordings with short-latency reflex responses. In nearly 90% of successful recordings, only single reflex responses (not dual) were seen which allowed us to compare pain ratings based on reflex latencies. We found that shorter latency reflexes were just as painful as those in the conventional latency range. We found a preponderance of short-latency painful reflex responses. Based on this finding, we suggest that short-latency responses must be considered in future studies. Whether these are signaled by the ultrafast nociceptors remains to be determined.

A contribuição dos potenciais evocados por eletrodo concêntrico e reflexo de retirada nociceptiva para a avaliação neurofisiológica de rotina da dor neuropática: estudo observacional transversal

A contribuição dos potenciais evocados por eletrodo concêntrico e reflexo de retirada nociceptiva para a avaliação neurofisiológica de rotina da dor neuropática: estudo observacional transversal

The contribution of concentric electrode-evoked potentials and nociceptive withdrawal reflex to the routine neurophysiological assessment of neuropathic pain: cross-sectional study

The contribution of concentric electrode-evoked potentials and nociceptive withdrawal reflex to the routine neurophysiological assessment of neuropathic pain: cross-sectional study

Are changes in nociceptive withdrawal reflex magnitude a viable central sensitization proxy? Implications of a replication attempt

ObjectiveThe nociceptive withdrawal reflex (NWR) has been proposed to read-out central sensitization (CS). Replicating a published study, it was assessed if the NWR magnitude reflects sensitization by painful heat. Additionally, NWR response rates were compared for two stimulation, the sural nerve at the lateral malleolus (SU) and the medial plantar nerve on the foot sole (MP), and three recording sites, biceps femoris (BF), rectus femoris (RF), and tibialis anterior (TA) muscles. Methods16 subjects underwent one experiment with six blocks of eight transcutaneous electrical stimulations to elicit the NWR while surface electromyography was collected. Tonic heat was concurrently applied in the same dermatome. Temperatures rose from 32 °C in the first to 46 °C in the last block following the previously published protocol. ResultsTonic heat did not influence NWR magnitude. The highest NWR response rate was obtained for MP–TA combination (79%). Regarding elicitation in all three muscles, SU stimulation outperformed MP (59% vs 57%). ConclusionsThe replication failed. NWR magnitude as a CS proxy in healthy subjects needs continued investigation. With respect to response rates, MP–TA proved efficient, whereas SU stimulation seemed preferable for multiple muscle recordings. SignificanceUnclear methodological descriptions in the original study affected CS and NWR replication. The NWR magnitude changes induced by CS may closely depend on the different stimulation methods used.

Quantitative spatial analysis reveals that the local axons of lamina I projection neurons and interneurons exhibit distributions that predict distinct roles in spinal sensory processing.

Our knowledge about the detailed wiring of neuronal circuits in the spinal dorsal horn (DH), where initial sensory processing takes place, is still very sparse. While a substantial amount of data is available on the somatodendritic morphology of DH neurons, the laminar and segmental distribution patterns and consequential function of individual axons are much less characterized. In the present study, we fully reconstructed the axonal and dendritic processes of 10 projection neurons (PNs) and 15 interneurons (INs) in lamina I of the rat, to reveal quantitative differences in their distribution. We also performed whole-cell patch-clamp recordings to test the predicted function of certain axon collaterals. In line with our earlier qualitative description, we found that lamina I INs in the lateral aspect of the superficial DH send axon collaterals toward the medial part and occupy mostly laminae I-III, providing anatomical basis for a lateromedial flow of information within the DH. Local axon collaterals of PNs were more extensively distributed including dorsal commissural axon collaterals that might refer to those reported earlier linking the lateral aspect of the left and right DHs. PN collaterals dominated the dorsolateral funiculus and laminae IV-VI, suggesting propriospinal and ventral connections. Indeed, patch-clamp recordings confirmed the existence of a dorsoventral excitatory drive upon activation of neurokinin-1 receptors that, although being expressed in various lamina I neurons, are specifically enriched in PNs. In summary, lamina I PNs and INs have almost identical dendritic input fields, while their segmental axon collateral distribution patterns are distinct. INs, whose somata reside in lamina I, establish local connections, may show asymmetry, and contribute to bridging the medial and lateral halves of the DH. PNs, on the other hand, preferably relay their integrated dendritic input to deeper laminae of the spinal gray matter where it might be linked to other ascending pathways or the premotor network, resulting in a putative direct contribution to the nociceptive withdrawal reflex.

Differences in central sensitisation between healthy men and women in Switzerland: a single-centre trial

<h2>Abstract</h2><h3>Background</h3> Many chronic pain conditions exhibit differences between men and women regarding prevalence, pain intensity, or treatment effects. Mechanisms underlying these differences are poorly understood. Central sensitisation, defined as an increased responsiveness of nociceptive neurons in the CNS to normal or subthreshold afferent input, is considered an important mechanism that can differ between men and women with chronic pain conditions. We aimed to assess differences in central sensitisation between healthy men and women, with the hypothesis that central sensitisation is more pronounced in healthy women than in men. <h3>Methods</h3> This single-centre trial followed a within-subject design and was conducted at the Balgrist University Hospital in Switzerland after approval by the Cantonal Ethics Board of Zurich. Healthy, pain-free adults aged 18–40 years with a BMI of less than 30 kg/m² and no history of chronic pain were recruited using advertisement and word-of-mouth. Biological sex (male or female) was self-reported. A validated sensitisation protocol was used by applying a contact thermode to the innervation area of the sural nerve on one foot. A sham protocol was used on the other foot. The protocols were performed in counterbalanced order. All participants were masked to the study design and protocols. The primary endpoint before and after the protocols, was the area of secondary hyperalgesia relative to the thermode, serving as a proxy of central sensitisation. Additionally, the nociceptive withdrawal reflex was repeatedly elicited at the sural nerve with two currents (corresponding to 120% and 140% of the individual reflex threshold current) and recorded from the biceps femoris by surface electromyography. The magnitude of the reflex response in the 90 ms to 150 ms post-elicitation interval was compared before and after the protocols. This study was registered with ClinicalTrials.gov, NCT05031286. <h3>Findings</h3> Between April 22, 2021, and Feb 19, 2022, 66 healthy participants were included in the trial. The median age of participants was 26 years (IQR 21–31) and 33 (50%) were women. Following the sensitisation protocol, secondary hyperalgesia was greater in women than men (12·4 cm² [SD 8·41] <i>vs</i> 8·2 cm² [6·90]; two-sided <i>t</i> test p=0·031). The effect of the sensitisation protocol on the magnitude of the biceps femoris nociceptive withdrawal reflex was stronger in women than in men for both currents (Cohen's d 0·32 <i>vs</i> 0·07 for 120% and 0·31 <i>vs</i> 0·15 for 140% reflex threshold current) with 99·6% versus 95·6% probability (Bayesian normal–normal model). No adverse effects were recorded during the trial. <h3>Interpretation</h3> The two tested outcomes (extent of secondary hyperalgesia and magnitude of the nociceptive withdrawal reflex) indicate that central sensitisation processes are more pronounced in healthy women than men. Because central sensitisation is suggested to influence pain chronification, more pronounced central sensitisation processes might constitute a sex-specific risk factor for developing chronic pain. <h3>Funding</h3> The Swiss National Science Foundation.

Spinal Nociception is Facilitated during Cognitive Distraction

The nociceptive withdrawal reflex (NWR) is a behavioral response to protect the body from noxious stimuli. The spatial characteristics of the stimulus modulate the reflex response to prevent damage to the affected tissue. Interneurons in the deep dorsal horn in the spinal cord encode the relationship between stimulus characteristics and the magnitude of the NWR and are also likely integrating spatial information of the nociceptive stimulus. The aim of this study was to use the NWR to investigate whether the spinal spatial integration of a simultaneous stimulus is modulated by shifting the attention of the participant towards (attention) or away from (distraction) the stimulus. We hypothesized that the descending activity shapes the receptive fields of the spinal neurons encoding spatial integration of nociception. Twenty healthy volunteers participated in the study. Single and simultaneous stimuli were delivered through two stimulating electrodes located in the arch and on the lateral side in the sole of the foot. The NWR was quantified by electromyography from the Tibialis Anterior and Biceps Femoris muscles during baseline and active tasks (attention and distraction). During the baseline task, spatial summation of the NWR was evoked during simultaneous stimulation. During the distraction task, the NWR was significantly larger compared to baseline, regardless of the sites being stimulated (single and simultaneous stimuli). In contrast, the NWR recorded during the attention task did not differ from baseline. These results further support that the spinal NWR pathway is under descending control which can be modulated by cognitive processes. The NWRs recorded over both proximal and distal muscles were similarly affected by the tasks, suggesting that the descending control affects the lower leg spinal system, with no discrimination between spinal segments.

Comparison of Threshold and Tolerance Nociceptive Withdrawal Reflexes in Horses.

Simple SummaryNociception is the physiological basis of the complex experience of pain. An established model for its quantification in equine studies is based on the nociceptive withdrawal reflex evoked by electrical stimulation of a sensory nerve. The reflex is recorded via electromyography and it is common to determine the threshold at which a nociceptive-specific reflex activity can be observed. In the present study, the classical methodology was expanded for a deeper understanding of the physiology of nociceptive reflexes in horses. First, for each individual horse, a threshold was determined as the minimal stimulation intensity able to evoke a nociceptive withdrawal reflex. Second, the stimulation intensity was stepwise increased up to tolerance, which was defined as the stimulus that is able to elicit the maximal tolerable behavioral reaction. The characteristics of the reflex activity on the electromyographic records were compared for threshold and tolerance stimulation intensities. At tolerance, the reflex became faster and wider than at threshold, indicating that either a spinal summation mechanism or the recruitment of faster sensory fibers occurs in response to high-intensity noxious stimuli. A novel endpoint (i.e., tolerance) can now be considered when applying the nociceptive withdrawal reflex model in equine studies.The nociceptive withdrawal reflex (NWR) is used to investigate nociception in horses. The NWR threshold is a classical model endpoint. The aims of this study were to determine NWR tolerance and to compare threshold and tolerance reflexes in horses. In 12 horses, the NWR was evoked through electrical stimulation of the digital nerve and recorded via electromyography from the deltoid. Behavioral reactions were scored from 0 to 5 (tolerance). First, the individual NWR threshold was defined, then stimulation intensity was increased to tolerance. The median NWR threshold was 7.0 mA, whereas NWR tolerance was 10.7 mA. Upon visual inspection of the records, two main reflex components R1 (median latency 44 ms) and R2 (median latency 81 ms) were identified at threshold. Increasing stimulation intensity to tolerance led to a significant increase in the amplitude and duration of R1 and R2, whereas their latency decreased. At tolerance, a single burst of early, high-amplitude reflex activity, with a median latency of 39 ms, was detected in 15 out of 23 stimulations (65%). The results of this study suggest that (1) it is feasible to determine NWR tolerance in horses and (2) high-intensity stimuli initiate ultrafast bursts of reflex activity, which is well known in practice and has now been quantified using the NWR model.

Exploring the effect of capsaicin-induced central sensitization on the upper limb nociceptive withdrawal reflex threshold.

The nociceptive withdrawal reflex (NWR) threshold is commonly employed in the lower limb to assess clinical and experimentally induced pain. However, no studies to date have investigated changes in spinal nociception in the upper limb, via the NWR threshold, following experimentally induced central sensitization (CS). We tested the hypothesis that experimentally induced CS of the C5-C6 spinal segment significantly reduces NWR thresholds in muscles of the upper limb. Upper limb NWR thresholds from 20 young, healthy adults were assessed by applying noxious electrical stimuli to the right index finger and recording muscle activity from the biceps brachii (BI), triceps brachii (TRI), flexor carpi ulnaris (WF), and extensor carpi radialis longus (WE) muscles via surface electromyography. Topical cream (either 0.075% capsaicin, or control) was applied to the C5-C6 dermatome of the lateral forearm (50 cm2). NWR thresholds were compared at baseline, and four 10-min intervals after topical application. WF muscle NWR thresholds were significantly reduced in the capsaicin session compared to control, while TRI muscle NWR thresholds were significantly reduced 40min after capsaicin application only (p < 0.05). There were no significant differences for BI or WE muscle NWR thresholds. We observed poor to moderate test-retest reliability for all upper limb NWR thresholds, a key contributor to the selective reduction in NWR thresholds among muscles. Accordingly, while our findings demonstrate some comparability to previously reported lower limb NWR studies, we concurrently report limitations of the upper limb NWR technique. Further exploration of optimal parameters for upper limb NWR acquisition is needed.

Does feedback based on FES-evoked nociceptive withdrawal reflex condition event-related desynchronization? An exploratory study with brain-computer interfaces

Introduction. Event-related desynchronization (ERD) is used in brain-computer interfaces (BCI) to detect the user’s motor intention (MI) and convert it into a command for an actuator to provide sensory feedback or mobility, for example by means of functional electrical stimulation (FES). Recent studies have proposed to evoke the nociceptive withdrawal reflex (NWR) using FES, in order to evoke synergistic movements of the lower limb and to facilitate the gait rehabilitation of stroke patients. The use of NWR to provide sensorimotor feedback in ERD-based BCI is novel; thererfore, the conditioning effect that nociceptive stimuli might have on MI is still unknown. Objetive. To assess the ERD produced during the MI after FES-evoked NWR, in order to evaluate if nociceptive stimuli condition subsequent ERDs. Methods. Data from 528 electroencephalography trials of 8 healthy volunteers were recorded and analyzed. Volunteers used an ERD-based BCI, which provided two types of feedback: intrisic by the FES-evoked NWR and extrinsic by virtual reality. The electromyogram of the tibialis anterior muscle was also recorded. The main outcome variables were the normalized root mean square of the evoked electromyogram (RMS norm ), the average electroencephalogram amplitude at the ERD frequency during MI () and the percentage decrease of relative to rest () at the first MI subsequent to the activation of the BCI. Results. No evidence of changes of the RMS norm on both the (p = 0.663) and the (p = 0.252) of the subsequent MI was detected. A main effect of the type of feedback was found in the subsequent (p < 0.001), with intrinsic feedback resulting in a larger Conclusions. No evidence of ERD conditioning was observed using BCI feedback based on FES-evoked NWR . Significance. FES-evoked NWR could constitute a potential feedback modality in an ERD-based BCI to facilitate motor recovery of stroke people.

Opioid Specific Effects on Central Processing of Sensation and Pain: A Randomized, Cross-Over, Placebo-Controlled Study

Moderate to severe pain is often treated with opioids, but central mechanisms underlying opioid analgesia are poorly understood. Findings thus far have been contradictory and none could infer opioid specific effects. This placebo-controlled, randomized, 2-way cross-over, double-blinded study aimed to explore opioid specific effects on central processing of external stimuli. Twenty healthy male volunteers were included and 3 sets of assessments were done at each of the 2 visits: 1) baseline, 2) during continuous morphine or placebo intravenous infusion and 3) during simultaneous morphine + naloxone or placebo infusion. Opioid antagonist naloxone was introduced in order to investigate opioid specific effects by observing which morphine effects are reversed by this intervention. Quantitative sensory testing, spinal nociceptive withdrawal reflexes (NWR), spinal electroencephalography (EEG), cortical EEG responses to external stimuli and resting EEG were measured and analyzed. Longer lasting pain (cold-pressor test – hand in 2° water for 2 minutes, tetanic electrical), deeper structure pain (bone pressure) and strong nociceptive (NWR) stimulations were the most sensitive quantitative sensory testing measures of opioid analgesia. In line with this, the principal opioid specific central changes were seen in NWRs, EEG responses to NWRs and cold-pressor EEG. The magnitude of NWRs together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated. The decreases in EEG activity were correlated to subjective unpleasantness scores. Brain activity underlying slow cold-pressor EEG (1-4Hz) was decreased, whereas the brain activity underlying faster EEG (8-12Hz) was increased. These changes were strongly correlated to subjective pain relief. This study points to evidence of opioid specific effects on perception of external stimuli and the underlying central responses. The analgesic response to opioids is likely a synergy of opioids acting at both spinal and supra-spinal levels of the central nervous system. Due to the strong correlations with pain relief, the changes in EEG signals during cold-pressor test have the potential to serve as biomarkers of opioid analgesia. PerspectiveThis exploratory study presents evidence of opioid specific effects on the pain system at peripheral and central levels. The findings give insights into which measures are the most sensitive for assessing opioid-specific effects.