Investigation of directional discrimination in the nociceptive system using temperature-controlled laser stimuli.

BACKGROUND: Cutaneous laser stimulation has commonly been employed to investigate the thermal properties of the nociceptive system. The aim of this study was to investigate how a temperature-controlled laser system improves the assessment of directional discrimination in the nociceptive system. METHODS: In total, twenty healthy volunteers participated in this study. To determine the directional discrimination threshold (stimulation length 50% correct, expressed in mm), thermal stimuli were delivered using a diode laser and the laser beam was perpendicularly displaced across the skin to give a linear stimulation in four different directions (distal, proximal, lateral and medial) and displacement lengths (3 for lateral-medial and 5 for distal-proximal). Two temperature control modes were used in the stimulation system, open-loop and closed-loop control. The subjects had to report the perceived stimulus direction, the degree of certainty regarding the perceived direction and the intensity of the perceived stimulus (0-10 numerical rating scale, 3: pain threshold). RESULTS: During closed-loop control, the orientation of stimuli was discriminated significantly more accurately than during open-loop control. During closed-loop control, the directional discrimination threshold was 31.9 and 26.1 mm for distal-proximal and lateral-medial directed stimuli, respectively. A numerical rating scale was significantly higher for the lateral/medial directions. Moreover, the variability of the discrimination threshold is reduced in the closed-loop control system. CONCLUSIONS: The findings show that discrimination ability is better in the lateral-medial directions compared to the distal-proximal directions. This study indicates that using a system enabling closed-loop temperature control, allows more robust probing of the temporo-spatial mechanisms in the nociceptive system. SIGNIFICANCE: This study shows that a newly developed temperature-controlled laser stimulation system enhances the possibilities to investigate the nociceptive temporo-spatial integration, as shown by a less variable directional discrimination threshold. The results also show that different orthogonal directions are discriminated differently. This new method allows a better investigation of the combined temporal and spatial mechanisms in the nociceptive system.

Influence of skin type and laser wavelength on laser-evoked potentials.

BACKGROUND: Infrared laser stimulation is a valuable tool in pain research, its primary application being the recording of laser-evoked brain potentials (LEPs). Different types of laser stimulators, varying in their skin penetrance, are likely to have a large influence on the LEPs, when stimulating different skin types. The aim of this study was to investigate how LEPs depend on laser type and skin location. METHODS: Two different laser stimulators (CO2 and Nd:YAP) were used to compare LEPs in healthy subjects. Stimuli were delivered to the hand dorsum and palm to investigate the effects of skin type on the evoked responses. Stimulus-evoked brain responses were recorded using EEG and perceived intensity ratings were recorded. Computational modelling was used to investigate the observed differences. RESULTS: LEPs evoked by stimulation of the hairy skin were similar between CO2 and Nd:YAP stimulation. In contrast, LEPs elicited from the palm were markedly different and barely present for CO2 stimulation. There was a significant interaction between laser type and skin type (RM-ANOVA, p < 0.05) likely due to smaller CO2 LEPs in the palm. CO2 stimuli to the palm also elicited significantly lower perceived intensities. The computational model showed that the observed differences were explainable by the laser absorption characteristics and skin thickness affecting the temperature profile at the dermo-epidermal junction (DEJ). CONCLUSIONS: This study shows that LEP elicitation depends on the combination of laser penetrance and skin type. Low penetrance stimuli, from a CO2 laser, elicited significantly lower LEPs and perceived intensities in the palm. SIGNIFICANCE: This study showed that the elicitation of laser-evoked potentials in healthy humans greatly depends on the combination of laser stimulator type and skin type. It was shown that high penetrance laser stimuli are capable of eliciting responses in both hairy and glabrous skin, whereas low penetrance stimuli barely elicited responses from the glabrous skin. Computational modelling was used to demonstrate that the results could be fully explained by the combination of laser type and skin thickness.

A novel temperature-controlled laser system to uniformly activate cutaneous thermal receptors during movable thermal stimulation.

Objective. Laser stimulators have been widely used in pain studies to selectively activate Aδand C nociceptors without coactivation of mechanoreceptors. Temperature-controlled laser systems have been implemented with low-temperature variations during stimulations, however, these systems purely enabled stationary stimulation. This study aimed to implement, test and validate a new laser stimulation system that controls skin temperature by continuously adjusting laser output during stimulus movement to allow accurate investigation of tempo-spatial mechanisms in the nociceptive system.Approach. For validation, laser stimuli were delivered to the right forearm of eight healthy subjects using a diode laser. The laser beam was displaced across the skin to deliver a moving thermal stimulation to the skin surface. To test the function and feasibility of the system, different stimulation parameters were investigated involving two control modes (open-loop and closed-loop), three displacement velocities (5, 10 and 12 mm s-1), two intensities (high 46 °C and low 42 °C), two stimulus lengths (20 and 100 mm) and two directions (distal and proximal).Main results. During closed-loop control, the stimulation error and variation of stimulation temperatures were significantly smaller than during open-loop control. The standard deviation of stimulation temperatures increased significantly with stimulation intensity and displacement length.Significance. This study showed that more accurate, less variable laser stimulations were delivered to the skin using closed-loop control during a movable stimulus. The more uniform skin temperature during stimuli is likely to ensure a more uniform nociceptor activation.

High-speed heating of the skin using a contact thermode elicits brain responses comparable to CO2 laser-evoked potentials.

OBJECTIVE: To compare nociceptive event-related brain potentials elicited by a high-speed contact-thermode vs an infrared CO2 laser stimulator. METHODS: Contact heat-evoked potentials (CHEPs) and CO2 laser-evoked potentials (LEPs) were recorded in healthy volunteers using a high-speed contact-thermode (>200 °C/s) and a temperature-controlled CO2 laser. In separate experiments, stimuli were matched in terms of target surface temperature (55 °C) and intensity of perception. A finite-element model of skin heat transfer was used to explain observed differences. RESULTS: For 55 °C stimuli, CHEPs were reduced in amplitude and delayed in latency as compared to LEPs. For perceptually matched stimuli (CHEPs: 62 °C; LEPs: 55 °C), amplitudes were similar, but CHEPs latencies remained delayed. These differences could be explained by skin thermal inertia producing differences in the heating profile of contact vs radiant heat at the dermo-epidermal junction. CONCLUSIONS: Provided that steep heating ramps are used, and that target temperature is matched at the dermo-epidermal junction, contact and radiant laser heat stimulation elicit responses of similar magnitude. CHEPs are delayed compared to LEPs. SIGNIFICANCE: CHEPs could be used as an alternative to LEPs for the diagnosis of neuropathic pain. Dedicated normative values must be used to account for differences in skin thermal transfer.

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.

Tempo-spatial integration of nociceptive stimuli assessed via the nociceptive withdrawal reflex in healthy humans.

Spatial information of nociceptive stimuli applied in the skin of healthy humans is integrated in the spinal cord to determine the appropriate withdrawal reflex response. Double-simultaneous stimulus applied in different skin sites are integrated, eliciting a larger reflex response. The temporal characteristics of the stimuli also modulate the reflex, e.g., by temporal summation. The primary aim of this study was to investigate how the combined tempo-spatial aspects of two stimuli are integrated in the nociceptive system. This was investigated by delivering single- and double-simultaneous stimulation and sequential stimulation with different interstimulus intervals (ISIs ranging 30-500 ms) to the sole of the foot of 15 healthy subjects. The primary outcome measure was the size of the nociceptive withdrawal reflex (NWR) recorded from the tibialis anterior (TA) and biceps femoris (BF) muscles. Pain intensity was measured using a numerical rating scale (NRS) scale. Results showed spatial summation in both TA and BF when delivering simultaneous stimulation. Simultaneous stimulation provoked larger reflexes than sequential stimulation in TA, but not in BF. Larger ISIs elicited significantly larger reflexes in TA, whereas the opposite pattern occurred in BF. This differential modulation between proximal and distal muscles suggests the presence of spinal circuits eliciting a functional reflex response based on the specific tempo-spatial characteristics of a noxious stimulus. No modulation was observed in pain intensity ratings across ISIs. Absence of modulation in the pain intensity ratings argues for an integrative mechanism located within the spinal cord governed by a need for efficient withdrawal from a potentially harmful stimulus.NEW & NOTEWORTHY Tempo-spatial integration of electrical noxious stimuli was studied using the nociceptive withdrawal reflex and a perceived intensity. Tibialis anterior and biceps femoris muscles were differentially modulated by the temporal characteristics of the stimuli and stimulated sites. These findings suggest that spinal neurons are playing an important role in the tempo-spatial integration of nociceptive information, leading to a reflex response that is distributed across multiple spinal cord segments and governed by an efficient defensive withdrawal strategy.

The two-point discrimination threshold depends both on the stimulation noxiousness and modality.

The two-point discrimination threshold (2PDT) has been used to investigate the integration of sensory information, especially in relation to spatial acuity. The 2PDT has been investigated for both innocuous mechanical stimuli and noxious thermal stimuli; however, previous studies used different stimulation modalities to compare innocuous and noxious stimuli. This study investigated the 2PDT in 19 healthy participants, using both thermal (laser) and mechanical stimulation modalities. Within each modality, both innocuous and noxious intensities were applied. Concurrent point stimuli were applied to the right volar forearm, with separation distances of 0-120 mm, in steps of 10 mm. 0 mm corresponds to a single point. Following each stimulus, the participants indicated the number of perceived points (1 or 2) and the perceived intensity (NRS: 0: no perception, 3: pain threshold, 10: maximum pain). The order of stimulation modality, intensity and distance was randomized. The 2PDT for innocuous and noxious mechanical stimuli was 34.7 mm and 47.1 mm, respectively. For thermal stimuli, the 2PDT was 80.5 mm for innocuous stimuli and 66.9 mm for noxious stimuli. The average NRS for thermal stimuli was 1.6 for innocuous intensities and 4.0 for noxious intensities, while for mechanical stimuli, the average NRS was 0.9 for innocuous intensities and 3.6 for noxious intensities. This study showed that the 2PDT highly depends on both stimulation modality and intensity. Within each modality, noxious intensities modulates the 2PDT differently, i.e., noxious intensities lowers the 2PDT for thermal stimuli, but increases the 2PDT for mechanical stimuli.

Spinal spatial integration of nociception and its functional role assessed via the nociceptive withdrawal reflex and psychophysical measures in healthy humans.

Animal studies have previously shown that deep dorsal horn neurons play a role in the processing of spatial characteristics of nociceptive information in mammals. Human studies have supported the role of the spinal neurons; however, the mechanisms involved, and its significance, remain to be clarified. The aim of this study was to investigate spatial aspects of the spinal integration of concurrent nociceptive electrical stimuli in healthy humans using the Nociceptive Withdrawal Reflex (NWR) as an objective indication of spinal nociceptive processing. Fifteen healthy volunteers participated in the study. Electrical stimuli were delivered, using five electrodes located across the sole of the foot in a mediolateral disposition, as a single or double simultaneous stimuli with varying Inter-Electrode Distances (IEDs). The stimulation intensity was set at 1.5× NWR threshold (TA muscle). The size of the NWR was quantified in the 60-180 ms poststimulus window as a primary outcome measure. Psychophysical measures were secondary outcomes. Single stimulation elicited significantly smaller NWRs and perceived intensity than double stimulation (p < .01), suggesting the presence of spatial summation occurring within the spinal processing. During double stimulation, increasing the inter-electrode distance produced significantly smaller NWR sizes (p < .05) but larger pain intensity ratings (p < .05). By the NWR, spatial summation was shown to affect the nociceptive processing within the spinal cord. The inhibited motor response obtained when simultaneously stimulating the medial and lateral side of the sole of the foot suggests the presence of an inhibitory mechanism with a functional, behaviorally oriented function.

New Insights into Cutaneous Laser Stimulation - Dependency on Skin and Laser Type.

Cutaneous laser stimulation is a proficient tool to investigate the function of the nociceptive system. However, variations in laser-skin interactions, causes by different skin anatomies and laser wavelength, affects the robustness of nociceptor activation. Thus, thoroughly understanding how the skin is heated by a laser pulse is important to characterize the thermal response properties of nociceptors. The study aim was to investigate how skin type and laser wavelength influences nociceptor activation during laser stimulation. Ten healthy subjects were exposed to brief CO2 (low skin penetrance) and Nd:YAP (high skin penetrance) laser stimuli delivered to the dorsum and palm of the hand, using three different intensities. Reaction times and perception intensities were recorded. A computational model simulated heat transfer in the skin and nociceptor activation in different skin types across different wavelengths and intensities. Intensity ratings were significantly lower and reaction-times significantly increased for CO2 laser stimuli in the palm compared to the dorsum. This was not the case for Nd:YAP laser stimuli. The computational model showed that these differences can be explained by the different skin absorption of CO2 and Nd:YAP lasers. For CO2 laser stimuli, the thicker stratum corneum of the glabrous skin reduces nociceptor activation, whereas the high penetrating Nd:YAP laser elicits a similar nociceptor activation, irrespective of skin type. Nociceptor activation during laser stimulation highly depends on skin composition and laser wavelength, especially for lasers having a low penetrance wavelength. A computational model showed that this difference could be explained primarily due to differences in skin composition.

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.

Cutaneous nociceptive sensitization affects the directional discrimination - but not the 2-point discrimination.

Background and aims Several pain conditions have been shown to reduce the discriminative abilities of external stimuli. The aim of this study was to investigate how cutaneous sensitization affects the tempo-spatial discrimination for both painful laser stimulation and mechanical stimulation. Methods Fifteen healthy subjects were presented with two different stimulation paradigms, a continuous line stimulation and a 2-point stimulation. Line stimulations were delivered in two different directions in lengths of 25, 50, 75, and 100 mm. Two-point distances from 0 to 100 mm were tested. The subjects reported the perceived intensity, and either direction (line stimulations) or number of perceived points (2-point stimulations). All stimuli were tested both before and after topical capsaicin (8% concentration) sensitization (30 min). Results All mechanical line stimulations were reported correctly before capsaicin and 3 stimulations (out of 240) were reported incorrectly after capsaicin. For the laser line stimulation, the directional discrimination threshold (DDT) was 69.5 mm before capsaicin and 76.3 mm after capsaicin. The 2-point discrimination threshold for laser stimulation was 70.3 mm before capsaicin and 68.0 mm after, for the mechanical stimuli it was 31.5 mm before capsaicin and 31.0 mm after capsaicin. The perceived intensities were increased for the laser line stimulations after capsaicin (linear mixed model (LMM), p < 0.001) and increased with stimulation length (LMM, p < 0.001). For mechanical stimuli, NRS was increased following capsaicin (LMM, p < 0.001). The intensities for both mechanical and laser 2-point stimuli increased after capsaicin and increased with distance between points (LMM, p < 0.01). Conclusions The findings show how cutaneous sensitization appears to affect directional discrimination to a larger extent than the 2-point discrimination. Implications This study is the first to investigate how directional discrimination is altered during sensitization. If such measures can be optimized they may provide a new method to probe the neural mechanisms in pain patients.

Tempo-spatial discrimination is lower for noxious stimuli than for innocuous stimuli.

The exteroceptive sensory system is responsible for sensing external stimuli in relation to time and space. The aim of this study was to investigate the tempo-spatial properties of the exteroceptive system using painful laser heat and nonpainful mechanical touch stimulation. Thirteen healthy subjects were stimulated on the volar forearm using 2 paradigms: a continuous stimulation along a line on the skin and a 2-point stimulation. The line stimulations were delivered in both the distal and proximal direction with lengths of 25, 50, 75, and 100 mm. The 2-point stimulations were assessed by simultaneous stimuli at a point-to-point distance ranging from 10 to 100 mm, in steps of 10 mm. The subjects reported the intensity (0-10 numeric rating scale, 3: pain threshold) and either direction (line stimuli) or number of perceived points (2-point stimuli). All mechanical line stimulations were reported correctly, ie, a directional discrimination threshold of less than 25 mm. For painful laser line stimulation, the directional discrimination threshold was 68.5 and 70.2 mm for distally and proximally directed stimuli, respectively. The 2-point discrimination threshold for painful laser stimulation (67.9 mm) was higher than for the mechanical stimulation (34.5 mm). Numeric rating scale increased both with line length and distance between the 2 points (linear mixed model, P < 0.001). The findings indicate that the tempo-spatial acuity of the exteroceptive system is lower for noxious stimuli than for innocuous stimuli. This is possible due to the larger receptive fields of nociceptive neurons and/or less lateral inhibition.

Membrane properties in small cutaneous nerve fibers in humans.

INTRODUCTION: Assessment of membrane properties is important for understanding the mechanisms of painful peripheral neuropathy, developing new diagnostic techniques, and screening/profiling of analgesics that target ion channels. METHODS: Small cutaneous nerves were activated electrically by small diameter (0.2 mm) cathodes, and large nerves were activated by ordinary patch electrodes. This new perception threshold tracking method combines perception threshold assessment and stimulation paradigms from conventional threshold tracking. RESULTS: The strength-duration time-constant of large fibers (580 µs ± 160 µs) was lower than the time constant of small fibers (1060 µs ± 690 µs; P < 0.01, paired t-test). Threshold electrotonus showed similar threshold reductions to sub-threshold prepulses, except for 80 ms hyperpolarizing prepulses, to which small fibers showed less threshold reduction than large fibers (repeated-measures analysis of variance, Bonferroni, P = 0.006). CONCLUSIONS: This is a reliable method to investigate the membrane properties of small cutaneous nerve fibers in humans and may be used in clinical settings as a diagnostic or profiling tool. Muscle Nerve 55: 195-201, 2017.

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.

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.

Distinct temporal filtering mechanisms are engaged during dynamic increases and decreases of noxious stimulus intensity.

Physical stimuli are subject to pronounced temporal filtering during afferent processing such that changes occurring at certain rates are amplified and others are diminished. Temporal filtering of nociceptive information remains poorly understood. However, the phenomenon of offset analgesia, where a disproportional drop in perceived pain intensity is caused by a slight drop in noxious heat stimulation, indicates potent temporal filtering in the pain pathways. To develop a better understanding of how dynamic changes in a physical stimulus are constructed into an experience of pain, a transfer function between the skin temperature and the perceived pain intensity was modeled. Ten seconds of temperature-controlled near-infrared (970 nm) laser stimulations above the pain threshold with a 1°C increment, decrement, or constant temperature were applied to the dorsum of the hand of healthy human volunteers. The skin temperature was assessed by an infrared camera. Offset analgesia was evoked by laser heat stimulation. The estimated transfer functions showed shorter latencies when the temperature was increased by 1°C (0.53 seconds [0.52-0.54 seconds]) than when decreased by 1°C (1.15 seconds [1.12-1.18 seconds]) and smaller gains (increase: 0.89 [0.82-0.97]; decrease: 2.61 [1.91-3.31]). The maximal gain was observed at rates around 0.06 Hz. These results show that temperature changes occurring around 0.06 Hz are best perceived and that a temperature decrease is associated with a larger but slower change in pain perception than a comparable temperature increase. These psychophysical findings confirm the existence of differential mechanisms involved in temporal filtering of dynamic increases and decreases in noxious stimulus intensity.

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.

Experimental and model-based analysis of differences in perception of cutaneous electrical stimulation across the sole of the foot.

During electrocutaneous stimulations, variation in skin properties across locations can lead to differences in neural activation. However, little focus has been given to the effect of different skin thicknesses on neural activation. Electrical stimulation was applied to six sites across the sole of the foot. The intensities used were two and four times perception threshold. The subjects (n = 8) rated the perception quality and intensity using the McGill Pain Questionnaire and a visual analog scale (VAS). A finite element model was developed and combined with the activation function (AF) to estimate neural activation. Electrical stimulation was perceived as significantly less sharp at the heel compared to all other sites, except one site in the forefoot (logistic regression, p < 0.05). The VAS scores were significantly higher in the arch than at the heel (RM ANOVA, p < 0.05). The model showed that the AF was between 91 and 231 % higher at the five other sites than at the heel. The differences in perception across the sole of the foot indicated that the CNS received different inputs depending on the stimulus site. The lower AF at the heel indicated that the skin thicknesses could contribute to the perceived differences.

Analysis of muscle fiber conduction velocity enables reliable detection of surface EMG crosstalk during detection of nociceptive withdrawal reflexes.

BACKGROUND: The nociceptive withdrawal reflex (NWR) is a polysynaptic spinal reflex that induces complex muscle synergies to withdraw a limb from a potential noxious stimulus. Several studies indicate that assessment of the NWR is a valuable objective tool in relation to investigation of various pain conditions. However, existing methodologies for NWR assessment evaluate standard surface electromyography (sEMG) measured over just one muscle and do not consider the possible interference of crosstalk originating from adjacent active muscles. The present study had two aims: firstly, to investigate to which extent the presence of crosstalk may affect NWR detection using a standardized scoring criterion (interval peak z-score) that has been validated without taking crosstalk into consideration. Secondly, to investigate whether estimation of muscle fiber conduction velocity can help identifying the propagating and non-propagating nature of genuine reflexes and crosstalk respectively, thus allowing a more valid assessment of the NWR. RESULTS: Evaluation of interval peak z-score did apparently allow reflex detection with high sensitivity and specificity (0.96), but only if the influence of crosstalk was ignored. Distinction between genuine reflexes and crosstalk revealed that evaluation of interval peak z-score incorporating a z-score threshold of 12 was associated with poor reflex detection specificity (0.26-0.62) due to the presence of crosstalk. Two different standardized methods for estimation of muscle fiber conduction velocity were employed to demonstrate that significantly different muscle fiber conduction velocities may be estimated during genuine reflexes and crosstalk, respectively. This discriminative feature was used to develop and evaluate a novel methodology for reflex detection from sEMG that is robust with respect to crosstalk. Application of this conduction velocity analysis (CVA) entailed reflex detection with excellent sensitivity (1.00 and 1.00) and specificity (1.00 and 0.96) for the tibialis anterior and soleus muscles. CONCLUSION: This study investigated the negative effect of electrical crosstalk during reflex detection and revealed that the use of a previously validated scoring criterion may result in poor specificity due to crosstalk. The excellent performance of the developed methodology in the presence of crosstalk shows that assessment of muscle fiber conduction velocity allows reliable detection of EMG crosstalk during reflex detection.

Novel cross correlation technique allows crosstalk resistant reflex detection from surface EMG.

Existing methods for withdrawal reflex detection from surface electromyography (sEMG) do not consider the potential presence of electrical crosstalk, which in practical applications may entail reduced detection accuracy. This study estimated muscle fiber conduction velocities (CV) for the tibialis anterior (TA) and soleus (SOL) muscles of both genuine reflexes and identified crosstalk, measured during antagonistic reflex responses. These estimations were used to develop and assess a novel method for reflex detection resistant to crosstalk. Cross correlations of two single differential (SD) sEMG signals recorded along the muscle fibers were performed and two features were extracted from the resulting correlograms (average CV and maximal cross correlation). Reflex detection based on evaluation of the extracted features was compared to a conventional reflex detection method (thresholding of interval peak z-scores), applied on both SD and double differential (DD) sEMG. Intramuscular electromyography (iEMG) was used as validation for reflex detection. Apparent CV due to electrical crosstalk alone were more than one order of magnitude higher than CV estimated for genuine reflexes. Conventional reflex detection showed excellent sensitivity but poor specificity (0.19-0.76) due to the presence of crosstalk. In contrast, cross correlation analysis allowed reflex detection with significantly improved specificity (0.91-0.97). The developed methodology may be readily implemented for more reliable reflex detection.