No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Direct isolation of ultra-late (C-fibre) evoked brain potentials by CO2 laser stimulation of tiny cutaneous surface areas in man
Abstract
In this study, it is reported that CO2 laser heat stimulation of tiny skin surface area (0.15 mm2) provides a unique method to directly and selectively activate C-fibre as assessed by the ultra-late brain potentials (peak latencies: N810, P996) evoked consistently across a set of stimulus energy levels. On a larger surface area (15.5 mm2), low energy stimulation also resulted in minute ultra-late potential, while higher intensities induced only late potentials related to A-delta fibre activity (peak latencies: N247, P394). The selective activation of C afferent sensory terminals in the skin by stimulation of tiny surface area is explained by their relative high density and lower activation threshold.
... Remaining epochs (23 ± 3) were averaged for each participant, stimulation site and time point. C-fiber laser-evoked potentials (CLEPs) were defined as in previous studies (Bragard et al., 1996;Jankovski et al., 2013). Two distinct peaks were identified (N2 and P2; Figure 3). ...
... Here we show similarly to Bragard et al. (1996) that CO2 laser heat stimuli delivered to tiny cutaneous surface areas can selectively activate heat-sensitive C-fibers. Indeed, the reaction times and the latency of the LEPs are compatible with the conduction velocity of unmyelinated fibers (Otsuru et al., 2009). ...
... Indeed, the reaction times and the latency of the LEPs are compatible with the conduction velocity of unmyelinated fibers (Otsuru et al., 2009). Important to note, the difference in LEP N2 latency between the study of Bragard et al. (1996) and the present study can be explained by the different conduction distances related to the different body parts that were stimulated (hand dorsum vs. volar forearm). The LEPs of the present study are not related to the activation of Aδ-fiber nociceptors. ...
Key points:
A recent animal study showed that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation at the spinal cord that is hypothesized to mediate secondary hyperalgesia in humans. Here this hypothesis was tested by predominantly activating C-fibre nociceptors in the area of secondary mechanical hyperalgesia induced by HFS in humans. It is shown that heat perception elicited by stimuli predominantly activating C-fibre nociceptors is greater, as compared to the control site, after HFS in the area of secondary mechanical hyperalgesia. This is the first study that confirms in humans the involvement of C-fibre nociceptors in the changes in heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS.
Abstract:
It has recently been shown that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation (LTP) at the spinal cord in animals, which has been hypothesized to be the underlying mechanism of secondary hyperalgesia in humans. Here we tested this hypothesis using a method to predominantly activate quickly responding C-fibre nociceptors in the area of secondary hyperalgesia induced by HFS in humans. HFS was delivered to one of the two volar forearms in 18 healthy volunteers. Before, 20 min and 45 min after HFS, short-lasting (10 ms) high-intensity CO2 laser heat stimuli delivered to a very small area of the skin (0.15 mm2 ) were applied to the area of increased mechanical pinprick sensitivity at the HFS-treated arm and the homologous area of the contralateral control arm. During heat stimulation the electroencephalogram, reaction times and intensity of perception (numerical rating scale 0-100) were measured. After HFS, we observed a greater heat sensitivity, an enhancement in the number of detected trials, faster reaction times and an enhancement of the N2 wave of C-fibre laser-evoked potentials at the HFS-treated arm compared to the control arm. This is the first study that confirms in humans the involvement of C-fibre nociceptors in enhanced heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS.
... The two nociceptive pathways (Aδ-and C-fibers) have distinct anatomical and physiological characteristics. By exploiting the differences in heat activation threshold [2][3][4] and epidermal nerve fiber density [2,5,6], it is possible to conceive experimental conditions that allow selective activation of Aδ-and C-fibers. ...
... This curve is experimentally validated in this study. To increase the probability of selective Aδ-or C-fiber activation, the application of a spatial filter seems a feasible method based on the differences in epidermal nerve fiber distribution [2,6]. ...
... The usage of the two different stimulation protocols combined with the spatial filter has increased the probability of [6,7]. ...
Background: Pain is perceived through different pathways involving thinly myelinated Aδ-fibers and unmyelinated C-fibers. Aδ-fibers are responsible for a quick, sharp pain, whereas C-fibers relate to a late-onset, burning sensation. Several studies suggest that it is essential to investigate nociceptive fibers separately and in relation to each other. The aim of this study was to selectively stimulate Aδ-and C-fibers using a 980-nm diode laser by varying the laser settings and the stimulated surface area in healthy subjects.
... In order to record C-LEP, the laser stimulation was carried out according to Bragard and co-workers protocol [24] that obtained the direct isolation of C-LEP from tiny cutaneous surfaces by means of a CO 2 laser. The laser stimuli (wavelength 1.34μm, pulse duration 10ms, 4mm beam diameter) were directed to the skin area of the right trigeminal maxillary branch region, close to the nasus-genius sulcus, but a thin aluminium disk, drilled with calibrated holes (~0.15mm 2 ) was interposed just above the skin surface [24]. ...
... In order to record C-LEP, the laser stimulation was carried out according to Bragard and co-workers protocol [24] that obtained the direct isolation of C-LEP from tiny cutaneous surfaces by means of a CO 2 laser. The laser stimuli (wavelength 1.34μm, pulse duration 10ms, 4mm beam diameter) were directed to the skin area of the right trigeminal maxillary branch region, close to the nasus-genius sulcus, but a thin aluminium disk, drilled with calibrated holes (~0.15mm 2 ) was interposed just above the skin surface [24]. Stimulus intensity was individually adapted in the HC individuals, so that sensations reported ranged from "barely detectable" to "slight pain". ...
... Indeed, there are two main problems in C-LEP recording: i) the preceding Aδ-LEP may hinder the following C-LEP; and ii) the extremely low range of conduction speed of the unmyelinated fibers limits the necessary synchronization of the input to produce a clear signal from the scalp (in fact, C-LEP have been mainly investigated in facial territories). There are two main methods to record C-LEP: i) Bragard et al. [24] and Opsommer et al. [30] employed a laser beam passing through a grid with micro-spots, without any substantial Aδ-LEP interference; and ii) Iannetti et al. [13] and Cruccu et al. [31] used very large and low-energy laser beams, directly focused on skin, thus stimulating warmth receptors of the skin overlying the spine. ...
It has been shown that the presence of Aδ-fiber laser evoked potentials (Aδ-LEP) in patients suffering from chronic disorders of consciousness (DOC), such as vegetative state (VS) and minimally conscious state (MCS), may be the expression of a residual cortical pain arousal. Interestingly, the study of C-fiber LEP (C-LEP) could be useful in the assessment of cortical pain arousal in the DOC individuals who lack of Aδ-LEP. To this end, we enrolled 38 DOC patients following post-anoxic or post-traumatic brain injury, who met the international criteria for VS and MCS diagnosis. Each subject was clinically evaluated, through the coma recovery scale-revised (CRS-R) and the nociceptive coma scale-revised (NCS-R), and electrophysiologically tested by means of a solid-state laser for Aδ-LEP and C-LEP. VS individuals showed increased latencies and reduced amplitudes of both the Aδ-LEP and C-LEP components in comparison to MCS patients. Although nearly all of the patients had both the LEP components, some VS individuals showed only the C-LEP ones. Notably, such patients had a similar NCS-R score to those having both the LEP components. Hence, we could hypothesize that C-LEP generators may be rearranged or partially spared in order to still guarantee cortical pain arousal when Aδ-LEP generators are damaged. Therefore, the residual presence of C-LEP should be assessed when Aδ-LEP are missing, since a potential pain experience should be still present in some patients, so to properly initiate, or adapt, the most appropriate pain treatment.
... The LEPs related to Aδ-fibers and C-fiber activations are characterized by different latencies reflecting different conduction velocities (CV) of these fibers in the peripheral nerves and spinal cord [4]. Differences in heat activation threshold and epidermal distribution density have been used to activate C-fibers separately [5,6]. Furthermore, when nerve compression was used to selectively block Aδ-fibers 'ultra-late' LEPS were isolated [7]. ...
... Our study questions the feasibility of the 'grid method' for generating an ultra-late LEP response in healthy subjects. In literature the 'grid method' is presented as the most eligible technique for stimulating C-fibers and generating corresponding ultra-late LEP responses [4,6]. However, as our study and former literature demonstrates, the selective activation of C-fiber receptors and recording of the related 'ultra late LEP' brain potentials remains difficult [13]. ...
... with none of the responses at latencies related to signals ascending through C-fibers 5,6 . Responses mediated exclusively by C-fibers, an ultra-late LEP (ULEP) at a latency of about 1000 ms, can be elicited only by special methods that allow their selective activation, such as low-power heating of the skin below Aδ threshold 7,8 , pressure nerve block 9 or the stimulation of tiny skin surfaces 10 . It is not clear yet why concomitant activation of Aδ-and C-fibers does not allow the individualization of both late and ultra-late LEPs 6,11,12,13 , interestingly, depending on the intensity of stimulation, both responses can occasionally be observed 7 , also related to this issue is the recent suggestion that laser pulses may also occasionally, in special circumstances, lead to tactile sensations 14 . ...
... Our results indicate that reproducible C-fiber evoked responses can be obtained using a low-power diode laser applied to tiny areas of blackened skin. Using this stimulation protocol, the ULEP was consistently elicited with latencies in accordance with those reported in other studies that used high-power CO 2 lasers applied to small areas of natural (non-blackened) skin 10,27,28,29,30 . The few investigators that have previously employed the darkening procedure reported only Aδ responses after high-intensity stimulation in three subjects 5 or have not focused on laser-evoked potentials, but on subjective pain and thermal thresholds 21,31 . ...
Objective
The evaluation of selective activation of C-fibers to record evoked potentials using the association of low-power diode laser (810 nm), tiny-area stimulation and skin-blackening.
Method
Laser-evoked potentials (LEPs) were obtained from 20 healthy young subjects. An aluminum plate with one thin hole was attached to the laser probe to provide tiny-area stimulation of the hand dorsum and the stimulated area was covered with black ink.
Results
The mean intensity used for eliciting the ultra-late laser-evoked potential (ULEP) was 70 ± 32 mW. All subjects showed a clear biphasic potential that comprised a negative peak (806 ± 61 ms) and a positive deflection (1033 ± 60 ms), corresponding to the ULEP related to C-fiber activation.
Conclusion
C-fiber-evoked responses can be obtained using a very low-power diode laser when stimulation is applied to tiny areas of darkened skin. This strategy offers a non-invasive and easy methodology that minimizes damage to the tissue.
... These fibers conduct more slowly than Aδ-fibers supposed to be involved in N2 and P2 generation and are already excited by lower stimulation temperature. It is hypothesized, that as long as Aδ-fiber mediated potentials occur, no C-fiber evoked potential can be recorded (Bragard et al., 1996;Opsommer et al., 1999;Qiu et al., 2001). In contrast to the simultaneous appearance of Aδ-and C-fiber mediated evoked potentials in disease (Granot et al., 2001) this has not been confirmed in healthy subjects (Mouraux and Plaghki, 2007). ...
... Furthermore, for being evoked by C-fiber excitation, this late component occurs too early when compared to the related painful laser stimulation (Baumgartner et al., 2005;Bragard et al., 1996;Magerl et al., 1999;Opsommer et al., 1999;Qiu et al., 2001;Truini et al., 2007). Due to this uncertain identity of the late positive component use of the earlier and more constant N2 as CHEP read out parameter seems generally recommendable. ...
Physical disability following spinal cord injury (SCI) is the most striking problem noted
by the general public. But for the affected subjects urogenital difficulties or
depression and pain are often more burdensome. Pain after SCI can have various
reasons but only neuropathic pain below the level of lesion (bNP) is thought to be
caused by injury of the spinal nervous tissue. This type of pain is in the focus of this
thesis. Once bNP has established it is mostly chronic and medication is generally
ineffective. Currently, more and more treatments trying to restore function after SCI
enter the clinical trial phase. Besides improving function, however, treatments
increasing nerve growth in the spinal cord risk to induce or exacerbate bNP.
Therefore, observation of bNP is a crucial factor in such interventional studies. A
method to objectively supervise bNP has, however, not yet been established.
The spinothalamic tract (STT) mainly transmits nociceptive and temperature
information in the spinal cord. This tract was dysfunctional in SCI subjects suffering
from bNP in clinical examinations. Nevertheless, STT dysfunction was not predictive
for bNP and sensory differences between subjects with and without bNP could not be
detected. In contrast to clinical examination which is always subjective and only
offers limited resolution, electrophysiological measures allow for a more detailed and
objective investigation.
The novel electrophysiological method of contact heat evoked potentials (CHEP)
measures STT function. Establishment of this method was the goal of the first study.
The painful stimulation on locations along the spine allowed the calculation of the
conduction velocity of the STT in healthy subjects. Furthermore the CHEP latency
depended linearly on the heat pain threshold with 1° C higher threshold leading to
approximately 10 ms longer latency. It was hypothesized that the rather low heating
rate combined with the time-consuming passive heat spread from skin surface to
nociceptors was responsible for this.
The second study aimed at clarifying this dependence through comparison of the
results of study 1 with those of a theoretical heat transfer model. According to this
model, 1° C higher pain threshold leads to approximately 15 ms longer CHEP
latency. The close similarity between the experimentally determined (study 1) and the
computed dependence, proved the influence of the pain threshold on CHEP latency.
Summary
Electrophysiological markers for Neuropathic Pain in SCI Subjects 2
Subjects suffering from neuropathic pain (NP) in general and not only in SCI, have
lowered EEG peak frequency. It was hypothesized in literature that the reduced EEG
peak frequency emerged from thalamic deafferentiation and from the ensuing
dysrhythmia in thalamocortical feedback loops. Therefore, the third study
investigated EEG peak frequency in addition to STT function and compared both
between SCI subjects with and without bNP and controls. The STT function
(measured with CHEP) below the level of injury was distinctly impaired in SCI
compared to control subjects. Furthermore, the EEG peak frequency was generally
lower in the SCI subjects. While the CHEP measurements did not reveal differences
between subjects with and without bNP, the EEG peak frequency was lowered in
subjects with bNP. This difference, however, was only apparent after the linear
dependence of EEG peak frequency from the level of SCI was taken into account. In
consideration of this dependence, the EEG peak frequency could in future be helpful
to supervise bNP both in studies aiming at restoring function or reducing pain after
SCI.
Currently, the clinical read-out parameter for STT function is pinprick sensation. In
the fourth study this pinprick sensation was traced over the first year after SCI.
Comparison of this STT function with the bNP state of the same subjects 2-5 years
after SCI disclosed larger functional STT recovery in subjects suffering from bNP.
Despite the different STT functional recovery, the initial and end measurements did
not discriminate between subjects with and without bNP. This was in agreement with
earlier studies. The results corroborate the above mentioned hypothesis that new
therapies intending to promote sensorimotor recovery after SCI could simultaneously
induce bNP by boosting recovery of spinothalamic function.
... In tES, several approaches have been conducted to evaluate the EF in the target region, including electrode montage (Bikson et al., 2010;Edwards et al., 2013;Opitz et al., 2015;Mikkonen et al., 2020;Salvador et al., 2021;Caulfield and George, 2022), multi-pair (channel) of tES electrodes (Datta et al., 2009;Khan et al., 2022), as well as uncertainty analysis (Saturnino et al., 2019b) and microscopic skin modeling (Gomez-Tames et al., 2016;Khadka and Bikson, 2020). One difficulty in the stimulation of the deep brain region is how to shape the EF in the target region because the EF is significantly affected by the head anatomy and tissue conductivity (Bragard et al., 1996;Gomez-Tames et al., 2018). Since the individualized human head modeling has become widely used, the optimization of the EF at individual level and group level using statistical analysis has been conducted (Laakso et al., 2015;Gomez-Tames et al., 2019a). ...
Electrode montage optimization for transcranial electric stimulation (tES) is a challenging topic for targeting a specific brain region. Targeting the deep brain region is difficult due to tissue inhomogeneity, resulting in complex current flow. In this study, a simplified protocol for montage optimization is proposed for multichannel tES (mc-tES). The purpose of this study was to reduce the computational cost for mc-tES optimization and to evaluate the mc-tES for deep brain regions. Optimization was performed using a simplified protocol for montages under safety constraints with 20 anatomical head models. The optimization procedure is simplified using the surface EF of the deep brain target region, considering its small volume and non-concentric distribution of the electrodes. Our proposal demonstrated that the computational cost was reduced by >90%. A total of six–ten electrodes were necessary for robust EF in the target region. The optimization with surface EF is comparable to or marginally better than using conventional volumetric EF for deep brain tissues. An electrode montage with a mean injection current amplitude derived from individual analysis was demonstrated to be useful for targeting the deep region at the group level. The optimized montage and injection current were derived at the group level. Our proposal at individual and group levels showed great potential for clinical application.
... Methodological differences such as inter-electrode distance, leading to differences in spatial summation [28,33], needle type (bipolar vs. unipolar), stimulus duration (2 ms in [39] vs. 0.04 ms in [1] and the current study), and the use of different muscles might explain divergent findings across studies. The pain quality for EPT cutan in the current study was most often "stinging" and "pricking," most probably corresponding to the stimulation of Aδ fibers [7,20], and with the 3rd most common sensation "burning" assumably corresponding to the stimulation of nociceptive C fibers [9,10], in line with findings of Schilder and colleagues [40]. Pathophysiologically, "burning" pain quality is also considered as a prototypical descriptor for neuropathic pain [8]. ...
To advance evidence-based practice and targeted treatments of low back pain (LBP), a better pathophysiological understanding and reliable outcome measures are required. The processing of nociceptive information from deeper somatic structures (e.g., muscle, fascia) might play an essential role in the pathophysiology of LBP. In this study, we measured the intra- and inter-session reliability of electrical detection and pain thresholds of cutaneous and muscle primary afferents of the lower back. Twenty healthy participants attended two study visits separated by 27.7 ± 1.7 days. To determine the location-specific electrical detection threshold (EDT) and pain threshold (EPT), needle electrodes were inserted in the epidermal layer over, and in the lumbar erector spinae muscle. Additionally, established quantitative sensory testing (QST) parameters were assessed. Reliability was determined by differences between measurements, intraclass correlation coefficients (ICC2,1), Bland–Altman plots, and standard error of measurement (SEM). Correspondence between QST parameters and electrical thresholds was assessed using Pearson’s correlation. Except for cutaneous EPT, no significant (p ≤ 0.05) intra- and inter-session differences were observed. Excellent intra-session reliability was shown for cutaneous and intramuscular electrical stimulations and all QST parameters (ICC: 0.76–0.93). Inter-session reliabilities were good (ICC: 0.74–0.75) except for electrical stimulations (ICC: 0.08–0.36). Limits of agreement and SEM were higher for inter-session than intra-session. A medium to strong relationship was found between electrical and mechanical/pressure pain thresholds. In conclusion, cutaneous and intramuscular electrical stimulation will potentially close an important diagnostic gap regarding the selective examination of deep tissue afferents and provide location-specific information for the excitability of non-nociceptive and nociceptive afferents.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00424-023-02851-7.
... However, previous studies demonstrated that selective activation of C fbers could be obtained with specifc LEP recording modalities [3] elicited ultralate LEPs (U-LEPs) from the hand, using a thulium laser on a tiny surface skin area (0.23 mm). Such a method is based on the higher density of C nociceptors as compared to a-delta nociceptors in the skin [4]. Despite the U-LEPs were obtained in allthe 9 healthy subjects, an earlier complex appeared as a correlate of Aδ fbers recruitment. ...
Introduction:
Although laser stimuli activate both Ad- and C-fibres, the corresponding laser evoked potentials (LEPs) remain restricted to the Ad-fibers input, while the C-fibers related potential is hardly detectable.
Aims:
To evaluate multichannel ultralate LEPs (U-LEPs) by using Nd : Yap laser pulses in healthy volunteers to stimulation of face and lower and upper limbs, in order to estimate the reliability of C-LEPs elicited from both trigeminal and somatic sites.
Methods:
Twenty healthy volunteers participated in two stimulation sessions to record Aδ-LEPs and C-LEPs. We used a Nd : YAP Laser and 62 EEG recording electrodes. Stimuli parameters were set to activate either small myelinated (Aδ), eliciting purely warmth sensations, or unmyelinated (C) afferents, and eliciting pinprick sensations.
Results:
At the trigeminal level, we obtained a negative-positive complex in a time interval compatible with the C fibers activation. In the somatic districts, the averaged responses consisted of an earlier negative-positive complex, followed by a later one. Single trials analysis of U-LEPs showed a maximal positive peak in a time interval in the range of C fibers. Topographical analysis of U-LEPs resembled that of LEPs. All subjects exhibited readable U-LEPs in at least 2 stimulated sites. Discussion. A purely warmth sensation seems to correspond to Aδ and C-fibers coactivation, at least in the somatic districts. While the related cortical waves seem hardly readable, their total absence could be a sign of systemic involvement of warm related C-fibers in specific clinical conditions.
... Based on differences in the distribution of C and Ad nociceptors (Ad < C), Plaghki's group reported the successful stimulation of C nociceptors by laser beams for the first time (Bragard et al., 1996). They stimulated a tiny area of the skin with a laser beam that was expected to hit C nociceptors exclusively: the results supported this. ...
Nerve conduction studies (NCS) are an essential aspect of the assessment of patients with peripheral neuropathies. However, conventional NCS do not reflect activation of small afferent fibers, including Aδ and C fibers. A definitive gold standard for laboratory evaluation of these fibers is still needed and therefore, clinical evaluation remains fundamental in patients with small fiber neuropathies (SFN). Several clinical and research techniques have been developed for the assessment of small fiber function, such as (i) microneurography, (ii) laser evoked potentials, (iii) contact heat evoked potentials, (iv) pain-related electrically evoked potentials, (v) quantitative thermal sensory testing, (vi) skin biopsy-intraepidermal nerve fiber density and (vii) corneal confocal microscopy. The first five are physiological techniques, while the last two are morphological. They all have advantages and limitations, but the combined use of an appropriate selection of each of them would lead to gathering invaluable information for the diagnosis of SFN. In this review, we present an update on techniques available for the study of small afferent fibers and their clinical applicability. A summary of the anatomy and important physiological aspects of these pathways, and the clinical manifestations of their dysfunction is also included, in order to have a minimal common background.
... (55). After applying a 0.5-30 Hz finite impulse response band-pass filter (56)(57)(58), data were segmented into epochs extending from −100 ms to +1,500 ms relative to stimulus onset (56,57,59,60). Epochs were baseline corrected using the −100 to 0 ms window (56,58,60) and then visually inspected to reject epochs with artifacts (amplitude value exceeding ± 100 μV) (56-58, 61). ...
Musculoskeletal injuries lead to sensitization of nociceptors and primary hyperalgesia (hypersensitivity to painful stimuli). This
occurs with back injuries, which are associated with acute pain and increased pain sensitivity at the site of injury. In some cases,
back pain persists and leads to central sensitization and chronic pain. Thus, reducing primary hyperalgesia to prevent central
sensitization may limit the transition from acute to chronic back pain. It has been shown that spinal manipulation (SM) reduces
experimental and clinical pain, but the effect of SM on primary hyperalgesia and hypersensitivity to painful stimuli remains
unclear. The goal of the present study was to investigate the effect of SM on pain hypersensitivity using a capsaicin-heat pain
model. Laser stimulation was used to evoke heat pain and the associated brain activity, which were measured to assess their
modulation by SM. Eighty healthy participants were recruited and randomly assigned to one of the four experimental groups:
inert cream and no intervention; capsaicin cream and no intervention; capsaicin cream and SM at T7; capsaicin cream and placebo.
Inert or capsaicin cream (1%) was applied to the T9 area. SM or placebo were performed 25 minutes after cream application. A
series of laser stimuli were delivered on the area of cream application 1) before cream application, 2) after cream application but
before SM or placebo, and 3) after SM or placebo. Capsaicin cream induced a significant increase in laser pain (p<0.001) and laser�evoked potential amplitude (p<0.001). However, SM did not decrease the amplification of laser pain or laser-evoked potentials by
capsaicin. These results indicate that segmental SM does not reduce pain hypersensitivity and the associated pain-related brain
activity in a capsaicin-heat pain model.
... There are several techniques for selective stimulation of thin fibres based on the electrophysiological differences among peripheral fibres: radiant heat stimulation by lasers for Aδ-fibres (Bromm et al., 1983;Bragard et al., 1996;Magerl et al., 1999;Opsommer et al., 2001;Nahra and Plaghki, 2003;Churyukanov et al., 2012) and intraepidermal electrical stimulation (IES) for both C-and Aδ-fibres (Inui et al., 2002). ...
Electrical stimulation of small fibres is gaining attention in the diagnosis of peripheral neuropathies, such as diabetes mellitus, and pain research. However, it is still challenging to characterise the electrical characteristics of axons in small fibres (Aδ and C fibres). In particular, in vitro measurement for human Aδ-fibre is difficult due to the presence of myelin and ethical reason. In this study, we investigate the in vivo electrical characteristics of the human Aδ-fibre to derive strength–duration (S–D) curves from the measurement. The Aδ-fibres are stimulated using coaxial planar electrodes with intraepidermal needle tip. For human volunteer experiments, the S–D curve of Aδ-fibre is obtained in terms of injected electrical current. With the computational analysis, the standard deviation of the S–D curve is mostly attributed to the thickness of the stratum corneum and depth of the needle tip, in addition to the fibre thickness. Then, we derive electrical parameters of the axon in the Aδ-fibre based on a conventional fibre model. The parameters derived here would be important in exploring the optimal stimulation condition of Aδ-fibres.
... Furthermore, it has been suggested that in conditions of skin inflammation or after capsaicin application, receptive fields behave dynamically and insensitive branches of mechanosensitive C-nociceptors can become responsive (Schmelz et al., 1994). Another difference between Ad-and Cfiber afferents could be receptor density, as it has been suggested that Ad-nociceptors are less densely distributed than Cnociceptors (Bragard et al., 1996;Rage et al., 2010). Furthermore, it is increasingly recognized that non-neuronal cells may contribute to the transduction of nociceptive stimuli applied onto the skin. ...
Localized neuropathic pain can be relieved following the topical application of high-concentration capsaicin. This clinical effect is thought to be related to the temporary desensitization of capsaicin- and heat-sensitive epidermal nociceptors. The objective of the present study was to examine whether the changes in thermal sensitivity induced by high-concentration topical capsaicin can be explained entirely by desensitization of capsaicin-sensitive afferents. For this purpose, we characterized, in 20 healthy human volunteers, the time course and spatial extent of the changes in sensitivity to thermal stimuli preferentially activating heat-sensitive A-fiber nociceptors, heat-sensitive C-fiber afferents, and cool-sensitive A-fiber afferents. The volar forearm was treated with a high-concentration capsaicin patch for 1 h. Transient heat, warm and cold stimuli designed to activate Aδ- and C-fiber thermonociceptors, C-fiber warm receptors, and Aδ-fiber cold receptors were applied to the skin before and after treatment at days 1, 3, and 7. Reaction times, intensity ratings, and quality descriptors were collected. The stimuli were applied both within the capsaicin-treated skin and around the capsaicin-treated skin to map the changes in thermal sensitivity. We found that topical capsaicin selectively impairs heat sensitivity without any concomitant changes in cold sensitivity. Most interestingly, we observed a differential effect on the sensitivity to thermal inputs conveyed by Aδ- and C-fibers. Reduced sensitivity to Aδ-fiber-mediated heat was restricted to the capsaicin-treated skin, whereas reduced sensitivity to C-fiber-mediated heat extended well beyond the treated skin. Moreover, the time course of the reduced sensitivity to C-fiber-mediated input was more prolonged than the reduced sensitivity to Aδ-fiber-mediated input.
... Later in the ERP waveform, a component specific to input from unmyelinated afferents has been identified. This ultra-late potential (ULP), first identified as a specific response to laser evoked stimulation of C-nociceptive fibres is recorded over frontal brain regions (Bragard, Chen, & Plaghki, 1996;Bromm & Lorenz, 1998;Bromm, Neitzel, Tecklenburg, & Treede, 1983;Valeriani et al., 2013). A ULP evoked by CT-targeted touch has also been reported (Ackerley, Eriksson, & Wessberg, 2013) in response to brush strokes delivered to the ventral surface of the forearm at a CT-optimal velocity (Ackerley et al., 2013). ...
The sense of touch is primarily considered a discriminative and exteroceptive sense, facilitating the detection, manipulation and exploration of objects, via an array of low threshold mechanoreceptors and fast conducting Aβ afferents. However, a class of unmyelinated, low threshold mechanoreceptors identified in the hairy skin of mammals have been proposed to constitute a second, anatomically distinct system coding the affective qualities of touch. Unlike Aβs, which increase their firing rate linearly with the velocity of a stimulus moving across their receptive field, the response of these C‐tactile afferents (CTs) is described by an inverted ‘U’ curve fit, responding optimally to a skin temperature stimulus moving at between 1‐10cm/s. Given the distinct velocity tuning of these fast and slow touch fibres, here we used ERPs to compare the time course of neural responses to 1st (fast) and 2nd (slow) touch systems. We identified a higher amplitude P300 in response to fast, Aβ targeted, versus slow CT‐targeted, stroking touch. In contrast, we identified a previously described, C‐fibre specific, ultra‐late‐potential (ULP) associated with CT‐targeted input. Of special note as regards the function of CTs is that the amplitude of the ULP was negatively correlated with self‐reported levels of autistic traits, which is consistent with the hypothesised affective and social significance of this response. Taken together these findings provide further support for distinct discriminative and affective touch systems and suggests the temporal resolution of EEG provides an as yet underutilised tool for exploring individual differences in response sensitivity to CT targeted touch.
... Studies using laser-heat as a model to investigate the nociceptive system at the dorsal horn of the spinal cord [133][134][135] , and at the brain 91,99,110,114,115,127,[136][137][138][139][140][141][142][143] , used laser with beam diameters down to 1 mm. While Devor and coworkers observed mainly that dorsal horn neurons responding to laser-heat stimuli were located in superficial and deep zones from the dorsal horn, and were able to evoke potentials through signals mediated by C-polymodal nociceptors 133 ; Sikandar and collaborators extended those observations by recordings in dorsal horn neurons in the spinal segment L4-L5 in rodents and detected response latencies to different laser intensities mediated by both C-(in all power intensities) and Aδ-fiber afferents (only at higher power intensities) 134 . ...
Noxious heat is a natural stimulus that activates peripheral sensory neurons expressing heat-gated ion channels. Recently, the TRPM3 channel emerged as a noxious heat sensor independent of TRPV1, which is also sensitive to the neurosteroid Pregnenolone sulphate (PS). Recently, evidence of a direct mechanism that controls the agonist-induced TRPM3 channel activity by activation of the µ-opioid receptor (MOR) has been described, through direct binding of the G-beta-gamma subunit to TRPM3. The submitted thesis investigated mechanisms of heat-induced nociception using near-infrared laser stimulation as a rapid and accurate way to apply noxious heat. Responses to laser-heat were analyzed: in vitro by functional assays on heterologous expression systems and primary culture of sensory neurons, and in vivo by behavioral experiments and electrophysiological recordings at the dorsal horn of the spinal cord. Laser-heat activates TRPV1 and TRPM3 channels in heterologous expression systems with activation thresholds of about 574 µJ and 615 µJ. The response amplitudes of TRPM3 upon activation with PS exceeded those of maximum laser stimulation (1.5 ± 0.003 of the ratio 340/380 versus 0.66 ± 0.011). Chemical- and thermal- induced activity of the TRPM3 channel co-expressing the MOR was reduced with DAMGO by 63.4% and 44.5%. In DRGs, 15-25% of all neurons analyzed (n= 550) functionally co-expressed TRPV1 and TRPM3, 38% expressed TRPV1 independent of TRPM3, 7-8% expressed TRPM3 but not TRPV1. DRG neurons displayed a direct inhibition by 18 ± 4.1% and 23 ± 3% when co-applying the MOR agonist DAMGO with PS. In the dorsal horn of the spinal cord, the processing of peripheral laser stimulation was carried out by a subset of WDR and HTM neurons, which were found at all depths of the dorsal horn (range: 120-820 µm). Laser-heat stimuli induced pain-behavior in vivo. All neurons that responded to suprathreshold laser-heat were nociceptive, including one third of WDR neurons and half of HTM neurons investigated. No laser-heat responses of LTM neurons were found. The peripheral input of the laser sensitive neurons was composed of C- and A- fibers; however, responses to laser-heat were transmitted by C-fibers. The sizes of the heat receptive fields ranged 10% - 60% of the mechanical receptive field and they located always inside them. The number of AP following laser stimulation was higher in HTM neurons compared to WDR neurons (14 ± 0.7 vs 9 ± 4.3), however not significant, and the latencies after onset of the laser stimulation were 266 ± 16 ms and 308.3 ± 55. The estimated temperature threshold for laser sensitive WDR neurons and HTM neurons (40.1 °C and 43.3 °C) was comparable to the mean heat withdrawal threshold in awake rats (41 °C). Differences in the proportions of neurons expressing TRPM3 and/or TRPV1 could be responsible for those differences in receptive field sizes. Since the threshold for laser-heat activation of the TRPM3 channel was higher than the threshold for TRPV1, a greater proportion of peripheral neurons containing TRPM3 might converge in dorsal horn laser sensitive HTM neurons than for laser sensitive WDR neurons.
... The majority of functional brain imaging studies on pain have described cortical responses associated with A-delta-fibermediated pain, or a combination of A-delta and C-fiber pain. Selective C-fiber stimulation, although quite difficult, can be provided by using conduction blockade of A-delta fibers or by applying weak (2-4 J/s) temperature-controlled laser heat stimuli to a tiny (0.4 mm diameter) skin area (Bragard et al., 1996;Kakigi et al., 2003;Forss et al., 2005). The physiological basis for this stimulus selectivity is the higher density and lower activation threshold of the C-than A-delta fibers of the skin. ...
Magnetoencephalography (MEG) records weak magnetic fields outside the human head and thereby provides millisecond-accurate information about neuronal currents supporting human brain function. MEG and electroencephalography (EEG) are closely related complementary methods and should be interpreted together whenever possible.
This manuscript covers the basic physical and physiological principles of MEG and discusses the main aspects of state-of-the-art MEG data analysis. We provide guidelines for best practices of patient preparation, stimulus presentation, MEG data collection and analysis, as well as for MEG interpretation in routine clinical examinations.
In 2017, about 200 whole-scalp MEG devices were in operation worldwide, many of them located in clinical environments. Yet, the established clinical indications for MEG examinations remain few, mainly restricted to the diagnostics of epilepsy and to preoperative functional evaluation of neurosurgical patients. We are confident that the extensive ongoing basic MEG research indicates potential for the evaluation of neurological and psychiatric syndromes, developmental disorders, and the integrity of cortical brain networks after stroke. Basic and clinical research is, thus, paving way for new clinical applications to be identified by an increasing number of practitioners of MEG.
... An earlier and smaller negative wave with a latency of 150-180 ms is detected at the temporal regions and is less affected by the patient's attention than the earlier signal, providing an advantage in terms of the reliability of the signal and, therefore, the definition of the abnormal responses in the clinical setting 181,182 . Specific techniques can be used to elicit ultra-late potentials with latencies of 750-1200 ms that are related to activation of C-fibres [183][184][185][186] . Abnormal laser-evoked potential latency indicates conduction abnormalities in the thermal nociceptive pathway, which includes peripheral nerves, plexus, roots, spinal cord and brainstem 181 . ...
Technical advances are rapidly changing the clinical and instrumental approach to peripheral nerve diseases. Magnetic resonance neurography, diffusion tensor imaging and nerve ultrasonography are increasingly entering the diagnostic workup of peripheral neuropathies as tools that complement neurophysiology and enable investigation of proximal structures, such as plexuses and roots. Progress in the design of magnetic resonance scanners and sequences, and the development of high-frequency ultrasound probes mean that high-resolution peripheral nerve imaging is possible, enabling detailed examination of nerve size, morphology and internal fascicular structure that can integrate nerve conduction studies into clinical practice. In the growing field of small-fibre neuropathy, in which traditional nerve conduction studies are of little or no use, skin biopsy has become a reliable tool for diagnosis. Corneal confocal microscopy, nociceptive evoked potentials and microneurography are emerging techniques that are mainly used in clinical research settings, but have increasing relevance to clinical practice. We review these new and emerging techniques and their effects on diagnosis, treatment strategies and prognosis in a variety of peripheral neuropathies, including entrapments, brachial plexopathies, immune and inherited neuropathies, and small-fibre neuropathies. We discuss the most promising research findings and their potential for future application in clinical practice.
... Free nerve endings of Aδ and C fibres are located in the epidermis, while mechanoreceptors of the tactile system in the upper layer of the dermis. Radiant heat stimulation by laser beams has been used in the study of nociception and pain perception in humans (Bromm et al 1983, Bragard et al 1996, Magerl et al 1999, Opsommer et al 2001, Nahra and Plaghki 2003, Churyukanov et al 2012. The reason for this trend is that laser stimulation, unlike conventional electrical stimulation, is able to stimulate Aδ-fibres selectively. ...
The in situ electric field in the peripheral nerve of the skin is investigated to discuss the selective stimulation of nerve fibres. Coaxial planar electrodes with and without intra-epidermal needle tip were considered as electrodes of a stimulator. From electromagnetic analysis, the tip depth of the intra-epidermal electrode should be larger than the thickness of the stratum corneum, the electrical conductivity of which is much lower than the remaining tissue. The effect of different radii of the outer ring electrode on the in situ electric field is marginal. The minimum threshold in situ electric field (rheobase) for free nerve endings is estimated to be 6.3 kV m−1. The possible volume for electrostimulation, which can be obtained from the in situ electric field distribution, becomes deeper and narrower with increasing needle depth, suggesting that possible stimulation sites may be controlled by changing the needle depth. The injection current amplitude should be adjusted when changing the needle depth because the peak field strength also changes. This study shows that intra-epidermal electrical stimulation can achieve stimulation of small fibres selectively, because Aβ-, Aδ-, and C-fibre terminals are located at different depths in the skin.
... Indeed, C-fibers can preferentially be activated when very small cutaneous surfaces are stimulated (i.e., less than 1 mm 2 ). Because C-fibers have a higher density than Aδ-fibers (Messlinger, 1996;, stimulating very small cutaneous surfaces increases the probability that only C-fibers are activated during each stimulation (Bragard, Chen, & Plaghki, 1996). With an infrared absorption coefficient (IAC) of the skin of 30 cm-1 at 1,470 nm (very similar to water's IAC, the skin containing approximately 70% water), the skin temperature increase during the stimulation is theoretically about 30°C; less in practice, due to light diffusion and thermal conduction within the skin. ...
Le vieillissement s’accompagne de changements de la perception de la douleur, avec notamment des modifications des seuils de douleur. L’objectif de ce travail de thèse était de déterminer les mécanismes sous-jacents à ces changements. Nous nous sommes basés sur l’étude de deux indicateurs : des données psychophysiques (i.e., jugements perceptifs) et des mesures électrophysiologiques. Nos premiers tests ont confirmé une diminution de la douleur perçue chez les séniors. Une série de 4 expérimentations nous a ensuite permis de montrer que l'augmentation du seuil de douleur chez les séniors avait à la fois une origine périphérique (i.e., atteinte des fibres sensorielles) et centrale (i.e., modification cérébrale). Au niveau périphérique, nous avons montré que seules les fibres myélinisées (fibres A delta) semblent altérées par le vieillissement. Au niveau central, nos résultats vont dans le sens d'un seuil de douleur augmenté en raison d'un déficit attentionnel chez les séniors.
... Because the N2P2 resulting from A∂ excitation is similar in morphology and topology to the ultra-late potential (Bragard et al., 1996, Opsommer et al., 2003 visualized when Aδ fibers are blocked, it is a possibility that they result from the same cortical generator (Bromm and Treede, 1987, Mouraux and Plaghki, 2006. Thus, it was proposed by several researchers that the reason the ultra-late potential was not visualized without A∂ suppression was that the generator was in a refractory period . ...
PhD Dissertation from Neuro and Cognitive Sciences Program, University of Maryland
... By this electrode arrangement, a high current intensity is gained when choosing low current stimulation. Furthermore, the electrical stimulation caused a pin-prick sensation that is a phenomenon associated with the excitation of Aδ -fiber nociceptors (42)(43)(44), and the NCVs achieved by stimulating these concentric electrodes fall within the range of Aδ-fibers (10,12,45,46). No PREP were detected at up to 2.5 mA of electrical stimulation intensity after topical application of lidocaine, which leads to a selective loss of thermal and pain sensation, but does not affect tactile sensation (47). ...
To investigate the usefulness of pain-related evoked potentials (PREP) elicited by electrical stimulation for the identification of small fiber involvement in patients with mixed fiber neuropathy (MFN). Eleven MFN patients with clinical signs of large fiber impairment and neuropathic pain and ten healthy controls underwent clinical and electrophysiological evaluation. Small fiber function, electrical conductivity and morphology were examined by quantitative sensory testing (QST), PREP, and skin punch biopsy. MFN was diagnosed following clinical and electrophysiological examination (chronic inflammatory demyelinating neuropathy: n = 6; vasculitic neuropathy: n = 3; chronic axonal neuropathy: n = 2). The majority of patients with MFN characterized their pain by descriptors that mainly represent C-fiber-mediated pain. In QST, patients displayed elevated cold, warm, mechanical, and vibration detection thresholds and cold pain thresholds indicative of MFN. PREP amplitudes in patients correlated with cold (p < 0.05) and warm detection thresholds (p < 0.05). Burning pain and the presence of par-/dysesthesias correlated negatively with PREP amplitudes (p < 0.05). PREP amplitudes correlating with cold and warm detection thresholds, burning pain, and par-/dysesthesias support employing PREP amplitudes as an additional tool in conjunction with QST for detecting small fiber impairment in patients with MFN.
... The earliest methods described were based on experimental pressure-block of group A fibres [9] or spectral analysis of the expected time windows [1]. Since then, a number of easier techniques have been proposed, such as the stimulation of tiny skin areas [7,54], selection of single trials devoid of A␦-LEPs [65] or stimulation at low intensity [13,49,67]. Each of these procedures is based on different physiological principles. ...
... Laser stimulators currently represent the most accurate tool for experimental studies of pain, 6 as they activate Ad-and Cnociceptors selectively and elicit sensations of "pure" pain without touch. 2,4,14,15 For these reasons, laser stimulation is considered the gold standard to investigate pain psychophysically and electrophysiologically, and it has been used in hundreds of human and rat studies. 7,12,13,24,25,28,34,45,46,48,52,55,57 Because of the different conduction velocity of Ad (;15 m/s) and C (;1 m/s) afferents, laser pulses elicit a double sensation: an initial Ad-related pricking pain is followed by a C-related burning pain. ...
Natural selection has shaped the physiological properties of sensory systems across species, yielding large variations in their sensitivity. Here, we used laser stimulation of skin nociceptors, a widely-used technique that is considered the gold standard to investigate pain in rats and humans, to provide a vivid example of how ignoring these variations can lead to serious misconceptions in sensory neuroscience. In six experiments, we characterized and compared the physiological properties of the electrocortical responses elicited by laser stimulation in rats and humans. We recorded the electroencephalogram (EEG) from the surface of the brain in freely-moving rats, and from the scalp in healthy humans. Laser stimuli elicited two temporally-distinct EEG responses, traditionally interpreted as reflecting the concomitant activation of different populations of nociceptors with different conduction velocities: small-myelinated Aδ-fibres and unmyelinated C-fibres. Our results show that this interpretation is valid in humans, but not in rats. Indeed, the early response recorded in rats does not reflect the activation of the somatosensory system, but of the auditory system by laser-generated ultrasounds. These results have wide implications: retrospectively, as they prompt for a reconsideration of a large number of previous interpretations of electrocortical rat recordings in basic, preclinical, and pharmacological research, and prospectively, as they will allow recording truly pain-related cortical responses in rats.This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivatives 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
... There was also a trend for smaller amplitude in the L 1 T condition in the time window of the C-P2 wave. 3 Figure 5 shows the average LBR waveforms in the L and L 1 T conditions. In both conditions, laser stimulation of the hand evoked a clear blink reflex with an onset latency of approximately 110 milliseconds. ...
The neural mechanisms of the powerful analgesia induced by touching a painful body part are controversial. A long tradition of neurophysiological studies in anaesthetized, spinal animals indicate that touch can gate nociceptive input at spinal level. In contrast, recent studies in awake humans have suggested that supra-spinal mechanisms can be sufficient to drive touch-induced analgesia. To investigate this issue, we evaluated the modulation exerted by touch on established electrophysiological markers of nociceptive function at both subcortical and cortical levels in humans. Aδ and C skin nociceptors were selectively activated by high-power laser pulses. As markers of subcortical and cortical function, we recorded the Laser-Blink Reflex (LBR), which is generated by brainstem circuits prior to the arrival of nociceptive signals at the cortex, and Laser-Evoked Potentials (LEPs), which reflect neural activity of a wide array of cortical areas. If subcortical nociceptive responses are inhibited by concomitant touch, supraspinal mechanisms alone are unlikely to be sufficient to drive touch-induced analgesia. Touch induced a clear analgesic effect, suppressed the LBR, and inhibited both Aδ-fibre and C-fibre LEPs. Thus, we conclude that touch induced-analgesia is likely to be mediated by a subcortical gating of the ascending nociceptive input, which in turn results in a modulation of cortical responses. Hence, supra-spinal mechanisms alone are not sufficient to mediate touch-induced analgesia.
... Although laser stimuli activate both A␦ and C fibers [26], the 'ultralate' potentials (750-1200 ms), related to C-fiber activation, can be obtained only with dedicated techniques, limiting its clinical applicability [25,39,83,142]. ...
... We did not elicit a clearly painful sensation with contact heat stimuli that evoked a cerebral potential mediated by C fibers without evidence for Aδ fiber excitation. The inability to evoke pain reliably, if at all, with single, brief C fiber selective stimuli is in accord with previous studies [9,14,17,27,29,31,[33][34][35][36][37]. Indeed, when psychophysical measures have been obtained, these brief C fiber stimuli have been rated below pain threshold. ...
... Indeed, it has been reported that C-LEPs can be recorded either in patients lacking myelinated afferents (Treede et al., 1988a;Lankers et al., 1991;Cruccu et al., 2003) or in healthy subjects using elegant but sophisticated techniques that avoid the activation of A␦-fibers by exploiting the different physiological properties of A␦-and C-nociceptors (Towell et al., 1996;Magerl et al., 1999). These techniques include using laser beams of extremely small diameters to exploit the higher density of C-fibers than A␦-fibers (Bragard et al., 1996), performing a nerve com- Figure 4. Relationship between LEP amplitude and subjective pain intensity. Left, Group-level average LEP waveforms, sorted according to perceived pain intensity (from 0 to 10, in steps of 1). ...
Intense radiant heat pulses concomitantly activate Aδ- and C-fiber skin nociceptors, and elicit a typical double sensation: an initial Aδ-related pricking pain is followed by a C-related prolonged burning sensation. It has been repeatedly reported that C-fiber laser-evoked potentials (C-LEPs) become detectable only when the concomitant activation of Aδ-fibers is avoided or reduced. Given that the saliency of the eliciting stimulus is a major determinant of LEPs, one explanation for these observations is that the saliency of the C-input is smaller than that of the preceding Aδ-input. However, even if the saliency of the C-input is reduced because of the preceding Aδ-input, a C-LEP should still be visible even when preceded by an Aδ-LEP response. Here we tested this hypothesis by applying advanced signal processing techniques (peak alignment and time-frequency decomposition) to electroencephalographic data collected in two experiments conducted in 34 and 96 healthy participants. We show that, when using optimal stimulus parameters (delivering >80 stimuli within a small skin territory), C-LEPs can be reliably detected in most participants. Importantly, C-LEPs are observed even when preceded by Aδ-LEPs, both in average waveforms and single trials. By providing quantitative information about several response properties of C-LEPs (latency jitter, stimulus-response and perception-response functions, dependency on stimulus repetitions and stimulated area), these results define optimal parameters to record C-LEPs simply and reliably. These findings have important clinical implications for assessing small-fiber function in neuropathies and neuropathic pain.
... Because the N2P2 resulting from A∂ excitation is similar in morphology and topology to the ultra-late potential (Bragard et al., 1996, Opsommer et al., 2003 visualized when Aδ fibers are blocked, it is a possibility that they result from the same cortical generator (Bromm and Treede, 1987, Mouraux and Plaghki, 2006. Thus, it was proposed by several researchers that the reason the ultra-late potential was not visualized without A∂ suppression was that the generator was in a refractory period . ...
... A second proposed method is based on the difference in the thermal activation threshold between A␦-and C-fibers, and heats the skin above the threshold of C-fibers but below the threshold of A␦-fibers [5,6]. A third proposed method takes advantage of the fact that the distribution density of C-fiber free nerve endings in the epidermis is greater than that of A␦-fibers [7,8]. ...
Intra-epidermal electric stimulation (IES) is an alternative to laser stimulation for selective activation of cutaneous Aδ-fibers. IES is based on the fact that nociceptive fiber terminals are located in the epidermis, whereas receptors of other fibers end deep in the dermis. IES can selectively stimulate C-fibers if the electrode structure and stimulation parameters are carefully selected. However, stable selective stimulation of C-fibers using IES has proven difficult and cannot currently be used in clinical settings. The purpose of the present study was to determine if IES performed using a modified electrode reliably stimulates C-fibers. Magnetoencephalographic responses to IES to the foot were measured in seven healthy subjects. IES elicited somatosensory evoked fields in all subjects. The mean peak latency was 1327±116ms in the opercular region contralateral to the stimulated side, 1318±90ms in the opercular region ipsilateral to the stimulated side, and 1350±139ms in the primary somatosensory cortex. These results indicate that IES performed using the modified electrode can selectively stimulate C-fibers and may be a useful tool for pain research as well as clinical evaluation of peripheral small fiber function.
... Indeed, C-fibers can preferentially be activated when very small cutaneous surfaces are stimulated (i.e., less than 1 mm 2 ). Because C-fibers have a higher density than Aδ-fibers (Messlinger, 1996;Ochoa & Mair, 1969), stimulating very small cutaneous surfaces increases the probability that only C-fibers are activated during each stimulation (Bragard, Chen, & Plaghki, 1996). With an infrared absorption coefficient (IAC) of the skin of 30 cm-1 at 1,470 nm (very similar to water's IAC, the skin containing approximately 70% water), the skin temperature increase during the stimulation is theoretically about 30°C; less in practice, due to light diffusion and thermal conduction within the skin. ...
Aging is associated with changes in thermosensitivity and decreases in the functionality of the autonomic thermoregulation. The underlying mechanisms are, however, not fully understood. Elderly subjects may undergo functional changes in the integration process of the thermal sensory system, especially in their thermal adaptation capacities. To verify this hypothesis, we compared thermal evoked responses in younger and older subjects exposed to thermoneutral (27°C) and warm (30°C) environments. In the warm environment, the amplitudes of thermal evoked potentials (EPs) were significantly lower in older than in younger subjects, whereas in the thermoneutral environment, the EP amplitudes were similar in both groups. These findings suggest that thermal adaptation capacities are reduced in elderly individuals, due to a dysfunction of C-fibers with aging, particularly expressed by lowered adaptation capacities to temperature variations.
The clinical investigation of the skin sensory function is well codified. For long, a cotton pad, a needle, a diapason (100 or 128 Hz), hot or cold water have been the main tools used by clinicians. Pieces of different fabrics or other various objects in metal, wood, or plastic which can be calibrated can also be used. It is then possible to investigate the perception of shapes, weights and textures. However these tools are not standardised and their main drawback is their selection by the investigator. Quantitative exploration, more adapted to clinical research and psychophysiology, requires several standardised and reproducible techniques which necessitate a more costly and complicated equipment.
Objectives
In 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.
Methods
In 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.
Results
Regarding 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.
Conclusions
Using 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.
Clinical neurophysiologic investigation of pain pathways in humans is based on specific techniques and approaches, since conventional methods of nerve conduction studies and somatosensory evoked potentials do not explore these pathways. The proposed techniques use various types of painful stimuli (thermal, laser, mechanical, or electrical) and various types of assessments (measurement of sensory thresholds, study of nerve fiber excitability, or recording of electromyographic reflexes or cortical potentials). The two main tests used in clinical practice are quantitative sensory testing and pain-related evoked potentials (PREPs). In particular, PREPs offer the possibility of an objective assessment of nociceptive pathways. Three types of PREPs can be distinguished depending on the type of stimulation used to evoke pain: laser-evoked potentials, contact heat evoked potentials, and intraepidermal electrical stimulation evoked potentials (IEEPs). These three techniques investigate both small-diameter peripheral nociceptive afferents (mainly Aδ nerve fibers) and spinothalamic tracts without theoretically being able to differentiate the level of lesion in the case of abnormal results. In routine clinical practice, PREP recording is a reliable method of investigation for objectifying the existence of a peripheral or central lesion or loss of function concerning the nociceptive pathways, but not the existence of pain. Other methods, such as nerve fiber excitability studies using microneurography, more directly reflect the activities of nociceptive axons in response to provoked pain, but without detecting or quantifying the presence of spontaneous pain. These methods are more often used in research or experimental study design. Thus, it should be kept in mind that most of the results of neurophysiologic investigation performed in clinical practice assess small fiber or spinothalamic tract lesions rather than the neuronal mechanisms directly at the origin of pain and they do not provide objective quantification of pain.
Introduction/objectives:
Verbal descriptors are an important pain assessment parameter. The purpose of this study was to explore the ability to discriminate deep muscle pain and overlying fascia pain according to verbal descriptors and compare the pattern with skin stimulation (from previously published data).
Methods:
In 16 healthy human subjects, electrical stimulation was chosen to excite a broad spectrum of nociceptive primary afferents innervating the respective tissues. The 24-item Pain Perception Scale (Schmerzempfindungsskala [SES]) was used to determine the induced pain quality.
Results:
Overall, affective (P = 0.69) and sensory scores (P = 0.07) were not significantly different between muscle and fascia. Factor analysis of the sensory descriptors revealed a stable 3-factor solution distinguishing superficial thermal ("heat pain" identified by the items "burning," "scalding," and "hot") from superficial mechanical ("sharp pain" identified by the items "cutting," "tearing," and "stinging") and "deep pain" (identified by the items "beating," "throbbing," and "pounding"). The "deep pain" factor was more pronounced for muscle than fascia (P < 0.01), whereas the other 2 factors were more pronounced for fascia (both P < 0.01). The patterns of skin and fascia matched precisely in sensory factors and on single-item level.
Conclusion:
The differences in sensory descriptor patterns between muscle and fascia may potentially guide treatment towards muscle or fascia in low back pain physiotherapeutic regimes. The similarity of descriptor patterns between fascia and skin, both including the terms "burning" and "stinging," opens the possibility that neuropathic back pain (when the dorsal ramus of the spinal nerve is affected) may be confused with low back pain of fascia origin.
There is now compelling evidence that selective stimulation of Aδ nociceptors eliciting first pain evokes robust responses in the primary somatosensory cortex (S1). In contrast, whether the C-fiber nociceptive input eliciting second pain has an organized projection to S1 remains an open question. Here, we recorded the electrocortical responses elicited by nociceptive-specific laser stimulation of the four limbs in 202 humans (both males and females, using EEG) and 12 freely moving rats (all males, using ECoG). Topographical analysis and source modeling revealed in both species, a clear gross somatotopy of the unmyelinated C-fiber input within the S1 contralateral to the stimulated side. In the human EEG, S1 activity could be isolated as an early-latency negative deflection (C-N1 wave peaking at 710–730 ms) after hand stimulation, but not after foot stimulation because of the spatiotemporal overlap with the subsequent large-amplitude supramodal vertex waves (C-N2/P2). In contrast, because of the across-species difference in the representation of the body surface within S1, S1 activity could be isolated in rat ECoG as a C-N1 after both forepaw and hindpaw stimulation. Finally, we observed a functional dissociation between the generators of the somatosensory-specific lateralized waves (C-N1) and those of the supramodal vertex waves (C-N2/P2), indicating that C-fiber unmyelinated input is processed in functionally distinct somatosensory and multimodal cortical areas. These findings demonstrated that C-fiber input conveys information about the spatial location of noxious stimulation across the body surface, a prerequisite for deploying an appropriate defensive motor repertoire.
The clinical investigation of the skin sensory function is well codified. For long, a cotton pad, a needle, a diapason (100 or 128 Hz), hot or cold water have been the main tools used by clinicians. Pieces of different fabrics or other various objects in metal, wood, or plastic which can be calibrated can also be used. It is then possible to investigate the perception of shapes, weights and textures. However these tools are not standardised and their main drawback is their selection by the investigator. Quantitative exploration, more adapted to clinical research and psychophysiology, requires several standardised and reproducible techniques which necessitate a more costly and complicated equipment.
Background and objectivesSearch strategyDefinitionsClinical examination and psychophysiological measuresLaboratory tests
Magnetoencephalography is sensitive primarily to current sources tangential to the skull. Therefore, currents generated in area 3b of primly somatosensory cortex (S1) and area 4 of primary motor cortex located on the posterior and anterior banks of the central sulcus, respectively, are easily detected. The SEFs generated by peripheral mixed nerve stimulation (e.g., median nerve) have been widely used to investigate the physiology of normal somatosensory cortical processing. In this chapter, we describe various SEF components elicited by median nerve simulation and their modulation by stimulus intensity and frequency, interfering stimulation, movement, age, medication, and disease. In addition, we describe the characteristics of SEFs generated by stimulation of various nerves and body parts and of those generated by different stimulus modalities, for example, stimulation by transcutaneous electrical currents, pneumatics, brushes, pins driven by piezoelectric actuators, lasers, intraepidermal electrical currents, intramuscular motor point, and passive movement.
Wir berichten über eine veröffentlichte Studie [5], in der die Eignung zweier thermischer Stimulationsverfahren, namentlich der Thermodenstimulation sowie der Laserstimulation, im Rahmen der mechanismenorientierten Schmerz-diagnostik untersucht wurde. Die ge-wonnenen Erkenntnisse sind mit Blick auf die quantitative sensorische Testung (QST; [11]) und des darin verwandten Thermodenverfahrens klinisch bedeut-sam.
Objectives:
Laser-evoked potentials (LEP) were assessed after peripheral nerve block of the lateral femoral cutaneous nerve (LFCN) in healthy volunteers from partially anesthetized skin areas to differentially stimulate mechano-insensitive nociceptors.
Methods:
An ultrasound-guided nerve block of the LFCN was performed in 12 healthy male subjects with Ropivacain 1%. After 30 min, the nerve block induced significantly larger anesthetic areas to mechanical stimuli than to electrical stimuli revealing an area of differential sensitivity. LEPs, reaction times and pain ratings were recorded in response to the laser stimuli of (1) completely anesthetic skin, (2) mechano-insensitive, but electrically excitable skin ('differential sensitivity'), (3) normal skin.
Results:
LEP latencies in the area of differential sensitivity were increased compared to unaffected skin (228 ± 8.5 ms, vs. 181 ± 3.6 ms, p < 0.01) and LEP amplitudes were reduced (14.8 ± 1.2 μV vs. 24.6 ± 1.7 μV, p < 0.01). Correspondingly, psychophysically assessed response latencies in the differentially anesthetic skin were increased (649 ms vs. 427 ms, p < 0.01) and pain ratings reduced (1.5/10 vs. 5/10 NRS, p < 0.01).
Conclusion:
The increase in LEP latency suggests that mechano-insensitive heat-sensitive Aδ nociceptors (MIA, type II) have a slower conduction velocity or higher utilization time than mechano-sensitive type II Aδ nociceptors. Moreover, widely branched, slowly conducting and mechano-insensitive branches of Aδ nociceptors can explain our finding. LEPs in the differentially anesthetized skin provide specific information about a mechanically insensitive but heat-sensitive subpopulation of Aδ nociceptors. These findings support the concept that A-fibre nociceptors exhibit a similar degree of modality specificity as C-fibre nociceptors.
Cortical neurons are excited by signals from the thalamus that are conducted via thalamocortical fibers. As the cortex receives these signals, electric currents are conducted through the apical dendrites of pyramidal cells in the cerebral cortex. These electric currents generate magnetic fields. These electric and magnetic currents can be recorded by electroencephalography (EEG) and magnetoencephalography (MEG), respectively. The spatial resolution of MEG is higher than that of EEG because magnetic fields, unlike electric fields, are not affected by current conductivity. MEG also has several advantages over functional magnetic resonance imaging (fMRI). It (1) is completely non-invasive; (2) measures neuronal activity rather than blood flow or metabolic changes; (3) has a higher temporal resolution than fMRI on the order of milliseconds; (4) enables the measurement of stimulus-evoked and event-related responses; (5) enables the analysis of frequency (i.e., brain rhythm) response, which means that physiological changes can be analyzed spatiotemporally; and (6) enables the detailed analysis of results from an individual subject, which eliminates the need to average results over several subjects. This latter advantage of MEG therefore enables the analysis of inter-individual differences.
Die evozierten Potentiale nach schmerzhaften Reizen sind eine Sonderform somatosensorisch evozierter Potentiale (SEP). Gegenüber den Standard-SEP zeichnen sie sich durch andere periphere und zentrale Leitungsbahnen aus (zur Übersicht s. Willis 1985): Schmerzhafte Reize aktivieren A3- und C-Fasern in peripheren Nerven. Diese primären Afferenzen werden bereits im Hinterhorn des Rückenmarks auf sekundäre Neurone umgeschaltet, deren Axone im kontralateralen Tractus spinothalamicus nach rostral projizieren. Diese Bahn verläuft weit lateral bis in den unteren Hirnstamm hinein und trifft erst kurz unterhalb des Thalamus auf den Lemniscus medialis. Deshalb können durch schmerzhafte Reize evozierte Potentiale in der neurologischen Topodiagnostik eine wichtige Ergänzung zu den SEP liefern.
We investigated C-fiber discharges and cerebral potentials evoked by weak CO2 laser beams applied to a tiny skin area in five healthy subjects. Microneurography was performed from the peroneal nerve in the right popliteal area. Cerebral potentials were recorded from the Cz electrode referred to linked earlobes. The mean conduction velocity of five stable single units was 1.1±0.3 m/s. The mean latency of the positive peak of cerebral potentials was 1327.4±46.2 ms. These findings indicated that this new stimulation method selectively activated C-fiber nociceptors of the skin.
Compared volleys induced by artifical stimuli can be recorded from peripheral nerves of human subjects with extraneural electrodes. In contrast, the study of the normal traffic of impulses requires other methods. A powerful technique for recording this type of activity with percutaneously inserted intraneural electrodes was introduced in 1966. The development of the technique was promoted by interest in studying somatosensory and proprioceptive mechanisms in organisms with an intact sensorium and intact volition, particularly human subjects. This method opened up the possibility of investigating a number of neural mechanisms and is has been used mainly for studies of proprioceptive mechanism, tactile and nociceptive cutaneous activity, and efferent sympathetic discharges. In addition, cutaneous thermosensitive activity and oral mechanosensitive activity have been analyzed. Single-unit activity has been recorded from large myelinated nerve fibers and from unmyelinated nerve fibers, whereas rather few recordings from small myelinate fibers have been reported. In addition, multiunit activity from myelinated and unmyelinated fibers has been studied. Pathological mechanisms as well as normal conditions have been analyzed. Our aim here is to review findings extracted by recording impulses in human nerves with emphasis on the implications these findings may have on current theories within a number of fields. As far as it is feasible, the findings from human subjects are related to knowledge based on studies in other species. This review is based on reports published or known to be in the process of publication when the article was being written.
Late and ultralate cerebral potentials in response to cutaneous heat (CO2 laser pulses) and electrical nerve stimuli were studied in a patient with hereditary motor and sensory neuropathy type I who showed severe impairment of myelinated nerve fibre function. Cerebral potentials in response to electrical stimuli were absent (tibial nerve) or small (median nerve). With the laser pulses applied to the foot only ultralate, but no late potentials were observed, indicating intact C-fibres, but disturbed A delta-fibres. Laser stimulation of the hand resulted in both late and ultralate components, indicating at least partly preserved A delta-fibre function. The results document the usefulness of laser stimuli in the assessment of small nerve fibre function.
The shape (amplitude and latency) of single cortical responses to argon laser stimulation was found to match six perceptual classes: three pre-pain and three pain. The amplitude of the pain related single cortical responses correlated with the perceived feeling of pain. Easy detectable responses were obtained because habituation to the stimuli was reduced and a high degree of attention was given to each stimulus. Single cortical responses to argon laser stimuli are suggested as a new quantitative technique with application in the assessment of function in the thermal and nociceptive pathways.
CO2 laser emitted radiant heat pulses of 20 ms duration were used to activate predominantly slowly conducting nociceptive cutaneous afferents in man. Stimuli of two-fold individual pain threshold caused stinging and burning pain and elicited cerebral potentials with latencies consistent with Aδ-fibre activity. After preferential block of the myelinated nerve fibres by pressure only the burning pain remained with significantly increased reaction time (about 1433 ms). The Aδ-fibre-induced evoked potential components disappeared, and a marked ultralate positive component became visible with mean peak latency of 1260 ms, consistent with C-fibre activity.
1. Radiant-heat stimuli of different intensities were delivered every 28 s to the thenar eminence of the hand of human subjects and to the receptive fields (RFs) of 58 "mechanothermal nociceptive" and 16 "warm" C-fibers, most of which innervated the glabrous skin of the monkey hand. A CO2 infrared laser under control via a radiometer provided a step increase in skin temperature to a level maintained within +/- 0.1 degrees C over a 7.5-mm-diameter spot. 2. Human subjects categorized the magnitude of warmth and pain sensations evoked by stimuli that ranged in temperature from 40 to 50 degrees C. The scale of subjective thermal intensity constructed from these category estimates showed a monotonically increasing relation between stimulus temperature and the magnitude of warmth and pain sensations. 3. The mechanothermal fibers had a mean RF size of 18.9 +/- 3.2 mm2 (SE), a mean conduction velocity of 0.8 +/- 0.1 m/s, mean thresholds of 43.6 +/- 0.6 degrees C for radiant heat and 5.95 +/- 0.59 bars for mechanical stimulation, and no spontaneous activity. In contrast, warm fibers had punctate RFs, a mean conduction velocity of 1.1 +/- 0.1 m/s, heat thresholds of less than 1 degrees C above skin temperature, no response to mechanical stimulation, and a resting level of activity in warm skin that was suppressed by cooling. 4. The cumulative number of impulses evoked during each stimulation in the nociceptive afferents increased monotonically as a function of stimulus temperature over the range described by humans as increasingly painful (45-50 degrees C). Nociceptive fibers showed little or no response to stimulus temperatures less than 45 degrees C that elicited in humans sensations primarily of warmth but not pain. In contrast, the cumulative impulse count during stimulation of each warm fiber increased monotonically with stimulus temperature over the range of 39-43 degrees C. However, for stimuli of 41-49 degrees C the cumulative impulse count in warm fibers was nonmonotonic with stimulus temperature. Warm-fiber response to stimuli of 45 degrees C or greater usually consisted of a short burst of impulses followed by cessation of activity. 5. The subjective magnitude of warmth and pain sensations in humans and the cumulative impulse count evoked by each stimulus in warm and nociceptive afferents varied inversely with the number, delivery rate, and intensity of preceding stimulations. 6. The results of these experiments suggest the following: a) that activity in the mechanothermal nociceptive C-fibers signals the occurrence of pain evoked by radiant heat, and that the frequency of discharge in these fibers may encode the intensity of painful stimulation; b) that activity in warm fibers may encode the intensity of warmth at lower stimulus temperatures, but is unlikely to provide a peripheral mechanism for encoding the intensity of painful stimulation at higher stimulus temperatures.
1. Impulses in cutaneous nerve fibres were recorded percutaneously with tungsten micro-electrodes from the superficial radial nerve of adult human subjects. 2. Eight units studied had conduction velocities below 1.5 m/sec, and thus belong to the class of C fibres. On the basis of their responsiveness to mechanical and to thermal stimuli the units were classified as 'polymodal nociceptors'. 3. Units were tested with 12 sec heat pulses starting from a base line temperature of 43.0-43.5 degrees C. Heat stimuli reaching three different maximal levels were applied in randomized order, the subjects being blind with respect to stimulus size. Each of the eight units studied was tested with more tha 20 stimuli and with four of them were 80-125 stimulus repetitions. 4. After each stimulus the subjects had to rate his sensations on a six-point rating scale extending from 'just noticeable' to 'very hot, painful'. 5. Discrimination between the three stimulus levels by the integtated spike discharges and by the ratings of the subject was compared using the P(A) measure of the Signal Detection Theory. It was found that both the neurophysiological and the psychophysical measurements provided about equal discrimination. 6. In addition it has been found that spike discharges and ratings share a common variance beyond their common dependence on the stimulus level. Among the factors contributing to this interdependence a 'temporal position effect' was the most significant. 7. In spite of this interdependence between discharge rates and subjective ratings, the latter gave a better estimation of the stimulus size than of the discharge rates of the individual C fibre under study. 8. It was concluded that the polymodal C-nociceptors might be instrumental for the quantitative aspects of heat pain sensation. The hypothesis was derived from the present results that, under the conditions of cour experiments, the loss of information in the course of central processing might be about equal to the gain by the parallel processing in a population of nociceptors excited by a stimulus.
Psychophysical experiments were carried out on 6 huma subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4-8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51-5% C). The magnitude of first and second pain sensations was estimated using cross-modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in Adelta and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of Adelta heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of singlt Adelta heat nociceptive afferents, C polymodal nociceptive afferents, and "warm" afferents of rhsus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers (greater than 1/3 sec). These spinal cord summation mechanisms could account for the summation of second pain.
Controlled radiant heat stimulation for a combined psychophysical and electrophysiological research in pain was achieved by the use of an infrared Laser beam. The computer controlled stimuli, being of very brief duration (down to 5 msec) and sharply localized, are suitable for recording of averaged evoked responses as well as for determination of pain and thermal thresholds. These stimuli can be applied to any locus on the skin. The threshold energy delivered by this technique is similar to that obtained by the Hardy-Wolff-Goodell method. Special precautions were taken to avoid injury to the skin and the eyes.
The processing of a sensory stimulus leading to a simple motor command was studied with scalp-recorded long latency cortical potentials in humans. Two sensory modalities were tested in their ability to activate descending motor pathways: auditory stimuli and painful cutaneous stimuli produced by a CO2 laser. Subjects were asked to react to stimuli with voluntary index finger movements. The stimulus-related and movement-related cortical potentials were recorded simultaneously with five midline electrodes on the scalp. The auditory reaction time, measured from the stimulus to the onset of electromyogram (EMG), was faster (150 ms) than the laser reaction time (350 ms). The onset of EMG of finger movements occurred only after the first negative components following auditory or laser stimuli but before the positive components. The latency from the auditory negativity to the onset of EMG was about 50 ms and the latency from the laser negativity to the onset of EMG was about 110 ms. This finding indicates that not only the peripheral afferent conduction but also central processing takes longer in a pain-related somatosensory task than in an auditory task. The frontal peak of Motor Potential (fpMP), a cortical potential related to the sensory feedback from movement, occurred with a constant latency after the onset of EMG (100 ms) and was unaffected by the task.
Argon laser induced event related responses to pricking pain (first pain) were recorded. The different recording parameters (recording site, filter setting, averaging technique), quantification parameters (amplitude, power) and variability between successive recordings were studied. The single responses were large, and averaging of 16-32 single trials was sufficient to obtain reliable averaged responses. The power (0.5-7.5Hz) of the averaged vertex recorded response was, for the range of intensities considered, the most sensitive parameter to quantify the stimulus and hence the intensity of pain perceived.
Late components of cerebral potentials evoked by brief heat pulses applied to various skin sites were used to monitor the afferent pathways of pain and temperature sensitivity. Radiation at 10.6 micron wave length generated by a CO2 laser stimulator predominantly activates superficial cutaneous A delta and C nociceptors and elicits late and ultralate cerebral potentials. This paper deals with the investigation of the component structure and topography of the A delta fibre mediated late potentials, which were compared with the corresponding late potentials in response to standard electrical nerve stimuli. In the upper limb both stimulus types evoked a large positive potential (nerve: 260 msec, skin: 390 msec latency), preceded by a negativity (nerve: 140 msec, skin: 250 msec). Whereas these components were always maximal at the vertex, an earlier negativity appeared over the somatosensory projection area (nerve: 70 msec, skin: 170 msec). After stimulation of the lower limb all latencies were delayed by 20-30 msec. As a rule, the heat-evoked potentials appeared about 100 msec later than the corresponding potentials after electrical nerve stimulation. Similarities in interpeak latencies and scalp topography indicated similar cerebral processing.
Pain-related somatosensory evoked potentials (SEPs) following CO2 laser stimulation were analyzed in normal volunteers. Low power and long wavelength CO2 laser stimuli to the hand induced a sharp pain which was associated with a large positive component, P320, recorded over the scalp. Amplitude decreased and latency increased with reduction in stimulus intensity and subjective pain feeling. P320 was maximal at the vertex but was distributed widely over the scalp. There were no topographic differences between left- and right-hand stimulation, or between hand and chest stimulation. Lidocaine injection to produce anesthetic nerve block resulted in loss of P320, but the potential was relatively preserved during ischemic nerve block. No potential corresponding to P320 could be recorded following electrical or mechanical tactile stimulation. We consider P320 to be generated by impulses arising from pain stimuli and ascending through A delta fibers. We propose the thalamus as a generator source from considering its scalp topography, but pain-specific cognition or perception may also be involved in generating this potential.
Evoked cerebral potentials were investigated in a patient with neurosyphilis, who showed the symptoms of delayed pain perception in the lower limbs: a pinprick to the legs was perceived with a latency of more than one second. After stimulation with CO2 laser radiant heat pulses, evoked cerebral potentials of upper limbs were observed in a latency range comparable to those of healthy subjects, with a negative peak at 250 ms and a positive peak at 370 ms. In contrast, after application of laser stimuli to body sites with delayed pain perception, latency of the evoked potentials drastically increased with a vertex negativity at 1300 ms and a positivity at 1420 ms. Evoked potential measurements with conventional electrical stimuli did not show any difference between affected and unaffected body sites, that is, stimulation of the affected body sites did not produce pathological potentials.
Brief radiant heat pulses, generated by a CO2 laser, were used to activate slowly conducting afferents in the hairy skin in man. In order to isolate C-fibre responses a preferential A-fibre block was applied by pressure to the radial nerve at the wrist. Stimulus estimation and evoked cerebral potentials (EP), as well as reaction times, motor and sudomotor activity were recorded in response to each stimulus. With intact nerve, the single supra-threshold stimulus induced a double pain sensation: A first sharp and stinging component (mean reaction time 480 ms) was followed by a second burning component lasting for seconds (mean reaction time 1350 ms). Under A-fibre block only one sensation remained with characteristics and latencies of second pain. The heat pulse evoked potential consisted of a late vertex negativity at 240 ms (N240) followed by a prominent late positive peak at 370 ms (P370). Later activity was not reliably present. Under A-fibre block this late EP was replaced by an ultralate EP beyond 1000 ms, which in the conventional average looked like a slow halfwave of 800 ms duration. This potential was distinct from eye movements, skin potentials or muscle artefacts. With cross-correlation methods waveforms similar to the N240/P370 were detected in the latency range from 900 to 1500 ms during A-fibre block, indicating a much greater latency jitter of the ultralate EP. Latency corrected averaging with a modified Woody filter yielded a grand mean ultralate EP (N1050/P1250), the shape of which was surprisingly similar to the late EP (N240/P370). The similarity of these components indicates that both EPs may be secondary responses to afferent input into neural centers, onto which myelinated and unmyelinated fibres converge. Such convergence may also explain through the known mechanisms of short term habituation and selective attention, why ultralate EPs are not reliably present without peripheral nerve block.
(1)Radiant heat pulses (10 sec in duration) at noxious levels were applied to the hind foot of the cat in order to establish quantitatively the response characteristics of single afferent units, and to evaluate the total afferent outflow.(2)In the plantar nerves, 16% of the C-fibers were activated by noxious heat (50 °C). The thresholds of the majority of these ‘C-heat receptors’ were between 40–45 °C. The discharges were related linearly to the level of skin temperature, the high correlation coefficient suggesting these receptors to be able to signal the intensity of heat stimuli.(3)The ‘C-heat receptors’ showed a steady discharge to long-lasting heat stimuli (e.g. 5 min). About half of them could be excited in addition by mechanical stimuli, mostly in a noxious range (⩽ 300g/0.8sq.mm). Sensitization was observed in some of the ‘C-heat receptors’ by repeated exposition to noxious heat.(4)Among myelinated fibers about half of the high threshold mechanoreceptors with group III afferents exhibited a response to heating above 45°C, there being however a low correlation between temperature and discharge frequency. In the low threshold mechanoreceptors of the pad with group II afferents (RA and SA) a suppression of the response to adequate mechanical stimulation occurred during heating of the skin.
A combined light and electron microscope study of the normal sural nerve in 7 people aged 15-59 years is reported. Qualitative and quantitative studies of the Schwann cells and fibroblasts, myelinated and unmyelinated fibres are made in isolated fascicles. Schwann cells predominate over fibroblasts in the ratio of about 9-1. Most Schwann cells, almost 80%, are attached to unmyelinated fibres. Factors influencing the densities of these cells per cross sectional area are discussed. Some ultrastructural features of the myelinated fibres are described and their numbers per sq.mm and frequency distribution of their sizes are produced. An indirect method is proposed for assessing the mean internodal length for earch of the myelinated fibre size populations in cross sections of fascicles of normal nerves by estimating the proportion of myelinated segments cut through their nucleus. The ultrastructure of unmyelinated fibres is described and the identification of axons of extreme diameter is discussed. Their densities and size frequency histograms are the first to be reported in man by systematic electron microscope studies. The average ratio of unmyelinated to myelinated fibre density is about 3.7:1 though it varies in the fascicles of the different individuals. The implications of axonal diameter in the presence of myelin are commented on.
Microelectroneurographic studies in man allow the comparison of stimulus induced activity in the single peripheral nerve unit with the subject's ratings of sensation. Relationships between stimulus intensity, single unit discharges, and pain ratings were investigated using a CO2 laser stimulator which delivers radiant heat pulses of 50 ms duration. Recordings were performed percutaneously from the radial nerve at the wrist. Receptor types were identified by their response to different stimulus modalities and by their reaction delay to electrical test stimuli within the receptive field. Receptive fields of identified units were stimulated with randomised series of different radiant heat intensities between half and double the individual pain threshold (5 to 20 W; stimulation area 64 mm2).
The largest receptor class observed to be activated by CO2 laser stimuli were polymodal C-nociceptors. None of them was spontaneously active. High discharge rates up to 75/s were not necessarily associated with pain but, if pain was felt, the impulse trains usually lasted for more than 60 ms. Inter-spike intervals were distributed over a wide range between 8 and 145 ms with a peak at about 25 ms. This peak was only slightly shifted by increasing the stimulus intensity. Higher correlations were found between the number of spikes and stimulus intensity. Measures of Signal Detection Theory indicated that the single unit discharges discriminated stimulus intensities better than the subjects' ratings. These findings underline the importance of temporal summation in the processing of C-fibre input with a considerable loss of information in the nociceptive system.
The peripheral neuronal correlates of heat pain elicited from normal skin and from skin made hyperalgesic following a mild heat injury were studied by simultaneously recording, in humans, evoked responses in C mechanoheat (CMH) nociceptors and the magnitude estimations of pain obtained from the same subjects. Subjects made continuous magnitude ratings of pain elicited by short-duration stimuli of 39-51 degrees C delivered to the hairy skin of the calf or foot before and at varying intervals of time after a heat injury induced by a conditioning stimulus (CS) of 50 degrees C, 100 s or 48 degrees C, 360 s. The stimuli were applied with a thermode pressed against the nociceptor's receptive field. For heat stimulations of normal skin, that is, uninjured skin, pain thresholds in 14 experiments with nine subjects ranged from 41 to 49 degrees C, whereas response thresholds for most of the 14 CMH nociceptors were 41 degrees C (in two cases, 43 degrees C). The latter suggested that spatial summation of input from many nociceptors was necessary at pain threshold. An intensity-response function was obtained for each CMH by relating the total number of nerve impulses evoked per stimulus to stimulus temperature. A corresponding magnitude scaling function for pain was obtained by relating the maximum rating of pain elicited by each stimulus to stimulus temperature. The relation between the subject's scaling function and the intensity-response function of his CMH nociceptor varied somewhat from one experiment to the next, regardless of whether the results were obtained from the same or from different subjects. However, when averages were computed for all 14 tests, there was a near linear relationship between the mean number of impulses elicited in the CMHs and the median ratings of pain, over the range of 45-51 degrees C. It was concluded that the magnitude of heat pain sensation was more closely related to the magnitude of response in a population of CMH nociceptors than in any individual nociceptor. At 0.5 min after the CS, the pain thresholds of most subjects were elevated, and the magnitude ratings of pain elicited by supra-threshold stimuli were lower than pre-CS values (hypoalgesia). Corresponding changes were seen in the increased thresholds and decreased responses (fatigue) of most CMHs. By 5-10 min after the CS, the pain thresholds of most subjects were lower, and their magnitude ratings of suprathreshold stimuli were greater than pre-CS values (hyperalgesia).(ABSTRACT TRUNCATED AT 400 WORDS)
Thermal stimulation with intense pulses of CO2 laser radiation has recently come into use as a method for generating robust cerebral evoked responses in man. Because the heat transient involved (at least 200°C/s) is at least an order of magnitude greater than that of most conventional thermal stimulators, we checked whether or not there might be anomalous activation of fiber types other than the well known cutaneous thermoreceptors. Recordings were made from primary afferent fibers in the rat sciatic nerve and second order somatosensory cells in the dorsal horn. Most of the laser-sensitive afferent fibers sampled were C polymodal nociceptors with lesser representation of other thermoreceptor types. There were no instances in which low threshold mechanoreceptors or other nonthermal afferent fibers were engaged. We conclude that the advantages of infrared laser stimulation are not compromised by a loss of receptor specificity.
In order to clarify the generator mechanism of pain-related evoked potentials (pain EPs), we studied the scalp topography of the pain EPs following CO2 laser stimulation of hand dorsum by using balanced sternovertebral electrodes as the noncephalic reference in 11 normal volunteers. We also examined the effects of predictive warning signal (light-emitting diode) on the pain EPs. In both the warned and unwarned conditions, all of the 22 hand stimulations showed a large negative component (N2) at the peak latency of about 213 ms followed by a large positive component (P2) at the peak latency of about 329 ms. A preceding small negative component (N1) at the peak latency of about 148 ms was detected in 12 of the 22 hand stimulations in the warned condition and in 13 of the 22 hand stimulations in the unwarned condition. P2 was significantly larger and occurred earlier in the warned condition than in the unwarned condition, whereas other components did not differ between the two conditions, suggesting that an increased attention of the subject to the stimulus influenced the generator mechanism of the P2 component. With regards to the scalp topography, N2 was maximal at Cz and widespread transversely to both sides, whereas P2 was maximal at Cz or Pz and spread more posteriorly than N2. These findings suggest that P2 is generated by a different mechanism from N2 and is most likely associated with pain-related cognitive function. N1 was localized to the contralateral central and midtemporal areas, confirming that the nociceptive inputs are perceived in the sensory cortex in humans. The question as to whether the N1 component is generated in the hand area of the primary somatosensory cortex or in the secondary somatosensory cortex, or in both areas, remains to be solved.
The present study was aimed at examining the specificity of the action of heterotopic nociceptive conditioning stimulation (HNCS) by comparing its effects of those induced by a mental task (MT). Five test stimuli made from short CO2 laser pulses (duration: 40 msec; diameter: 10 mm; intensity: 0.25-0.8 Joules) were delivered every 30 to 45 sec at random to 4 different spots on the skin of the upper lip in 3 groups of 10 healthy subjects. The two most intense stimuli were perceived as painful, the two least intense stimuli as warm, and the intermediate stimulus as hot or near painful. Perception (VAS), reaction time (T) and cerebral evoked potentials (CEPs) were monitored before, during and after conditioning stimulation consisting either of HNCS (hand submerged in cold water) or of MT (arithmetic subtraction). Pain perception (first pain) threshold was increased in both conditioning stimulations; however, the stimulus-response curve and the neurophysiological correlates were differently affected. During HNCS, the stimulus-response curve was depressed and T was increased mainly for the intermediate stimulus, whilst CEP power density was reduced for all stimulus intensities; discrimination performance near pain threshold was dramatically depressed. During MT, the stimulus-response curve was shifted down toward higher stimulus intensities, T was equally increased for all stimulus intensities, whereas CEP power density was not changed; discrimination performance remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Similarity of thresh-old temperatures for first pain sensation, laser-evoked potentials, and nociceptor activation
- R D Treede
- R A Meyer
- R P Lesser
Treede, R.D., Meyer, R.A. and Lesser, R.P., Similarity of thresh-old temperatures for first pain sensation, laser-evoked potentials, and nociceptor activation. In G.F. Gebhart, D.L. Hammond and T.A. Jensen (Eds.), Proceedings of the 7th World Congress on Pain, IASP Press, Seattle, 1994, pp. 857-865.
Generator mechanism of pain-related evoked po-tentials following CO 2 laser stimulation of the hand: scalp topog-raphy and effect of predictive warning signal
- M Miyazaki
Miyazaki, M., Generator mechanism of pain-related evoked po-tentials following CO 2 laser stimulation of the hand: scalp topog-raphy and effect of predictive warning signal, J. Clin. Neuro-physiol., 1 I (1994) 242-254.
Are cerebral evoked potentials reliable indices of first or second pain
- S W Harkins
- D D Price
- M A Katz
Harkins, S.W., Price, D.D. and Katz, M.A., Are cerebral evoked potentials reliable indices of first or second pain? In J.J. Bonica, U. Lindblom and A. lggo (Eds.), Advances in Pain Research and Therapy, Vol. 5, Raven Press, New York, 1983, pp. 185-191.
Are cerebral evoked potentials reliable indices of first or second pain?
- Harkins
Similarity of threshold temperatures for first pain sensation, laser-evoked potentials, and nociceptor activation
- Treede
Human Brain Electrophysiology: Evoked Potentials and Evoked Magnetic Fields in Science and Medicine
- Regan