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Evoked cerebral potential correlates of C-fibre activity in man
Abstract
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.
... The origin of the idea that led to the data collected and presented herein came from an awareness of human pain research based on EEG data collected in association with laser heat stimuli (Chen et al., 1979, Bromm et al., 1983, Arendt-Nielsen and Bjerring, 1988. The EEG feature elicited by the laser stimuli is the laser evoked potential (LEP), and correlates with the magnitude of subjective pain reported. ...
... The experience of pain begins with activation of two types of peripheral free nerve endings in the skin, the Aδ and C fibers, which have distinctly different properties and code for different sensations. The result of nociceptive laser heat stimulus is a perception of a sharp first pain, and a burning second pain at least 700 ms later mediated by Aδ and C fibers, respectively (Bromm et al., 1983, Bromm and Treede, 1984, Bromm and Lorenz, 1998, Millan, 1999, Mouraux et al., 2003, Opsommer et al., 2003, Forss et al., 2005. The conductance speed of these fibers corresponds to the timings of the two pain sensations as Aδ fibers are small myelinated fibers with a conductance speed of about 4-30 m/s as opposed to the unmyelinated C fibers with a conductance speed of 0.4-1.8 ...
... Therefore, although LEPs may belong to the general class of vertex potentials, they may also be an appropriate neurocorrelate of nociception. The LEP, also known as the N2P2 shown in Figure II-1, has a negative component with mean peak latency 180-290 ms (N2), followed by a larger positive component with a mean peak latency of 300-450 ms (P2) when stimulating the dorsum of the hand (Bromm et al., 1983, Bromm and Treede, 1984. These latencies may vary with the laboratory according to Arendt-Nielsen (1994), and if MEG is used, the latencies are shorter (Frot et al., 1999). ...
PhD Dissertation from Neuro and Cognitive Sciences Program, University of Maryland
... The origin of the idea that led to the data collected and presented herein came from an awareness of human pain research based on EEG data collected in association with laser heat stimuli , Bromm et al., 1983, Arendt-Nielsen and Bjerring, 1988. The EEG feature elicited by the laser stimuli is the laser evoked potential (LEP), and correlates with the magnitude of subjective pain reported. ...
... The experience of pain begins with activation of two types of peripheral free nerve endings in the skin, the Aδ and C fibers, which have distinctly different properties and code for different sensations. The result of nociceptive laser heat stimulus is a perception of a sharp first pain, and a burning second pain at least 700 ms later mediated by Aδ and C fibers, respectively (Bromm et al., 1983, Bromm and Treede, 1984, Bromm and Lorenz, 1998, Millan, 1999, Mouraux et al., 2003, Opsommer et al., 2003, Forss et al., 2005. The conductance speed of these fibers corresponds to the timings of the two pain sensations as Aδ fibers are small myelinated fibers with a conductance speed of about 4-30 m/s as opposed to the unmyelinated C fibers with a conductance speed of 0.4-1.8 ...
... Therefore, although LEPs may belong to the general class of vertex potentials, they may also be an appropriate neurocorrelate of nociception. The LEP, also known as the N2P2 shown in Figure II-1, has a negative component with mean peak latency 180-290 ms (N2), followed by a larger positive component with a mean peak latency of 300-450 ms (P2) when stimulating the dorsum of the hand (Bromm et al., 1983, Bromm and Treede, 1984, 1987. These latencies may vary with the laboratory according to Arendt-Nielsen (1994), and if MEG is used, the latencies are shorter (Frot et al., 1999). ...
... Despite the concomitant activation of A␦-and C-fibers from noxious stimuli and despite the fact that the subjects report the perception of both A␦-fiber-related first pain and delayed C-fiber-related second pain, only evoked potentials with latencies compatible with A␦-fibers are recorded [50,51]. Bromm et al. (1983) showed, as the first group, that ultralate responses with a latency of approximately 1260 ms could be recorded by suppressing the A␦-fiber activity using a preferential block of the superficial radial nerve [52], and this finding has been repeated more recently [53][54][55]. Other experimental techniques have been reported to activate C-fibers selectively (see [29] for review). ...
... Despite the concomitant activation of A␦-and C-fibers from noxious stimuli and despite the fact that the subjects report the perception of both A␦-fiber-related first pain and delayed C-fiber-related second pain, only evoked potentials with latencies compatible with A␦-fibers are recorded [50,51]. Bromm et al. (1983) showed, as the first group, that ultralate responses with a latency of approximately 1260 ms could be recorded by suppressing the A␦-fiber activity using a preferential block of the superficial radial nerve [52], and this finding has been repeated more recently [53][54][55]. Other experimental techniques have been reported to activate C-fibers selectively (see [29] for review). ...
... LEP ultralate responses have been reported with a latency of approximately 700-1150 ms [5,6,52,54,58,65], although longer latencies (1000-1500 ms) have also been described [59]. This is compatible with results using CHEPs where ultralate responses with latencies >800 ms were identified [55]. ...
Background and purpose
Conventional neurophysiological techniques do not assess the function of nociceptive pathways and are inadequate to detect abnormalities in patients with small-fiber damage. This overview aims to give an update on the methods and techniques used to assess small fiber (Aδ- and C-fibers) function using evoked potentials in research and clinical settings.
Methods
Noxious radiant or contact heat allows the recording of heat-evoked brain potentials commonly referred to as laser evoked potentials (LEPs) and contact heat-evoked potentials (CHEPs). Both methods reliably assess the loss of Aδ-fiber function by means of reduced amplitude and increased latency of late responses, whereas other methods have been developed to record ultra-late C-fiber-related potentials. Methodological considerations with the use of LEPs and CHEPs include fixed versus variable stimulation site, application pressure, and attentional factors. While the amplitude of LEPs and CHEPs often correlates with the reported intensity of the stimulation, these factors may also be dissociated. It is suggested that the magnitude of the response may be related to the saliency of the noxious stimulus (the ability of the stimulus to stand out from the background) rather than the pain perception.
Results
LEPs and CHEPs are increasingly used as objective laboratory tests to assess the pathways mediating thermal pain, but new methods have recently been developed to evaluate other small-fiber pathways. Pain-related electrically evoked potentials with a low-intensity electrical simulation have been proposed as an alternative method to selectively activate Aδ-nociceptors. A new technique using a flat tip mechanical stimulator has been shown to elicit brain potentials following activation of Type I A mechano-heat (AMH) fibers. These pinprick-evoked potentials (PEP) have a morphology resembling those of heat-evoked potentials following activation of Type II AMH fibers, but with a shorter latency. Cool-evoked potentials can be used for recording the non-nociceptive pathways for cooling. At present, the use of cool-evoked potentials is still in the experimental state. Contact thermodes designed to generate steep heat ramps may be programmed differently to generate cool ramps from a baseline of 35 °C down to 32 °C or 30 °C. Small-fiber evoked potentials are valuable tools for assessment of small-fiber function in sensory neuropathy, central nervous system lesion, and for the diagnosis of neuropathic pain. Recent studies suggest that both CHEPs and pinprick-evoked potentials may also be convenient tools to assess sensitization of the nociceptive system.
Conclusions
In future studies, small-fiber evoked potentials may also be used in studies that aim to understand pain mechanisms including different neuropathic pain phenotypes, such as cold- or touch-evoked allodynia, and to identify predictors of response to pharmacological pain treatment.
Implications
Future studies are needed for some of the newly developed methods.
... In contrast, LEPs mediated by C-®bers were not easily obtained in healthy humans despite evidence that C-®bers were readily excited by brief laser heat pulses in animals and humans (Devor et al., 1982;Bromm et al., 1984). LEPs in the 1000 ms latency range were ®rst reported under experimental A-®ber conduction blockade (Bromm et al., 1983;Harkins et al., 1983;Bromm and Treede, 1987a) and were called ultralate LEPs, because their latency was even longer than that of late LEPs. Without nerve block, ultralate LEPs were dif®cult to discern from background EEG and could only be isolated by analysis of single trials devoid of late LEP (Towell et al., 1996) or by spectral analysis of the expected time window (Arendt-Nielsen, 1990;Bragard et al., 1996;Becker et al., 1998). ...
... In addition, Ad-®ber-related cortical activation is likely to induce a refractory state of the cortical generator, rendering the cortex less sensitive to subsequent C-®ber-related input (Bromm and Treede, 1987a,b). When A-®ber input was eliminated by selective conduction blockade of peripheral nerves (Bromm et al., 1983;Harkins et al., 1983;Bromm and Treede, 1987a) or by disease Treede et al., 1995a), ultralate potentials were still not easily visualized due to pronounced latency variability of single trials. This second problem was solved by the use of adaptive ®ltering methods (Bromm and Treede, 1987a,b; for method see Woody, 1967), single trial selection in combination with time-shifted averaging (Towell et al., 1996; for method see Purves and Boyd, 1993), or by spectral analysis in the delta (0.5±2.5 Hz, Arendt-Nielsen, 1990) or delta and theta band (0.5±7.5 Hz, Bragard et al., 1996). ...
... 1. The peak latency of ultralate LEPs is consistent with a conduction velocity slower than that of Ad-®bers, but no direct estimates of conduction velocity were obtained (Arendt-Nielsen, 1990;Bragard et al., 1996), 2. Ultralate LEPs were recorded under conditions of complete conduction blockade of peripheral A-®bers, when only C-®bers were still conducting (Bromm et al., 1983;Harkins et al., 1983), 3. Ultralate LEPs disappeared completely upon local anesthetic blockade of remaining conducting nerve ®bers (Bromm and Treede, 1987a). ...
... Different approaches have been proposed to activate C-fibres selectively. Bromm et al. (1983) showed that prolonged pressure applied against a peripheral nerve can preferentially block the conduction of myelinated A-fibres [2]. Bragard et al. (1996) showed that thermal stimuli delivered using a very small surface area (eg, 0.15 mm 2 ) can increase the probability of selectively activating C-fibre afferents, which are thought to be more densely distributed in the epidermis than Ad-fibre afferents [1,25]. ...
... Different approaches have been proposed to activate C-fibres selectively. Bromm et al. (1983) showed that prolonged pressure applied against a peripheral nerve can preferentially block the conduction of myelinated A-fibres [2]. Bragard et al. (1996) showed that thermal stimuli delivered using a very small surface area (eg, 0.15 mm 2 ) can increase the probability of selectively activating C-fibre afferents, which are thought to be more densely distributed in the epidermis than Ad-fibre afferents [1,25]. ...
... The feasibility of recording C-fibre LEPs has already been demonstrated in previous studies [1,2,4,16,19,21,26,[28][29][30]35,38]. However, these approaches have failed to translate into a clinical diagnostic tool because they are difficult to implement and often unreliable. ...
C‐fibre laser‐evoked potentials can be obtained reliably at single‐subject level from the hand and foot using a temperature‐controlled CO2 laser combined with an adaptive algorithm based on reaction times. ABSTRACT: Brain responses to the activation of C‐fibres are obtained only if the co‐activation of Aδ‐fibres is avoided. Methods to activate C‐fibres selectively have been proposed, but are unreliable or difficult to implement. Here, we propose an approach combining a new laser stimulator to generate constant‐temperature heat pulses with an adaptive paradigm to maintain stimulus temperature above the threshold of C‐fibres but below that of Aδ‐fibres, and examine whether this approach can be used to record reliable C‐fibre laser‐evoked brain potentials. Brief CO2 laser stimuli were delivered to the hand and foot dorsum of 10 healthy subjects. The stimuli were generated using a closed‐loop control of laser power by an online monitoring of target skin temperature. The adaptive algorithm, using reaction times to distinguish between late detections indicating selective activation of unmyelinated C‐fibres and early detections indicating co‐activation of myelinated Aδ‐fibres, allowed increasing the likelihood of selectively activating C‐fibres. Reliable individual‐level electroencephalogram (EEG) responses were identified, both in the time domain (hand: N2: 704 ± 179 ms, P2: 984 ± 149 ms; foot: N2: 1314 ± 171 ms, P2: 1716 ± 171 ms) and the time‐frequency (TF) domain. Using a control dataset in which no stimuli were delivered, a Receiver Operating Characteristics analysis showed that the magnitude of the phase‐locked EEG response corresponding to the N2‐P2, objectively quantified in the TF domain, discriminated between absence vs presence of C‐fibre responses with a high sensitivity (hand: 85%, foot: 80%) and specificity (hand: 90%, foot: 75%). This approach could thus be particularly useful for the diagnostic workup of small‐fibre neuropathies and neuropathic pain.
... This has implications for social touch and affliative behavior; decreases in the perception of the pleasantness of touch correlate with decreased brain activations in the insula [22] and also with autistic traits [2,6,36]. Studies originating in the field of pain research have previously identified ultra-late components in electroencephalography (EEG), which relate to the activation of C-pain unmyelinated, slowlyconducting afferents [4,5,15]. The co-activation of A pain afferents can inhibit the detection of the C pain afferent input [4,5] but techniques such as using selective conduction blocks [4,5], very small areas of skin [3], sub-threshold stimuli (e.g. ...
... Studies originating in the field of pain research have previously identified ultra-late components in electroencephalography (EEG), which relate to the activation of C-pain unmyelinated, slowlyconducting afferents [4,5,15]. The co-activation of A pain afferents can inhibit the detection of the C pain afferent input [4,5] but techniques such as using selective conduction blocks [4,5], very small areas of skin [3], sub-threshold stimuli (e.g. heat; [11] ) or special analyses [5] can help visualize late EEG components. ...
... Studies originating in the field of pain research have previously identified ultra-late components in electroencephalography (EEG), which relate to the activation of C-pain unmyelinated, slowlyconducting afferents [4,5,15]. The co-activation of A pain afferents can inhibit the detection of the C pain afferent input [4,5] but techniques such as using selective conduction blocks [4,5], very small areas of skin [3], sub-threshold stimuli (e.g. heat; [11] ) or special analyses [5] can help visualize late EEG components. ...
... Based on characteristics differentiating Ad-and C-fibres, several methods have been proposed to activate C-fibre afferents selectively [5]. A first method exploits the fact that unmyelinated C-fibres are more resistant to pressure than myelinated A-fibres, and consists in applying prolonged force against a peripheral nerve such as to block selectively the nerve conduction of A-fibres [10,11]. A second method takes advantage of the fact that the distribution density of C-fibres in the epidermis is greater than that of Ad-fibres, and consists in using a very small stimulation surface area to elicit isolated C-fibre responses [12,13]. ...
... This is justified by the fact that the nerve conduction velocity of unmyelinated C-fibres is much slower than the nerve conduction velocity of myelinated Adfibres (61 m/s vs. 610 m/s; [8,11,181920). Taking into account the peripheral conduction distance of afferent input originating from the hand, and taking into account the distribution of reaction times to laser stimuli after blocking the conduction of myelinated fibres [10,11], a criterion of 650 ms was chosen to discriminate between C-fibre responses (reaction time $650 ms) and Ad-fibre responses (reaction time ,650 ms) [11,20]. Additional evidence that reaction-times can be used to distinguish between Ad-and Cfiber responses is provided by Opsommer et al. [21], showing that the time interval between the two peaks of the bimodal distribution of reaction-times increases with peripheral distance. ...
... As shown inFigure 2, and as predicted by previous results (e.g.10111221,22]), the frequency distribution of reaction-times appeared bimodal, and the arbitrarily-defined cut-off to discriminate between Ad-fibre (reaction-time ,650 ms) and C-fibre (reaction-time $650 ms) responses effectively separated the two response categories. The bimodal nature of this distribution was confirmed by comparing directly the fitting of the data to a model describing a unimodal distribution vs. the fitting of the data to a model describing a bimodal distribution. ...
Brief high-power laser pulses applied onto the hairy skin of the distal end of a limb generate a double sensation related to the activation of Aδ- and C-fibres, referred to as first and second pain. However, neurophysiological and behavioural responses related to the activation of C-fibres can be studied reliably only if the concomitant activation of Aδ-fibres is avoided. Here, using a novel CO(2) laser stimulator able to deliver constant-temperature heat pulses through a feedback regulation of laser power by an online measurement of skin temperature at target site, combined with an adaptive staircase algorithm using reaction-time to distinguish between responses triggered by Aδ- and C-fibre input, we show that it is possible to estimate robustly and independently the thermal detection thresholds of Aδ-fibres (46.9±1.7°C) and C-fibres (39.8±1.7°C). Furthermore, we show that both thresholds are dependent on the skin temperature preceding and/or surrounding the test stimulus, indicating that the Aδ- and C-fibre afferents triggering the behavioural responses to brief laser pulses behave, at least partially, as detectors of a change in skin temperature rather than as pure level detectors. Most importantly, our results show that the difference in threshold between Aδ- and C-fibre afferents activated by brief laser pulses can be exploited to activate C-fibres selectively and reliably, provided that the rise in skin temperature generated by the laser stimulator is well-controlled. Our approach could constitute a tool to explore, in humans, the physiological and pathophysiological mechanisms involved in processing C- and Aδ-fibre input, respectively.
... A 2.5-cm wide rubber band was placed on the wrist to compress the superficial radial nerve against the underlying bone. The band was loaded with a 1.3 kg hanging weight generating a slowly developing but rapidly reversible conduction block (LaMotte and Thalhammer, 1982;Bromm et al., 1983;Ziegler et al., 1999;Magerl et al., 2001). The volunteers were advised to keep the hand still during block induction. ...
... In our data, the ratio of C versus A-nociceptor mediation of pain was $2:1, whereas the fibre count ratios were 5:1. This difference supports the concept that A-fibres may contribute more to the magnitude of sensation than C-fibres (Bromm et al., 1983;Magerl et al., 1999;Cruccu et al., 2003). However, the better frequencyfollowing properties of A-fibre nociceptors may have moderately magnified the A-fibre component in relation to the C-fibre component, thereby favouring it's uncovering. ...
Long-term potentiation in the spinal dorsal horn requires peptidergic C-fibre activation in animals. Perceptual correlates of long-term potentiation following high-frequency electrical stimulation in humans include increased sensitivity to electrical stimuli at the high frequency stimulation site (homotopic pain-long-term potentiation) and increased sensitivity to pinprick surrounding the high frequency stimulation site (heterotopic pain-long-term potentiation, equivalent to secondary hyperalgaesia). To characterize the peripheral fibre populations involved in induction of pain-long-term potentiation, we performed two selective nerve block experiments in 30 healthy male volunteers. Functional blockade of TRPV1-positive nociceptors by high-concentration capsaicin (verified by loss of heat pain) significantly reduced pain ratings to high frequency stimulation by 47% (P < 0.001), homotopic pain-long-term potentiation by 71% (P < 0.01), heterotopic pain-long-term potentiation by 92% (P < 0.001) and the area of secondary hyperalgesia by 76% (P < 0.001). The selective blockade of A-fibre conduction by nerve compression (verified by loss of first pain to pinprick) significantly reduced pain ratings to high frequency stimulation by 37% (P < 0.01), but not homotopic pain-long-term potentiation (-5%). It had a marginal effect on heterotopic pain-long-term potentiation (-35%, P = 0.059), while the area of secondary hyperalgesia remained unchanged (-2%, P = 0.88). In conclusion, all nociceptor subclasses contribute to high frequency stimulation-induced pain (with a relative contribution of C > Aδ fibres, and an equal contribution of TRPV1-positive and TRPV1-negative fibres). TRPV1-positive C-fibres are the main inducers of both homotopic and heterotopic pain-long-term potentiation. TRPV1-positive A-fibres contribute substantially to the induction of heterotopic pain-long-term potentiation. TRPV1-negative C-fibres induce a component of homotopic self-facilitation but not heterotopic pain-long-term potentiation. TRPV1-negative A-fibres are the main afferents mediating pinprick pain and hyperalgesia, however, they do not appear to contribute to the induction of pain-long-term potentiation. These findings show that distinct peripheral fibre classes mediate induction of long-term potentiation-like pain amplification, its spatial spread to adjacent skin (i.e. secondary hyperalgesia), and the resulting enhanced sensitivity to pinprick in humans. Nociceptive afferents that induce pain amplification can be readily dissociated from those mediating pain. These findings add substantially to our understanding of the mechanisms of pain amplification, that form the basis for understanding the mechanisms of hyperalgesia encountered in patients.
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... 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, like in most human studies on nocifensive reflexes (Shahani and Young, 1971;Meinck et al., 1981;Ellrich and Treede, 1998;Andersen et al., 1999;Sonnenborg et al., 2001;Sandrini et al., 2005), investigations on the reflex behavior of individuals with SCI used suprathreshold electrical (Kugelberg et al., 1960;Grimby, 1963;Andersen et al., 2004;Biurrun Manresa et al., 2014) rather than thermal stimuli (Willer et al., 1979;Mørch et al., 2007) to evoke withdrawal reflexes. While electrical stimulation paradigms typically activate non-selectively both large and small primary afferents (Sandrini et al., 2005), the use of radiant heat stimuli enables to more selectively stimulate thinly-myelinated A-delta fibers and unmyelinated C-fibers (Bromm et al., 1983;Bromm and Treede, 1987;Magerl et al., 1999). ...
Investigating nocifensive withdrawal reflexes as potential surrogate marker for the spinal excitation level may widen the understanding of maladaptive nociceptive processing after spinal cord injury (SCI). The aim of this prospective, explorative cross-sectional observational study was to investigate the response behavior of individuals with SCI to noxious radiant heat (laser) stimuli and to assess its relation to spasticity and neuropathic pain, two clinical consequences of spinal hyperexcitability/spinal disinhibition. Laser stimuli were applied at the sole and dorsum of the foot and below the fibula head. Corresponding reflexes were electromyography (EMG) recorded ipsilateral. Motor responses to laser stimuli were analyzed and related to clinical readouts (severity of injury/spasticity/pain), using established clinical assessment tools. Twenty-seven participants, 15 with SCI (age 18–63; 6.5 years post-injury; AIS-A through D) and 12 non-disabled controls, [non-disabled controls (NDC); age 19–63] were included. The percentage of individuals with SCI responding to stimuli (70–77%; p < 0.001), their response rates (16–21%; p < 0.05) and their reflex magnitude (p < 0.05) were significantly higher compared to NDC. SCI-related reflexes clustered in two time-windows, indicating involvement of both A-delta- and C-fibers. Spasticity was associated with facilitated reflexes in SCI (Kendall-tau-b p ≤ 0.05) and inversely associated with the occurrence/severity of neuropathic pain (Fisher’s exact p < 0.05; Eta-coefficient p < 0.05). However, neuropathic pain was not related to reflex behavior. Altogether, we found a bi-component motor hyperresponsiveness of SCI to noxious heat, which correlated with spasticity, but not neuropathic pain. Laser-evoked withdrawal reflexes may become a suitable outcome parameter to explore maladaptive spinal circuitries in SCI and to assess the effect of targeted treatment strategies. Registration: https://drks.de/search/de/trial/DRKS00006779.
... Predominantly, interest in this domain came from Ackerley, Eriksson and Wessberg [39], who reported activation including an ultra-late potential (ULP) recorded for CT-targeted stimulation, later replicated by Haggarty et al [40]. Similarly, a late positive potential is recorded in response to unmyelinated pain afferent (C-nociceptor) stimulation in response to laser heat stimuli [41,42]. Both potentials are recorded in the frontal lobe late in the typical time frame for ERP epochs (>1000ms). ...
Electroencephalography (EEG) is one of the major tools to non-invasively investigate cortical activations from somatosensation in humans. EEG is useful for delineating influences on the processing pathways of tactile stimulation and for mapping the dynamics between the cortical areas involved in and linked to tactile perception. This chapter focuses on the process of recording somatosensory EEG from mechanical tactile stimulation, including affective touch, and their related cortical activations. Practical and participant-specific challenges are detailed, and best practices are shared. In addition, the main areas of research in tactile perception using EEG are discussed. These include perception, attention, and multisensory perception, as well as emotional and self-other processing. We discuss the major considerations when conducting these types of research.Key wordsTactileSomatosensoryElectroencephalography
EEG
ERPs
SEPs
MultisensoryAttentionAffect
... 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.
... 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.
... (1996) showed that short-lasting high-intensity CO2 laser stimuli delivered to a very small area of the skin (0.15 mm 2 ) predominantly activate C-fibers. Specifically, they showed that such stimuli were detected with very late reaction times and elicited ERPs within a very late time window, compatible with the conduction velocity of unmyelinated C-fibers (Bromm et al. 1983;Bromm and Treede, 1987). The selectivity for C-fibers of such stimuli is explained by the fact that high-intensity stimuli delivered to a tiny area of the skin can be expected to predominantly activate CMH, as these have a much higher skin innervation density than AMH (Plaghki and Mouraux 2002). ...
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.
... Recent studies have revealed a possible interaction between the C-and A␦-fiber-mediated nociceptive systems. It has been reported that C-fiber LEPs (C-LEPs) become detectable only when the concomitant activation of A␦-fibers is avoided or reduced (Bromm et al., 1983;Mouraux et al., 2003), an inhibitory interaction of human cortical responses to stimuli preferentially exciting A␦ or C fibers exists (Tran et al., 2008), and that the cold hyperalgesia could result from activated C fibers by blocking A␦ fibers in healthy humans (Wasner et al., 2004). Another LEP study showed that the C-LEP amplitudes increased depending on the subjective pain intensity, there was a significant negative correlation between A␦-and C-LEP amplitudes at high energies, but there was a positive correlation at low-energies (Hu et al., 2014). ...
Neuropathic pain can result from neuronal hyperexcitability and complex interactions of the nociceptive pathways. Intraepidermal electrical stimulation (IES) is a novel technique that can selectively activate Aδ and C fibers. To investigate patterns of changes in Aδ- and C-mediated brain responses in patients with neuropathic pain using IES, we recorded pain-related evoked potential (PREP) after IES of Aδ and C fibers in 20 patients with neuropathic pain and 15 age-matched healthy volunteers. We evaluated PREP latencies, amplitudes, and amplitude ratios of PREPs after C/Aδ-fiber stimulation. PREP amplitudes after Aδ-fiber stimulation tended to be smaller in the patient group, whereas there were no significant differences in amplitudes after C-fiber stimulation between the patient and normal control groups. PREP amplitude ratios after C/Aδ-fiber stimulation were significantly greater in the patient group than in the control group, and the higher ratio tended to be associated with a greater visual analog scale score. Patients with neuropathic pain had a tendency towards decreased Aδ amplitudes and significantly increased C/Aδ PREP amplitude ratios and this ratio appeared to be associated with the intensity of pain. Our findings suggest that decreased inhibition of the Aδ to C nociceptive systems is associated with generation of neuropathic pain.
... 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]. The use of a special grid seems to be the most feasible method to generate a C-fiber related brain potential [8]. ...
... 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.
... Several methods to stimulate C-fibers by laser beams have been proposed based on the differential characteristics of A␦-and C-fibers [2]. A first proposed method exploits the fact that unmyelinated C-fibers are more resistant to ischemic compression block than myelinated fibers [3,4]. 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]. ...
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.
... However, these tools have not been developed into clinical applications universally because of several limitations, such as the cost, cumbersome procedure, and invasiveness. Laser stimulation can also stimulate C fibers selectively by restricting the energy of the laser beams and stimulus area (Bragard et al., 1996;Tran et al., 2001;Qiu et al., 2004), or blocking Ad fibers (Bromm et al., 1983). However, LEPs related to C-fiber stimulation have been used in only three clinical studies (Cruccu et al., 2003;Valeriani et al., 2004;Truini et al., 2008) and one case report (Lankers et al., 1991) of patients with small-nerve-fiber dysfunction because of the technical difficulty, especially in the limbs (Haanpää et al., 2011). ...
Objective
To investigate whether intraepidermal electrical stimulation (IES) can evaluate nociceptive Aδ- and C-fiber dysfunctions of an experimental model of small-fiber neuropathy (SFN) with transdermal lidocaine.
Methods
Lidocaine tape or placebo was applied to the dorsum of the feet in 14 healthy subjects. Reaction time (RT), sensory threshold, and evoked potentials (EPs) were measured using IES before, and 30 and 60 min after lidocaine/placebo application.
Results
All subjects felt pricking sensations following Aδ-fiber stimulation, and light painful sensations such as pricking, tingling, or burning following C-fiber stimulation using IES. RT was divided bimodally between Aδ- and C-fiber stimulations. At 30 min, lidocaine increased the sensory threshold and decreased the amplitude of EPs in both fiber stimulations. At 60 min, lidocaine’s effects were greater for C fibers than for Aδ fibers. The sensory threshold and amplitude of EPs were unchanged among placebo sessions.
Conclusions
IES demonstrated differential effects of transdermal lidocaine on nociceptive Aδ and C fibers, and elucidated the pathophysiology of the experimental model of SFN.
Significance
IES has advantages in terms of cost, convenience, and invasiveness. It may have potential for a clinical tool to elucidate the pathophysiology of patients with SFN, including the differences between Aδ and C fibers.
... However, these studies did not consider the possibility of a contamination by an auditory EP in response to the noise generated by the pneumatic stimulation. Noteworthy, these EPs have a latency that is relatively close to that of nociceptive EPs to laser stimulation [1,13,14] or late components of somatosensory EPs [4,5], but also compatible with that of the N 100 component of cortical auditory EPs [11]. Therefore, even if it is most likely that these EPs do not correspond to primary brain responses such as the SEP N 20 or the AEP N a P a peak, but rather to a secondary process, this questions the actual somatosensory nature of the obtained EPs. ...
... However, these studies did not consider the possibility of a contamination by an auditory EP in response to the noise generated by the pneumatic stimulation. Noteworthy, these EPs have a latency that is relatively close to that of nociceptive EPs to laser stimulation [1,13,14] or late components of somatosensory EPs [4,5], but also compatible with that of the N 100 component of cortical auditory EPs [11]. Therefore, even if it is most likely that these EPs do not correspond to primary brain responses such as the SEP N 20 or the AEP N a P a peak, but rather to a secondary process, this questions the actual somatosensory nature of the obtained EPs. ...
In this study, evoked potentials (EPs) to a pneumatic, innocuous, and calibrated stimulation of the skin were recorded in 22 volunteers.
Air-puff stimuli were delivered through a home-made device (INSA de Lyon, Laboratoire Ampère, CHU de Saint-Étienne, France) synchronized with an EEG recording (Micromed(®)).
A reproducible EP was recorded in 18 out of 22 subjects (82% of cases) with a mean latency of about 120-130ms, and maximal amplitude at Cz. This EP actually consisted of two components, an auditory and a somatosensory one. Indeed, it was significantly decreased in amplitude, but did not disappear, when the noise generated by the air-puff was masked. We also verified that a stimulation close to the skin but not perceived by the subject was not associated with any EP. Conduction velocity between hand and shoulder was calculated around 25m/s.
This preliminary study demonstrates that pneumatic EPs can be recorded in normal volunteers.
... However, previous studies frequently activated nociceptors simultaneously rather than selectively. Selective activation of Ad-or C-nociceptors can be achieved by making use of differences in resistance to ischemic pressure be-tween fibers91011, differences in heat thresholds between fibers [37], differences in distribution density of the fibers [8,41,42], and differential responses of fibers to the heating rate of the skin and to pharmacological treatment [40,626364656668]. The present study was designed to separate C-and Ad-fiber activation by exploiting differences in thermal thresholds, rate of thermal activation sensitivity, and spatial properties of the nociceptor types. ...
... But, if the stimulus selectively excites C receptors, the short distance becomes an advantage and the C-LEPs appear more easily and are more stable and high-amplitude than those after limb stimulations. Various techniques have been used to provide a selective activation of C fibers: experimental block of group A fibers [7]; spectral analysis of expected time window [3] [5]; selection of single trials devoid of Ad-LEPs [47]: " microspot " stimulation [5,36]; or stimulus intensities below the Ad activation threshold [27,32,49]. ...
The majority of the studies on laser evoked potentials (LEPs) have been focused on hand and foot stimulations and only lately on the trigeminal system. Because of a high receptor density in the facial skin and the very short conduction distance, LEP recordings after trigeminal stimulation are easier and quicker than those after stimulation of the limb extremities. Laser pulses with a stimulus intensity close to perception threshold can evoke well-defined LEPs. Few trials are sufficient to yield stable and reproducible averages. Even ultralate LEPs related to the C-fibre input are comparatively easily obtained from the trigeminal territory. The brain generators of the main LEP waves are probably very close for the trigeminal and limb stimulations. Trigeminal LEPs have been found absent or delayed in patients with trigeminal neuralgia, trigeminal neuropathies, posterior fossa tumors, and brainstem infarctions or demyelinating plaques. Conversely, trigeminal LEPs appear to be enhanced in patients with migraine. High-intensity pulses directed to any trigeminal division also elicit reflex responses: a blink-like reflex in the orbicularis oculi and a single silent period in the contracting masseter muscle. The availability of a neurophysiological method of assessing function of the trigeminal nociceptive pathways reaching both the cerebral cortex and the brainstem reflex circuits, has provided new opportunities for investigating the pathophysiology of orofacial pain syndromes. Résumé La majorité des études portant sur les potentiels évoqués laser (PEL) se sont focalisées sur la stimulation de la main ou du pied, et seulement récemment sur la stimulation du système trigéminal. Du fait de la haute densité des récepteurs sur la peau du visage et de la très faible vitesse de conduction, les enregistrements des PEL obtenus en réponse à une stimulation trigéminale sont plus faciles à réaliser et plus rapides que ceux obtenus après une stimulation des membres supérieurs ou inférieurs. Les pulses laser délivrés avec une intensité de stimulation proche du seuil de perception donnent en général des PEL déjà bien définis. Un petit nombre d'essais est suffisant pour obtenir des réponses reproductibles et stables. Même les PEL ultra-tardifs, correspondant à une stimulation des fibres C sont obtenus plus facilement en stimulant le territoire trigéminal. Les générateurs cérébraux des principaux PEL sont probablement les mêmes pour des stimulations des membres inférieurs/supérieurs et pour des stimulations trigéminales. Les PEL obtenus en réponse à des stimulations trigéminales sont absents ou retardés chez des patients présentant une névralgie trigéminale, des neuropathies trigéminales, des tumeurs de la fosse postérieure, des infarctus du tronc cérébral ou des plaques de démyélinisation. Inversement, l'amplitude des PEL obtenus en réponse à des stimulations trigéminales est augmentée chez les patients migraineux. La délivrance de stimulations à haute intensité sur chaque division trigéminale entraîne aussi des réponses réflexes : un réflexe de clignement dans la zone orbitaire de l'oeil et une période de silence au sein du muscle masséter en contraction. La possibilité d'utiliser une méthode neurophysiologique pour explorer les fonctions du système nociceptif trigéminal, et celle du cortex aux circuits réflexes du tronc cérébral, a ouvert de nouvelles perspectives dans l'étude de la pathophysiologie des syndromes de douleur orofaciale.
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.
After the current section, the history (1.2.) of evoked potentials (EP—for abbreviations, see the end of this chapter) is briefly presented, followed by a discussion of how EPs can be broken down into components (1.3.). General methodology (2.) is then presented, covering recording techniques (2.l.), including electrodes and their placement (2.1.1.), reference electrodes (2.1.2.), EEG amplifying, filtering, and digitizing (2.1.3.), and recording artifacts (2.1.4.). The discussion of methodology then turns to analysis techniques (2.2.), from averaging and peak detection (2.2.l.), and alternative analysis methods (2.2.2.), to factor analysis (2.2.3.), spectral analysis (2.2.4.), and topographical display (2.2.5.). Increasing use is being made of methods of generator localization (2.3.), from scalp EPs (2.3.1.), from evoked magnetic fields (2.3.2.), and from depth recordings and brain lesions (2.3.3.).
Background:
We have recently shown that visual deprivation from birth exacerbates responses to painful thermal stimuli. However, the mechanisms underlying pain hypersensitivity in congenital blindness are unclear.
Methods:
To study the contribution of Aδ- and C-fibres in pain perception, we measured thresholds and response times to selective C- and Aδ-fibre activation in congenitally blind, late blind and normally sighted participants. Ultrafast constant-temperature heat pulses were delivered to the hand with a CO2 laser using an interleaved adaptive double staircase procedure. Participants were instructed to respond as quickly as possible when detecting a laser-induced sensation. We used a 650 ms cut-off criterion to distinguish fast Aδ- from slow C-fibre-mediated sensations.
Results:
Congenitally blind participants showed significantly faster reaction times to C- but not to Aδ-fibre-mediated sensations. In contrast, thresholds for Aδ- and C-fibre stimulation did not differ between groups. Late blind individuals did not differ from sighted controls in any aspect. A follow-up experiment using only suprathreshold stimuli for Aδ- and C-fibre activation confirmed these findings and further showed that congenitally blind individuals detected significantly more C-fibre-mediated stimuli than sighted controls. A decomposition analysis of the reaction times indicated that the faster response times in the congenitally blind are due to more efficient central processing of C-fibre-mediated sensations.
Conclusion:
The increased sensitivity to painful thermal stimulation in congenital blindness may be due to more efficient central processing of C-fibre-mediated input, which may help to avoid impending dangerous encounters with stimuli that threaten the bodily integrity. WHAT DOES THIS STUDY ADD?: Hypersensitivity to heat pain in congenital blindness is associated with faster responses to C-fibre activation, likely caused by more efficient central processing of C-fibre-mediated input.
Studies of cerebral evoked potentials are vigorously developing, and somatosensory evoked potentials (SEP) appear to attract a major share of interest. The remarkable length of the somatosensory pathway from peripheral skin to cerebral cortex makes it vulnerable at many different points to a variety of pathological conditions. Neural generators all along this pathway can be revealed through appropriate SEP recordings methodologies and a variety of electrode montages can be used to resolve diagnostic issues in neurological patients.
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.
The study of nociceptive processing in the cerebral cortex has come a long way. In addition to the primary and secondary somatosensory cortex, limbic areas such as the anterior and mid-cingulate cortex and the insula have also been recognized as part of the nociceptive network, and more recently also cognitive areas in the prefrontal cortex. Limbic areas are usually considered to mediate emotional processes, but they are also involved in autonomic and motor functions. In this way, the cortical nociceptive network mirrors the subcortical networks, which also include many connections to autonomic and motor nuclei. Images of brain activation by painful stimuli leave the impression that at least half of the brain participates in processing nociceptive information. At other times, many of the same areas participate in visual, motor, emotional, cognitive, or other signal processing. In that sense, our current understanding of the nociceptive network in the brain is consistent with our current understanding of how the brain uses distributed processing for its many functions. It is not clear, however, to what extent any part of the cerebral cortex is specific for nociception. The best candidate region for such a function lies in the parasylvian cortex, in the vicinity of the secondary somatosensory cortex and the dorsal insula. Cortical activity possesses properties necessary for involvement in pain perception, like somatotopic representation of painful stimuli, correlation with stimulus intensity, modulation with attention, modulation with expectation and other psychological variables, and distinct brain regions showing differential activity for sensory and affective dimensions of pain, as well as attenuation of responses with analgesic drugs. Thus, human brain imaging studies have asserted the role of the cortex in acute pain. However, perception of pain automatically directs attention to the source of pain, results in autonomic responses, motor reflexes to escape from the pain, and other emotional and cognitive responses. Therefore, the extent to which cortical activity in acute pain reflects secondary processes remains to be determined. In chronic pain, the clinical brain imaging studies indicate reduced information transmission through the thalamus to the cortex, and increased activity in prefrontal cortex (PFC), mostly in medial PFC coupled with atrophy in dorsolateral PFC. The observations regarding cortical and thalamic activity changes in chronic pain are consistent with the notion that chronic pain conditions preferentially engage brain areas involved in cognition/emotion and decrease activity in regions involved in sensory evaluation of nociceptive inputs.
This article, without presuming to be comprehensive, gives a brief outline of the development of research on neuropathic pain in Germany. Current clinical research on this subject focusses on the validation of human models, patient phenotyping, mechanism-based classification and treatment as well as on molecular pathomechanisms. This clinical research is based to a large extent on the work of several internationally recognized basic researchers in the 1990s. In particular, findings from system physiology led to the analysis of clinical phenotypes and the underlying pathophysiology. In parallel, basic research achieved international top levels through the development of innovative methods. Close cooperation, building of consortia and European networking made major contributions to the success of this research.
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.
Sensory neuropathy usually impairs tactile sensations related to large myelinated afferents (Aβ) as well as thermal-pain sense related to small myelinated (Aδ) and unmyelinated (C) afferents. By selectively affecting large or small fibres, some sensory neuropathies may also provoke a dissociated sensory loss. Standard nerve conduction studies and somatosensory evoked potentials assess Aβ-fibre function only. Laser pulses selectively excite free nerve endings in the superficial skin layers and evoke Aδ-related brain potentials (LEPs). From earlier studies and new cases we collected data on 270 patients with sensory neuropathy. LEPs often disclosed subclinical dysfunction of Aδ fibres and proved a sensitive and reliable diagnostic tool for assessing small-fibre function in sensory neuropathy.
It is customary to consider that a purely sensory and painful neuropathy accompanied by normal electroneuromyographic examination may be or must be a small fiber neuropathy. This leads to perform specific tests, such as measuring the intra-epidermal nerve fiber density on skin biopsy or neurophysiological tests, such as evoked potentials to noxious stimuli (laser) or quantification of thermal sensory thresholds. However, these tests are only sensitive to the loss of small fibers (A-delta and C), which does not reflect the mechanisms responsible for peripheral neuropathic pain. Selective loss of small sensory fibers inherently generates a sensory deficit that does not necessarily present a painful character. Also, assigning the cause of a painful neuropathy to a small fiber neuropathy has no pathophysiological sense, although there are indirect links between these two conditions. In fact, it is not possible to explain univocally peripheral neuropathic pain, which reflects complex and diverse mechanisms, involving different types of nerve fibers. In this context, the clinical and laboratory approach must be improved to better understand the underlying mechanisms. It is imperative to interpret the data provided by laboratory tests and to correlate these data to the clinical signs and symptoms presented by the patients. Thus, one must go beyond many a priori and misinterpretations that unfortunately exist in this area at present and are not based on any solid pathophysiological basis.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
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.
This article reviews the diagnostic issues and the therapeutic management of small fibre neuropathy (SFN), and a detailed literature analysis of its association with primary Sjögren's syndrome (pSS). A diagnosis of SFN should be raised in the presence of diffuse neuropathic painful manifestations (burning sensation, paresthesia, pricking, allodynia or hyperesthesia) and neurovegetative signs. The neurological examination and the electroneuromyogram are usually normal. The diagnosis of SFN can be confirmed by the evidence of decreased intra-epidermal nerve fibre density after a skin punch biopsy or the presence of abnormal nonconventional neurophysiological tests exploring the A-delta and C small nerve fibres (laser-evoked potentials, quantitative sensory tests, cutaneous sympathic reflex, autonomic function tests). The association of SFN and pSS has been scarcely evaluated, probably because of its lack of awareness and the low availability of the required diagnostic procedures. According to our literature review, pSS may be present in 9 to 30% of patients with SFN. Conversely, a pure SFN is present in 3 to 9% of patients with pSS where it may represent 25 to 35% of pSS-associated peripheral neuropathies. The treatment of SFN is mainly symptomatic and based on antalgic neuropsychotropic drugs and conventional analgesics. Corticosteroids and immunosuppressive drugs are usually unsuccessful. The effectiveness of intravenous immunoglobulins is only supported by a few case reports. SFN deserves to be separately evaluated among pSS-associated peripheral neuropathies. This requires a better availability of the appropriate diagnostic procedures, the investigation of underlying immunopathological mechanisms and the assessment of the new treatments recently proposed in pSS, mainly rituximab.
Copyright © 2010 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.
Pain-temperature sensation and other somatosensory sensations, such as touch or vibration, ascend through different peripheral and central pathways, so both pain SEP and pain SEF are useful for elucidating the pathophysiology of various types of sensory impairments. Somatosensory evoked potential (SEP) relating to pain (pain SEP) can be recorded by different types of lasers, including CO2 argon, Nd-YAG, and thulium laser. Differences among these types depend mainly on the wavelengths, as this parameter determines skin reflectance, absorbency, scattering, and transmittance (Chen et al. 1998a,b). Recently, CO2 laser stimulation (10.6 11m wavelength) has become popular. Other important factors causing a change of pain SEP waveforms are attention or distraction effects. The chapter describes these factors in brief and mentions several important findings. The amplitude of the P2 component is significantly reduced during sleep and during distraction (mental calculation or memorizing numbers). This change positively correlates with a decrease of visual analog scale (VAS). These results indicate that vigilance and attentiveness to the painful stimuli should be monitored during the acquisition of pain SEP.
Het onderzoek naar pijn, haar ontstaansmechanismen en mogelijke farmacologische en andere behandelingen vergt adequate meetinstrumenten
om de activiteit van verschillende typen zenuwcellen van elkaar te kunnen onderscheiden. Pijn in de huid ontstaat door prikkeling
van de nociceptoren of vrije zenuweinden. Al naargelang het type en de lokalisatie van de nociceptor zal de prikkel snel worden
doorgegeven via de Aδ-vezels (gemyeliniseerde vezels) of langzamer via de C-vezels (dunne ongemyeliniseerde vezels). Deze twee typen zenuwvezels zijn de belangrijkste voor de pijntransmissie.
This review summarizes the results of studies using the intracutaneous pain model in the assessment of nociceptive information transfer from cutaneous afferents to pain-relevant cortical structures, as measured by spontaneous and stimulus-evoked electroencephalographic activity. The application of multivariate statistical analyses, such as principal component analysis, on the late brain potentials, results in the identification of two pain-related principal components with loading maxima around 150 and 250 ms after stimulation, which vary with the reported painfulness of the stimulus. The application of pain-related evoked cerebral potentials in studies of pain-relieving drugs makes possible a quantitative comparison of their analgesic potency. The drugs tested were acetaminophen, phenazone, acetylsalicylcic acid, ibuprofen, anpirtolin, diclofenac, denaverine, flupirtine, imipramine, meperidine, naloxone, pentazocine, tilidine and tramadol, several of them in different dosages and formulations. The interstudy comparison revealed that there was a high correlation (r = 0.91) between pain relief at the subjective measurement level and a decrease in pain-related brain potentials.
Zusammenfassung: Schmerz ist ein kompliziertes Resultat verschiedener neuronaler Aktivitäten unseres Gehirns und nicht nur das einfache Ergebnis der Tätigkeit des peripheren nozizeptiven Systems. Schmerz resultiert aus dem Zusammenspiel verschiedener Module im Gehirn, die sich in verschiedenen Hirnarealen befinden. Er wird durch Erwartungen, Lernprozesse, Erfahrungen und Coping modifiziert. Elektrophysiologische Begleiterscheinungen, die mit der zentralnervösen Schmerzverarbeitung assoziiert sind, erlauben dabei eine Charakterisierung der ablaufenden Informationsverarbeitungsprozesse. Neben der grundlagentheoretischen Bedeutung spielt hier die Evaluation verschiedener Therapieansätze eine herausragende Rolle. Darüber hinaus konnte mit Hilfe der Hirnelektrizität nachgewiesen werden, daß auch die kortikalen Module des nozizeptiven Systems im Zusammenhang mit Schmerzverarbeitung funktionell reorganisiert werden. Die relativ neuen quellenanalytischen Ansätze lassen einen weiteren, deutlichen Erkenntnisgewinn über die Rolle einzelner Hirnstrukturen bei der Verarbeitung und Behandlung von Schmerz erwarten.
Pain is a natural alarm that aids the body in avoiding potential danger and can also present as an important indicator in clinics. Infrared laser-evoked potentials can be used as an objective index to evaluate nociception. In animal studies, a short-pulse laser is crucial because it completes the stimulation before escape behavior. The objective of the present study was to obtain the temporal and spatial temperature distributions in the skin caused by the irradiation of a short-pulse laser. A fast speed infrared camera was used to measure the surface temperature caused by a CO2 laser of different durations (25 and 35 ms) and power. The measured results were subsequently implemented with a three-layer finite element model to predict the subsurface temperature. We found that stratum corneum was crucial in the modeling of fast temperature response, and escape behaviors correlated with predictions of temperature at subsurface. Results indicated that the onset latency and duration of activated nociceptors must be carefully considered when interpreting physiological responses evoked by infrared irradiation.
Background/aims
Brief noxious heat stimuli activate Aδ and C fibers, and contact heat evoked potentials (CHEPs) can be recorded from the scalp. Under standard conditions, late responses related to AS fibers can be recorded. This study examines C-fiber responses to contact heat stimuli.
Methods
A preferential A-fiber blockade by compression to the superficial radial nerve was applied in 22 healthy subjects. Quality and intensity of heat evoked pain (NRS, 0–10), and CHEPs were examined at baseline, during nerve compression, and during further nerve compression with topical capsaicin (5%).
Results
During the A-fiber blockade, 3 subjects had CHEPs with latencies below 400 ms, 8 subjects within 400–800 ms and 6 subjects later than 800 ms. Pain intensity to contact heat stimuli was reduced and fewer subjects reported the heat stimuli as stinging. Following acute capsaicin application, ultralate CHEPs with latencies >800 ms could be recorded in 13 subjects, pain intensity to the contact heat stimuli was increased ( p <0.01) and more subjects reported the heat stimuli as being more warm/hot-burning.
Conclusion
The results indicate that following a compression to the superficial radial nerve, CHEPs compatible within complete A fibers or C fibers were recorded. Following sensitization with capsaicin, C-fiber responses were recorded in 62% of subjects.
The effects of smoking and nicotine on ultralate laser evoked potentials (LEPs), the EEG responses to C-fiber stimulation by a laser beam, were investigated in humans. Ultralate LEPs were repeatedly measured in two sessions, one after smoking, and the other in abstinence from smoking. The dominant frequency of the background EEG alpha activity, heart rate and venous plasma nicotine concentration were also measured. The peak-to-peak amplitude of the two major components (N2 and P2) of ultralate LEPs was significantly correlated both with the plasma nicotine concentration and with the background alpha frequency. The results suggest an arousal effect of nicotine on C-fiber mediated pain. The effect of nicotine on C-fiber LEPs was in the opposite direction of that on A fiber LEPs. The difference between C and A fibers might indicate a difference in effects of nicotine on first and second pain responses.
We recorded evoked potentials (EPs) induced by intra-epidermal electrical stimulation using a needle electrode with specific parameters. We identified the fibers activated by this specific stimulation by assessing the conduction velocity (CV) of the peripheral nerve. The EPs were recorded from the Cz electrode (vertex) of the International 10-20 system in ten healthy male subjects. The dorsum of the left hand and forearm were stimulated with an intensity of 0.01 mA above the sensory threshold. The mean P1 latency of EPs for the hand and forearm were 1007 ± 88 and 783 ± 80 ms, respectively, and the CV estimated from the latency of P1 was 1.5 ± 0.7 m/s. The CV indicated that the fibers activated by the stimulation were C fibers. Since the method of stimulation is convenient and non-invasive, it should be useful for investigating the functions of small fibers.
Laser stimuli selectively activate thermonociceptors in the skin, thus enabling the recording of cortical responses, which specifically reflect transmission along pain and temperature (spinothalamic) pathways (laser-evoked potentials, or LEPs). The usefulness of LEPs in the diagnosis of central pain stems therefore from the fact that this kind of neuropathic pain is most often the result of a lesion in pain-temperature central pathways. In the last decade, LEPS have demonstrated their capacity to detect even minute lesions of thermo-nociceptive systems. LEP abnormality during stimulation of a painful area strongly substantiates the neuropathic character of the pain, while the interpretation of a normal LEP is more ambiguous. Indeed, in rare instances central pain may stem from lesions involving exclusively non-nociceptive pathways and in these cases only the recording of somatosensory evoked potentials (SEPs) to electrical non-noxious stimulation will enable electrophysiological confirmation of the neuropathic quality of the pain. In cases of clinical symptoms of pain and hypaesthesia with strictly normal (or enhanced) LEPs and SEPs, the possibility of a somatoform or non-organic pain disorder should be considered.
Diffuse peripheral neuropathy (polyneuropathy) can be suspected in case of distal, symmetric pain affecting the lower limbs. Burning feet is usually considered a sign of small-fiber neuropathy, but this statement is probably wrong. In fact, patients with painful feet are heterogeneous, presenting both large and small fiber sensory neuropathies. Various neurophysiological methods can be applied to characterize painful neuropathies. Neurophysiological testing includes: 1) conventional electroneuromyographic assessment, comprising nerve conduction studies and needle electromyography; 2) H-reflex recording to assess proprioceptive fibers; 3) sympathetic skin reflex (SSR) recording to assess autonomic fibers; 4) quantitative sensory testing (QST) to mechanical or thermal stimuli; 5) somatosensory evoked potentials to electrical (SSEP) or laser (LEP) stimulation. An electrophysiological battery, comprising thermal QST, SSR and LEP recordings, can be used to assess small nerve fibers. An electrophysiological battery, comprising mechanical QST, H-reflex and SSEP recordings, can be used to assess large nerve fibers. The comparative analysis of results provided by these two batteries of investigation could help determine pain mechanisms involved in painful neuropathies. However, conventional electroneuromyographic assessment remains the first-line test in all cases. In the present text, the various neurophysiological methods for the evaluation of peripheral neuropathy are presented with particular emphasis on the value of LEP recordings in the diagnosis of small-fiber neuropathies.
La prise en charge diagnostique et thérapeutique des douleurs neuropathiques reste difficile car les lésions causales ne sont
pas toujours clairement identifiées. Dans le cas des atteintes périphériques, l’électrophysiologie et en particulier l’électromyographie
tiennent une place essentielle dans l’identification des fibres nerveuses impliquées et dans le suivi de leurs lésions. L’impact
sur les phénomènes de sensibilisation des centres médullaires peut également être apprécié par l’exploration des réflexes
de flexion en déterminant leurs seuils d’apparition et leurs caractéristiques de facilitation après stimulations répétitives.
Cette revue a pour objectif de décrire de façon pratique ces méthodes de quantification et de décrire les principales étiologies
périphériques en cause.
The diagnosis and the treatment of neuropathic pains may be difficult because the initial lesion of the nervous system isn’t
always clearly identified. In the case of peripheral neuropathy, electrophysiological methods and more specifically electromyography
plays a central role in the identification of the damaged fibers as well as the follow up of their lesions. Moreover, the
central impact of peripheral disease on the spinal cord sensitization can also be evaluated through the study of nociceptive
flexion reflexes, their thresholds and facilitation features after repetitive stimulations. This review will describe these
methods from a very practical point of view and describe the most frequent peripheral etiology of painful neuropathies.
A surface-negative transepidermal steady potential of approximately 30 mV exists in all areas of cephalic skin. Positive deflections of up to 2.5 mV may be superimposed upon this resting potential following sensory stimulation and probably reflect sweat gland activity. These phasic potential shifts may contaminate the scalp-recorded electroencephalogram markedly. Electrodermal potentials may be eliminated by puncturing the skin at the electrode site.RésuméUn potentiel stable surface négative trans-épidermique d'approximativement 30 mV existe sur toutes les régions du cuir chevelu. Des déflexions positives supérieures à 2.5 mV peuvent se superposer à ce potentiel de repos après stimulation sensorielle et reflètent probablement l'activité des glandes sudoripares. Ces déflexions phasiques de potentiel peuvent contaminer de façon importante l'électroencéphalogramme enregistré sur le scalp. Les potentiels électrodermaux peuvent être éliminés en ponctionnant la peau au siège de l'électrode.
Pain thresholds in humans were determined for heat stimulations of the skin before and after a mild injury induced by a single conditioning stimulus (CS) of 50 degrees C and 100 sec duration. The same stimuli were delivered to the receptive fields of C fiber and A fiber mechanoheat-sensitive nociceptors (CMH and AMH nociceptors, respectively) and of low threshold warm and cold receptors in the anesthetized monkey and to the receptive fields of CMH nociceptors recorded percutaneously from the peroneal nerve of awake humans. Pain thresholds in normal skin were matched only by the response thresholds of CMH and not AMH nociceptors. Immediately following heat injury, some pain thresholds and CMH response thresholds were elevated, but by 5 to 10 min after the CS, pain and CMH thresholds were lowered to 2 to 6 degrees C below normal (hyperalgesia and nociceptor sensitization). No other type of cutaneous receptor studied exhibited changes in threshold similar to those observed for pain and for CMH nociceptors. The magnitude of hyperalgesia in humans and the magnitude of sensitization of CMH nociceptors in monkeys following heat injury were greater for hairy than for glabrous skin. The time course of the development of hyperalgesia was not altered by ischemia or conduction block in A fibers. The results support the conclusion that altered activity in CMH nociceptors is a major peripheral determinant of cutaneous hyperalgesia following a mild heat injury to the skin.
Single trial event-related cerebral potentials (ERPs) in response to skin stimuli of various intensities and qualities in man were investigated in respect to their nociceptive information content. Electrical constant current stimuli (20 msec, 2 - 8 mA) and mechanical force controlled stimuli (20 msec, 0.8 - 3.2 N) were applied to the tip of the left middle finger. Four intensities of each stimulus quality were given, each intensity appearing 40 times in standardized randomized order. EEG segments (between 5 sec before and 500 msec after stimulus onset) were subjected to computer analysis. ERP wave form was shown to depend upon the amount of alpha waves in the prestimulus EEG. For analysis, only subjects with low power in the alpha band were selected. Principal component analysis was applied to all single trial ERPs measured using the variance-covariance matrix of association. Six principal components (PCs) were extracted accounting for about 90% of total variance. Five of the extracted PCs had well located loading maxima: PC1 (50 - 80 msec), PC4 (140 - 160 msec), PC3 (200 - 250 msec), PC4 (280 - 360 msec), PC5 (400 - 500 msec); PC6 appeared polyphasic. Analysis of variance of the mean PC scores revealed that one PC (PC1) discriminated between quality, and 4 PCs (PC1 - PC4) between quantity of stimulation. Eliminating effects of stimulus intensity resulted in two PCs (PC2, PC4) which distinguished exclusively between non-pain and pain. PCA applied to disjunctive subsets of ERPs, corresponding to the different experimental conditions, yielded practically identical sets of PCs, such that no specific ERP component emerged when pain was reported.
The relationships between different parameters of the evoked cerebral response to noxious thermal stimulation, stimulus intensity, and subjective pain were investigated in seven normal human volunteers. The evoked response was characterized by late events: a small negative peak at 164--180 ms, followed by a high amplitude positive peak at 372--391 ms. The only correlation found in this study was between the amplitude of the positive component and the qualitative and quantitative aspects of the verbal report of pain. This was manifested by a linear trend of association: an increase in the evoked response amplitude was accompanied by an increase in the magnitude of the subjective sensation. The findings suggest that the evoked response to noxious heat reflects not a mere transduction of the physical parameters of the stimulus, but rather a complex interpretative action at the cerebral level.
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.
Thesis (M.S.)--University of Washington, 1983. Includes bibliographical references (leaves [39]-54).
Cerebral potentials evoked by noxious CO2 laser stimuli in man have been referred to nociceptive A delta units. This paper shows 1) that ultra short (5 - 50 ms) high power (less than or equal to 50 W) CO2 laser skin stimuli are able to activate nociceptive C units in man, and 2) that these C nociceptors have to be assumed to terminate in the very superficial skin layer (less than or equal to 300 microns depth).
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.
Are cerebral evoked potentials reliable indices of first or second pain?
- Harkins