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Inhibition of cortical responses to Aδ inputs by a preceding C-related response: Testing the “first come, first served” hypothesis of cortical laser evoked potentials
Abstract
Although laser pulses activate concomitantly Adelta and C fibres, the corresponding brain evoked responses remain strictly limited to the Adelta component, without any potential consistent with C-fibre activation. To investigate whether this phenomenon depends on the order of arrival to the cortex ("first come first served" hypothesis) or is simply explained by A-to-C inhibition and/or lower energy associated with the desynchronised C-fibre input, we devised an experiment where the physiological order of arrival to the cortex was artificially inverted. Following a conditioning C-pulse, the cortical response to a second laser stimulus was significantly attenuated, whether it was Adelta or C. Thus, a C-volley was able to depress the response to a subsequent Adelta stimulus, in support of the "first come first served" hypothesis. However, the conditioning C-fibre stimulus attenuated significantly more a subsequent C-volley than a subsequent Adelta-volley, indicating that the suppression effect does not depend solely on the order of arrival to the cortex, but also on the ratio of energy per unit time conveyed by the successive inputs. This supports the notion that cortical evoked potentials to laser pulses (and probably to other sensory stimuli) reflect networks detecting rapid energy changes relative to a preceding baseline. The output of such networks should depend both on the time elapsed between successive inputs and on the relative energy per unit time conveyed by successive volleys. Such dedicated networks aimed at detecting energy changes may be related to orienting reactions, and can be dissociated from subjective perception.
... Myelinated Aδ-fibers are known to have faster conduction velocities (± 10 m/s) than unmyelinated C-fibers (± 1 m/s). Aδ-or C-fiber related activity was defined as a response time less than 650 ms or between 650 and 2,500 ms, respectively [2,13,14]. Response times longer than 2,500 ms were classified as stimulus not detected. From the number of responses in relation to the amount of stimuli, the response rate was derived. ...
... A mixture of two Gaussian distributions can be seen, with peak responses at 500 and 1,000 ms. The cut-off point lies at 650 ms, which corresponds to the cut-off between Aδ-and C-fiber response times described in literature [2,13,14]. ...
... Our results indicate that using 650 ms as a cut-off point to discriminate between Aδ-and C-responses is valid (Fig. 3). This matches the cut-off described in literature, which is also 650 ms [2,13,14]. When examining the response times per individual in general, two clusters can be seen that represent Aδand C-fiber responses. ...
Background: Pain is perceived through different pathways involving thinly myelinated Aδ-fibers and unmyelinated C-fibers. Aδ-fibers are responsible for a quick, sharp pain, whereas C-fibers relate to a late-onset, burning sensation. Several studies suggest that it is essential to investigate nociceptive fibers separately and in relation to each other. The aim of this study was to selectively stimulate Aδ-and C-fibers using a 980-nm diode laser by varying the laser settings and the stimulated surface area in healthy subjects.
... This threshold corre- sponded to a level of 4-5 on a verbal numerical scale ranging from 0 to 10 (where 0 = no sensation and 10 = unbearable pain; the intermediate levels being: 1 = barely perceived; 2 = lightly pricking, not painful; 3 = clearly pricking, not painful; 4 = barely painful, like pulling a hair; 5 = painful, prompting to rub the skin; 6 = very painful and distressing; 7 and more = strongly unpleasant pain). The energy density (around 80 mJ/mm 2 ) needed to reach pain thresholds was in the range of standard values established in our laboratory [45] and in previous studies [37,56,57]. To avoid skin damage, fatigue, or habituation of nociceptors, the heat spot was slightly shifted a few millimetres after each stimulus. ...
... Such a ubiquitous phenomenon has been purportedly explained by the so-called ''first come first served hypothesis''. This hypothesis states that some cortical responses behave as detectors of abrupt energy changes [43], and are mostly sensitive to the first of a series of sensory volleys reaching the cortex, while not responding to subsequent inputs of lower energy arriving shortly after [17,55,56]. This ''first come first served '' hypothesis has been successfully tested by combining Ad-and C-fibre activation using 2 laser beams [55,56], and could also explain why even a minimal coactivation of Ab responses by the concentric electrode should give rise preferentially to Ab SEPs, and occlude any subsequent Ad response [8,59]. ...
... This hypothesis states that some cortical responses behave as detectors of abrupt energy changes [43], and are mostly sensitive to the first of a series of sensory volleys reaching the cortex, while not responding to subsequent inputs of lower energy arriving shortly after [17,55,56]. This ''first come first served '' hypothesis has been successfully tested by combining Ad-and C-fibre activation using 2 laser beams [55,56], and could also explain why even a minimal coactivation of Ab responses by the concentric electrode should give rise preferentially to Ab SEPs, and occlude any subsequent Ad response [8,59]. Unfortunately, a very small contingent of non- nociceptive Ab fibres stimulated by the planar electrode, ascending through dorsal columns, may suffice to produce sizeable cortical CE-SEPs, which will dominate the waveform and prevent the detection of spinothalamic lesions. ...
Laser-evoked potentials (LEPs) are acknowledged as the most reliable laboratory tool for assessing thermal and pain pathways. Electrical stimulation with a newly developed planar concentric electrode, delivering stimuli limited to the superficial skin layers, has been suggested to provide selective activation of Aδ fibres without the inconveniences linked to laser stimulation. The aim of our study was to compare the scalp and intracranial responses to planar concentric electrode stimulation (CE-SEPs) with those of LEPs and standard somatosensory-evoked potentials (SEPs). Sixteen healthy subjects, 6 patients with intracortical electrodes, and 2 patients with selective lesions of the spinothalamic pathway were submitted to Neodymium:Yttrium-Aluminium-Perovskite laser stimulations, and electrical stimulations using standard electrodes or planar concentric electrodes (CE). In both healthy controls and epileptic implanted patients, CE- and standard SEPs showed significantly shorter latencies than LEPs. This is consistent with Aβ-fibre activation, peripheral activation time being unable to account for longer LEP latencies. In the patients with spinothalamic lesions, LEPs were absent after stimulation of the affected territory, while CE-SEPs were still present. For these 2 reasons, we conclude that the planar CE does not selectively activate the Aδ and C fibers, but coexcites a significant proportion of large myelinated Aβ fibres that dominate the ensuing cortical response. The use of CE-SEPs for the detection of spinothalamic system lesions is therefore not warranted; the planar electrode can, however, represent a useful tool to study nociceptive reflexes, which can be reliably elicited even in the presence of Aβ coactivation.
... For each subject and ISI, the amplitudes of the N1 and N2–P2 waves of the S2-LEP were measured from the subtracted average waveforms. To examine changes of S2-LEP magnitude as a function of ISI, the amplitudes of the S2-LEP peaks were expressed as a percentage of the amplitude of the LEP peaks recorded in the SINGLE condition (i.e., the same procedure used by Truini et al. 2004 Truini et al. , 2007). Statistical comparisons were performed using Prism 5.0 (GraphPad Software, San Diego, CA). ...
... The observations that when laser stimuli are presented in pairs, the S2-LEP is significantly reduced at short ISIs (Raij et al. 2003; Truini et al. 2004 Truini et al. , 2007), has been interpreted as a consequence of " neuronal refractoriness " of polysynaptic nociceptive afferent pathways and LEP generators (Truini et al. 2004) and as evidence that " only the earliest of a series of somatosensory volleys elicits cerebral responses synchronous enough to yield ERPs " (Truini et al. 2007), thus supporting the view that the first afferent volley obligatorily affects the processing of the second afferent volley ( " first come, first served " hypothesis; Garcia-Larrea 2004). This " first come, first served " hypothesis has been also suggested as an explanation for the lack of a clear C-fiber LEP following an A-fiber LEP (GarciaLarrea 2004). ...
... The observations that when laser stimuli are presented in pairs, the S2-LEP is significantly reduced at short ISIs (Raij et al. 2003; Truini et al. 2004 Truini et al. , 2007), has been interpreted as a consequence of " neuronal refractoriness " of polysynaptic nociceptive afferent pathways and LEP generators (Truini et al. 2004) and as evidence that " only the earliest of a series of somatosensory volleys elicits cerebral responses synchronous enough to yield ERPs " (Truini et al. 2007), thus supporting the view that the first afferent volley obligatorily affects the processing of the second afferent volley ( " first come, first served " hypothesis; Garcia-Larrea 2004). This " first come, first served " hypothesis has been also suggested as an explanation for the lack of a clear C-fiber LEP following an A-fiber LEP (GarciaLarrea 2004). ...
Brief radiant laser pulses selectively activate skin nociceptors and elicit transient brain responses (laser-evoked potentials [LEPs]). When LEPs are elicited by pairs of stimuli (S1-S2) delivered at different interstimulus intervals (ISIs), the S2-LEP is strongly reduced at short ISIs (250 ms) and progressively recovers at longer ISIs (2,000 ms). This finding has been interpreted in terms of order of arrival of nociceptive volleys and refractoriness of neural generators of LEPs. However, an alternative explanation is the modulation of another experimental factor: the novelty of the eliciting stimulus. To test this alternative hypothesis, we recorded LEPs elicited by pairs of nociceptive stimuli delivered at four ISIs (250, 500, 1,000, 2,000 ms), using two different conditions. In the constant condition, the ISI was identical across the trials of each block, whereas in the variable condition, the ISI was varied randomly across trials and single-stimulus trials were intermixed with paired trials. Therefore the time of occurrence of S2 was both less novel and more predictable in the constant than in the variable condition. In the constant condition, we observed a significant ISI-dependent suppression of the biphasic negative-positive wave (N2-P2) complex of the S2-LEP. In contrast, in the variable condition, the S2-LEP was completely unaffected by stimulus repetition. The pain ratings elicited by S2 were not different in the two conditions. These results indicate that the repetition-suppression of the S2-LEP is not due to refractoriness in nociceptive afferent pathways, but to a modulation of novelty and/or temporal predictability of the eliciting stimulus. This provides further support to the notion that stimulus saliency constitutes a crucial determinant of LEP magnitude and that a significant fraction of the brain activity time-locked to a brief and transient sensory stimulus is not directly related to the quality and the intensity of the corresponding sensation, but to bottom-up attentional processes.
... Laser stimulators determine concurrent activation of adelta and C nociceptors. Te late cortical responses induced by C fbers are masked by the previous activation of the faster fbers, according to the physiological properties of the cortex as "frst comes, frst serves" [2]. However, previous studies demonstrated that selective activation of C fbers could be obtained with specifc LEP recording modalities [3] elicited ultralate LEPs (U-LEPs) from the hand, using a thulium laser on a tiny surface skin area (0.23 mm). ...
... In this study, we confrmed that the stimulation with the Nd : YAP laser with the modality described by Truini et al. [2] is able to induce a warm not painful sensation in both the face and limbs. Tis subjective sensation did not correspond to the presence of clear cortical waves in all subjects even at the trigeminal level, where robust C-fbers related responses have been described [9,10]. ...
Introduction:
Although laser stimuli activate both Ad- and C-fibres, the corresponding laser evoked potentials (LEPs) remain restricted to the Ad-fibers input, while the C-fibers related potential is hardly detectable.
Aims:
To evaluate multichannel ultralate LEPs (U-LEPs) by using Nd : Yap laser pulses in healthy volunteers to stimulation of face and lower and upper limbs, in order to estimate the reliability of C-LEPs elicited from both trigeminal and somatic sites.
Methods:
Twenty healthy volunteers participated in two stimulation sessions to record Aδ-LEPs and C-LEPs. We used a Nd : YAP Laser and 62 EEG recording electrodes. Stimuli parameters were set to activate either small myelinated (Aδ), eliciting purely warmth sensations, or unmyelinated (C) afferents, and eliciting pinprick sensations.
Results:
At the trigeminal level, we obtained a negative-positive complex in a time interval compatible with the C fibers activation. In the somatic districts, the averaged responses consisted of an earlier negative-positive complex, followed by a later one. Single trials analysis of U-LEPs showed a maximal positive peak in a time interval in the range of C fibers. Topographical analysis of U-LEPs resembled that of LEPs. All subjects exhibited readable U-LEPs in at least 2 stimulated sites. Discussion. A purely warmth sensation seems to correspond to Aδ and C-fibers coactivation, at least in the somatic districts. While the related cortical waves seem hardly readable, their total absence could be a sign of systemic involvement of warm related C-fibers in specific clinical conditions.
... That is, the subjects did not report on a second, delayed, heat sensation after the 51 °C stimuli. This observation is consistent with previous investigations [14,30] and the suppression of C fiber evoked responses following the excitation of Aδ fibers [17,31]. Furthermore, the 51 > 41 fMRI contrast excludes activations mediated by the most heat-sensitive C afferents, leaving only the possibility of some fMRI activations by high threshold C heat nociceptors that did not evoke a cerebral potential. ...
... We did not elicit a clearly painful sensation with contact heat stimuli that evoked a cerebral potential mediated by C fibers without evidence for Aδ fiber excitation. The inability to evoke pain reliably, if at all, with single, brief C fiber selective stimuli is in accord with previous studies [9,14,17,27,29,31,[33][34][35][36][37]. Indeed, when psychophysical measures have been obtained, these brief C fiber stimuli have been rated below pain threshold. ...
... That is, the subjects did not report on a second, delayed, heat sensation after the 51 °C stimuli. This observation is consistent with previous investigations [14,30] and the suppression of C fiber evoked responses following the excitation of Aδ fibers [17,31]. Furthermore, the 51 > 41 fMRI contrast excludes activations mediated by the most heat-sensitive C afferents, leaving only the possibility of some fMRI activations by high threshold C heat nociceptors that did not evoke a cerebral potential. ...
... We did not elicit a clearly painful sensation with contact heat stimuli that evoked a cerebral potential mediated by C fibers without evidence for Aδ fiber excitation. The inability to evoke pain reliably, if at all, with single, brief C fiber selective stimuli is in accord with previous studies [9,14,17,27,29,31,3334353637. Indeed, when psychophysical measures have been obtained, these brief C fiber stimuli have been rated below pain threshold. ...
Brief heat stimuli that excite nociceptors innervated by finely myelinated (Aδ) fibers evoke an initial, sharp, well-localized pain ("first pain") that is distinguishable from the delayed, less intense, more prolonged dull pain attributed to nociceptors innervated by unmyelinated (C) fibers ("second pain"). In the present study, we address the question of whether a brief, noxious heat stimulus that excites cutaneous Aδ fibers activates a distinct set of forebrain structures preferentially in addition to those with similar responses to converging input from C fibers. Heat stimuli at two temperatures were applied to the dorsum of the left hand of healthy volunteers in a functional brain imaging (fMRI) paradigm and responses analyzed in a set of volumes of interest (VOI).
Brief 41°C stimuli were painless and evoked only C fiber responses, but 51°C stimuli were at pain threshold and preferentially evoked Aδ fiber responses. Most VOI responded to both intensities of stimulation. However, within volumes of interest, a contrast analysis and comparison of BOLD response latencies showed that the bilateral anterior insulae, the contralateral hippocampus, and the ipsilateral posterior insula were preferentially activated by painful heat stimulation that excited Aδ fibers.
These findings show that two sets of forebrain structures mediate the initial sharp pain evoked by brief cutaneous heat stimulation: those responding preferentially to the brief stimulation of Aδ heat nociceptors and those with similar responses to converging inputs from the painless stimulation of C fibers. Our results suggest a unique and specific physiological basis, at the forebrain level, for the "first pain" sensation that has long been attributed to Aδ fiber stimulation and support the concept that both specific and convergent mechanisms act concurrently to mediate pain.
... Studies examining the effect of stimulus repetition on the magnitude of nociceptive-evoked brain responses have shown that when nociceptive stimuli are repeated at a short and regular inter-stimulus interval, they elicit brain responses of reduced magnitude as compared to the responses elicited by nociceptive stimuli that are presented for the first time . The effect of repetition on nociceptive-evoked brain responses is largely determined by the duration of the interstimulus interval: the shorter the interval, the more pronounced the decrement of response magnitude (Bromm and Treede, 1987;Raij et al., 2003;Truini et al., 2004Truini et al., , 2007. A number of investigators have proposed that this repetition suppression results from refractoriness (Raij et al., 2003;Truini et al., 2007). ...
... The effect of repetition on nociceptive-evoked brain responses is largely determined by the duration of the interstimulus interval: the shorter the interval, the more pronounced the decrement of response magnitude (Bromm and Treede, 1987;Raij et al., 2003;Truini et al., 2004Truini et al., , 2007. A number of investigators have proposed that this repetition suppression results from refractoriness (Raij et al., 2003;Truini et al., 2007). Accordingly, repetition suppression would result from the fact that the neural receivers of the repeated stimulus enter a transient state of refractoriness following their prior activation. ...
Neuroimaging and neurophysiological studies have shown that nociceptive stimuli elicit responses in an extensive cortical network including somatosensory, insular and cingulate areas, as well as frontal and parietal areas. This network, often referred to as the "pain matrix", is viewed as representing the activity by which the intensity and unpleasantness of the perception elicited by a nociceptive stimulus are represented. However, recent experiments have reported (i) that pain intensity can be dissociated from the magnitude of responses in the "pain matrix", (ii) that the responses in the "pain matrix" are strongly influenced by the context within which the nociceptive stimuli appear, and (iii) that non-nociceptive stimuli can elicit cortical responses with a spatial configuration similar to that of the "pain matrix". For these reasons, we propose an alternative view of the functional significance of this cortical network, in which it reflects a system involved in detecting, orienting attention towards, and reacting to the occurrence of salient sensory events. This cortical network might represent a basic mechanism through which significant events for the body's integrity are detected, regardless of the sensory channel through which these events are conveyed. This function would involve the construction of a multimodal cortical representation of the body and nearby space. Under the assumption that this network acts as a defensive system signaling potentially damaging threats for the body, emphasis is no longer on the quality of the sensation elicited by noxious stimuli but on the action prompted by the occurrence of potential threats.
... Possible explanations for these findings include (1) the higher baseline temperature reduces the time required to reach the peak temperature of 51 • C, leading to the activation of a greater number of nerve fibers, and (2) at the higher temperature, the ultra-late C-fiber response does not influence the late Aδ response (Truini et al., 2007;Lagerburg et al., 2015). ...
Background: Contact heat evoked potentials (CHEPs) is used to diagnose small fiber neuropathy (SFN). We established the normal values of CHEPs parameters in Chinese adults, optimized the test technique, and determined its reproducibility.
Methods: We recruited 151 healthy adults (80 men; mean age, 37 ± 14 years). CHEPs was performed on the right forearm to determine the optimal number of stimuli, and then conducted at different sites to establish normal values, determine the effects of demographic characteristics and baseline temperature, and assess the short- (30 min) and long-term (1 year) reproducibility. N2 latency/height varied with age and sex, while P2 latency/height and N2–P2 amplitude varied with age. The optimal number of stimuli was three.
Results: N2 latency/height (t = 5.45, P < 0.001) and P2 latency/height (χ² = −4.06, P < 0.001) decreased and N2–P2 amplitude (t = −5.01, P < 0.001) and visual analog scale score (χ² = −5.84, P < 0.001) increased with increased baseline temperature (35 vs. 32°C). CHEPs parameters did not differ with time (baseline vs. 30 min vs. 1 year).
Conclusion: We established normal CHEPs values in Chinese adults. We found that CHEPs parameters changed with baseline temperature and that the short- and long-term test reproducibility were satisfactory.
... Some researchers initially interpreted the response decrement induced by stimulus repetition as a consequence of neuronal or psychological refractoriness 11,24,25 , but these interpretations have been ruled out by a number of studies showing that (i) when stimuli are repeated at an unpredictable ISI, stimulus repetition does not lead to a response decrement 10,12,14,15,23 ; (ii) the response decrement is not reflected in the perceived intensity of the stimulus 13,18 ; and (iii) the duration of neuronal refractoriness has been estimated to last only a few milliseconds, whereas the response decrement is observed at longer ISIs 13,26 . ...
Salient nociceptive and non-nociceptive stimuli elicit low-frequency local field potentials (LFPs) in the human insula. Nociceptive stimuli also elicit insular gamma-band oscillations (GBOs), possibly preferential for thermonociception, which have been suggested to reflect the intensity of perceived pain. To shed light on the functional significance of these two responses, we investigated whether they would be modulated by stimulation intensity and temporal expectation - two factors contributing to stimulus saliency. Insular activity was recorded from 8 depth electrodes (41 contacts) implanted in the left insula of 6 patients investigated for epilepsy. Thermonociceptive, vibrotactile, and auditory stimuli were delivered using two intensities. To investigate the effects of temporal expectation, the stimuli were delivered in trains of three identical stimuli (S1-S2-S3) separated by a constant 1-s interval. Stimulation intensity affected intensity of perception, the magnitude of low-frequency LFPs, and the magnitude of nociceptive GBOs. Stimulus repetition did not affect perception. In contrast, both low-frequency LFPs and nociceptive GBOs showed a marked habituation of the responses to S2 and S3 as compared to S1 and, hence, a dissociation with intensity of perception. Most importantly, although insular nociceptive GBOs appear to be preferential for thermonociception, they cannot be considered as a correlate of perceived pain.
... Responses mediated exclusively by C-fibers, an ultra-late LEP (ULEP) at a latency of about 1000 ms, can be elicited only by special methods that allow their selective activation, such as low-power heating of the skin below Aδ threshold 7,8 , pressure nerve block 9 or the stimulation of tiny skin surfaces 10 . It is not clear yet why concomitant activation of Aδ-and C-fibers does not allow the individualization of both late and ultra-late LEPs 6,11,12,13 , interestingly, depending on the intensity of stimulation, both responses can occasionally be observed 7 , also related to this issue is the recent suggestion that laser pulses may also occasionally, in special circumstances, lead to tactile sensations 14 . ...
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.
... Nociceptive threshold was obtained in all subjects with energy densities of 50-79 mJ/ mm 2 . These pain threshold values were within the normal [Leandri et al., 2006;Perchet et al., 2008;Truini et al., 2007]. To avoid damaging the skin, stimulus blocks consisted of a maximum of 20 laser pulses and the heat spot was slightly shifted over the skin surface between two successive stimuli to avoid habituation and especially peripheral nociceptor fatigue [Schwarz et al., 2000]. ...
... The mechanism of pain processing has been studied by analyzing subjective pain intensity scores and physiological measures such as brain potentials and autonomic functions following noxious stimulation that induces the whole range from modest to strong pain. However, pain-related brain potentials such as laser evoked potentials are modulated by the level of attentiveness (Garcia-Larrea et al., 1997) or stimulus-related factors such as saliency ; therefore, it is still debated as to whether the vertex "N2-P2" potential in laser evoked potentials reflects the distinctive response in central pain processing or rather attentional or orienting response that often appears regardless of sensory modality (Garcia-Larrea et al., 1997;Baumgärtner & Treede, 2009;Iannetti et al., 2008;Lee et al., 2009;Mouraux et al., 2011;Truini et al., 2004Truini et al., , 2007. We assume that if the subject's attentiveness is kept constant and stimulus-related factors are fairly controlled, feeble noxious stimulation at the pain perceptual threshold of the subject will minimize the attentional or orienting aspects of the pain-evoked response and, thereby, allow us to analyze physiological measures such as evoked potentials closely related to pain processing proper. ...
To test the hypothesis that a respiratory cycle influences pain processing, we conducted an experimental pain study in 10 healthy volunteers. Intraepidermal electrical stimulation (IES) with a concentric bipolar needle electrode was applied to the hand dorsum at pain perceptual threshold or 4 times the perceptual threshold to produce first pain during expiration or inspiration either of which was determined by the abrupt change in an exhaled CO2 level. IES-evoked potentials (IESEPs), sympathetic skin response (SSR), digital plethysmogram (DPG), and subjective pain intensity rating scale were simultaneously recorded. With either stimulus intensity, IES during expiration produced weaker pain feeling compared to IES during inspiration. The mean amplitude of N200/P400 in IESEPs and that of SSR were smaller when IES was applied during expiration. The magnitude of DPG wave gradually decreased after IES, but a decrease in the magnitude of DPG wave was less evident when IES was delivered during expiration. Regardless of stimulus timing or stimulus intensity, pain perception was always concomitant with appearance of IESEPs and SSR, and changes in DPG. Our findings suggest that pain processing fluctuates during normal breathing and that pain is gated within the central nervous system during expiration.
... Therefore, it is likely that late and ultra-late responses share common generators. It has been suggested that due to a refractory period of these generators following A␦-input, the later arriving C-fiber input does not elicit an ultralate response due to the generators being in a state of transient refractory and a first come, first served effect [51,67]. However, Mouraux et al. (2004) questioned this hypothesis and demonstrated that the second of two consecutive stimuli could elicit a response unaffected by the proposed refractory period [68]. ...
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.
... The mechanism of pain processing has been studied by analyzing subjective pain intensity scores and physiological measures such as brain potentials and autonomic functions following noxious stimulation that induces the whole range from modest to strong pain. However, pain-related brain potentials such as laser evoked potentials are modulated by the level of attentiveness (Garcia-Larrea et al., 1997) or stimulus-related factors such as saliency ; therefore, it is still debated as to whether the vertex "N2-P2" potential in laser evoked potentials reflects the distinctive response in central pain processing or rather attentional or orienting response that often appears regardless of sensory modality (Garcia-Larrea et al., 1997;Baumgärtner & Treede, 2009;Iannetti et al., 2008;Lee et al., 2009;Mouraux et al., 2011;Truini et al., 2004Truini et al., , 2007. We assume that if the subject's attentiveness is kept constant and stimulus-related factors are fairly controlled, feeble noxious stimulation at the pain perceptual threshold of the subject will minimize the attentional or orienting aspects of the pain-evoked response and, thereby, allow us to analyze physiological measures such as evoked potentials closely related to pain processing proper. ...
... 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.
... Interestingly, in the case of noxious stimuli and the application of short ISIs, this reduced cortical activity is not accompanied with an altered pain perception [36]. Several mechanisms are proposed to explain this RS at short ISIs [37], including refractoriness in nociceptive afferent pathways [38] and temporal predictability [36]. However, since in the current study ISIs of the US (i.e. the SEP-evoking stimuli) were identical between the paired and random group and furthermore relatively long (i.e. 2 seconds during the baseline measurement and varying from 13 to 324 seconds during session 2 and 3). ...
Somatosensory-evoked potentials (SEPs) are used in humans and animals to increase knowledge about nociception and pain. Since the SEP in humans increases when noxious stimuli are administered unpredictably, predictability potentially influences the SEP in animals as well. To assess the effect of predictability on the SEP in animals, classical fear conditioning was applied to compare SEPs between rats receiving SEP-evoking electrical stimuli either predictably or unpredictably. As in humans, the rat's SEP increased when SEP-evoking stimuli were administered unpredictably. These data support the hypothesis that the predictability of noxious stimuli plays a distinctive role in the processing of these stimuli in animals. The influence of predictability should be considered when studying nociception and pain in animals. Additionally, this finding suggests that animals confronted with (un)predictable noxious stimuli can be used to investigate the mechanisms underlying the influence of predictability on central processing of noxious stimuli.
... Others report capsaicin increasing LEP amplitudes related to C fiber activity but not A␦ activity (Tzabazis et al. 2011), while contact heat-evoked potentials have decreased N2/P2 latencies but unchanged amplitudes after capsaicin (Madsen et al. 2012). Taken together these results suggest a central interaction of activity evoked by A␦ and C fibers, and our data indicate that enhanced C nociceptor ongoing activity following mustard oil sensitization desynchronizes the A␦-mediated signaling (Tran et al. 2008;Truini et al. 2007). ...
Everyday painful experiences are usually single events accompanied by tissue damage and yet most experimental studies of cutaneous nociceptive processing in the brain use repeated laser, thermal or electrical stimulation that do not damage the skin. In this study the nociceptive activity in the brain evoked by tissue damaging skin lance was analysed using electroencephalography (EEG) in twenty healthy adult volunteers (thirteen male and seven female) aged 21-40 years. Time frequency analysis of the evoked activity revealed a distinct late event related vertex potential (Lance Event Related Potential, LERP) at 100-300 ms consisting of a phase-locked energy increase between 1-20 Hz (delta-beta bands). A pairwise comparison between lance and sham control also revealed a period of ultra-late stronger desynchronization following lance in the delta band (1-5 Hz). Skin application of mustard oil before lancing, which sensitises a subpopulation of nociceptors expressing the cation channel, TRPA1, did not affect the ultra-late desynchronisation but reduced the phase-locked energy increase in delta and beta bands, suggesting a central interaction between different modalities of nociceptive inputs. Verbal descriptor screening of individual pain experience revealed that lance pain is predominantly due to Aδ fibre activation, but when individuals describe lances as C fibre mediated, an ultra-late delta-band event related desynchronisation occurs in the brain evoked activity. We conclude that pain evoked by acute tissue damage is associated with distinct Aδ- and C-fibre mediated patterns of synchronization and desynchronization of EEG oscillations in the brain.
... Yet, the present experiment does not allow us to answer whether the purported mismatch responses may rely only on sensory memory mechanisms (Naatanen, Paavilainen, Rinne, & Alho, 2007) or whether they are contributed by neural refractoriness and lateral inhibition mechanisms (May & Tiitinen, 2010). Interestingly, previous research in the domain of cortical responses elicited by repeated nociceptive stimuli of identical energy (Iannetti, Hughes, Lee, & Mouraux, 2008;Wang, Mouraux, Liang, & Iannetti, 2010) seems to support the notion that the suppression of nociceptive-related ERPs are strongly determined by the novelty (as a function of saliency) of the eliciting stimulus (Valentini, Torta, Mouraux, & Iannetti, 2011;Wang et al., 2010), rather than by neural refractoriness per se (Truini, Galeotti, Cruccu, & Garcia-Larrea, 2007;Truini et al., 2004). However, contemporary research in the field of auditory MMN increasingly put forth the idea that neural adaptation and sensory memory may be reconciled within the predictive coding framework (Garrido, Kilner, Stephan, & Friston, 2009). ...
We studied whether nociceptive mismatch negativity (nMMN) could be obtained as result of nociceptive fibers stimulation. The purported nMMN revealed a topography similar to the somatosensory MMN (sMMN), which was observed at the bilateral temporal regions of the scalp. Importantly, only early negativities (100-250 ms) located at these regions revealed a selective modulation associated to the processing of deviancy regardless of the attentional focus. The amplitude modulation of the sMMN had an earlier onset than the nMMN (110 ms vs. 182 ms) as well as a larger difference of latency between the contralateral and the ipsilateral onset of the activity (52 ms vs. 4 ms). Altogether, these observations provide evidence that (a) a nMMN can be elicited by nociceptive stimuli, and (b) the nMMN is topographically similar to the sMMN while differing in latency and possibly in functional organization of their generators.
... Nociceptive threshold was obtained in all subjects with energy densities of 50-79 mJ/ mm 2 . These pain threshold values were within the normal [Leandri et al., 2006;Perchet et al., 2008;Truini et al., 2007]. To avoid damaging the skin, stimulus blocks consisted of a maximum of 20 laser pulses and the heat spot was slightly shifted over the skin surface between two successive stimuli to avoid habituation and especially peripheral nociceptor fatigue [Schwarz et al., 2000]. ...
Behavioral reactions to sensory stimuli during sleep are scarce despite preservation of sizeable cortical responses. To further understand such dissociation, we recorded intracortical field potentials to painful laser pulses in humans during waking and all-night sleep. Recordings were obtained from the three cortical structures receiving 95% of the spinothalamic cortical input in primates, namely the parietal operculum, posterior insula, and mid-anterior cingulate cortex. The dynamics of responses during sleep differed among cortical sites. In sleep Stage 2, evoked potential amplitudes were similarly attenuated relative to waking in all three cortical regions. During paradoxical, or rapid eye movements (REM), sleep, opercular and insular potentials remained stable in comparison with Stage 2, whereas the responses from mid-anterior cingulate abated drastically, and decreasing below background noise in half of the subjects. Thus, while the lateral operculo-insular system subserving sensory analysis of somatic stimuli remained active during paradoxical-REM sleep, mid-anterior cingulate processes related to orienting and avoidance behavior were suppressed. Dissociation between sensory and orienting-motor networks might explain why nociceptive stimuli can be either neglected or incorporated into dreams without awakening the subject. Hum Brain Mapp, 2011. © 2011 Wiley-Liss, Inc.
... Noxious cutaneous laser stimulation was used to measure pain thresholds and subsequently to evoke pain-related cortical potentials (laser-evoked potentials, LEPs) that are widely used to investigate peripheral and central pain pathways in pain research and clinical studies [47,111]. In general, standard LEPs assess the activation of Ad fibers, whereas C fiber investigation requires specific protocols [112]. ...
Noninvasive cortical stimulation (NICS) can produce analgesic effects by means of repetitive transcranial magnetic stimulation or transcranial direct current stimulation (tDCS). Such effects have been demonstrated on chronic ongoing pain, as in acute provoked pain. The investigation of induced changes in the perception of experimental pain by NICS could help clinicians and researchers to better understand the mechanisms of action involved with these techniques and the role played by the cortex in the integration of nociceptive information. This review presents current literature data on the modulation of experimental pain perception by cortical stimulation. The observations found that NICS analgesic effects depend on the method used to provoke pain (referring to the type of nerve fibers and neural circuits that are recruited to mediate pain) and the parameters of cortical stimulation (especially the nature of the cortical target). The motor cortex (precentral cortical area) is the most widely used target for pain modulation. However, other targets, such as the dorsolateral prefrontal cortex, could be of particular interest to modulate various components of pain. Further developments in NICS techniques, such as image-guided navigated brain stimulation, might lead to improvement in the beneficial effects of NICS on pain. Finally, we discuss whether the results obtained in experimental pain can be transposed to the problem of chronic pain and whether they can be used to optimize cortical stimulation therapy for pain disorders.
... Ã P = 0.04; ÃÃ P < 0.001. tsDCS probably because even a minimal afferent input is sufficient to maintain it normal (Truini et al., 2007(Truini et al., , 2010. Second the subjective pain rating to laser and cold stimuli markedly differs from clinical pain. ...
Despite concerted efforts from pharmacologic research into neuropathic pain, many patients fail to achieve sufficient pain relief with medication alone. For this reason, increasing interest centres on neurostimulation techniques. We assessed whether transcutaneous spinal direct current stimulation (tsDCS) modulates conduction in ascending nociceptive spinal pathways. We measured changes induced by anodal and cathodal tsDCS over the thoracic spinal cord on face‐ and foot‐laser evoked potentials (LEPs) and foot‐cold pressor test responses in 20 healthy subjects. Whereas anodal tsDCS reduced the amplitude of the N1 and N2 components of foot‐LEPs ( P < 0.05) neither anodal nor cathodal tsDCS changed LEPs evoked by face stimulation. Pain tolerance to the cold pressor test was significantly higher after anodal than after cathodal tsDCS ( P < 0.05). Conversely, no difference was found in the pain threshold or pain ratings to the cold pressor test between the two polarity conditions.
Our data suggest that anodal tsDCS over the thoracic spinal cord might impair conduction in the ascending nociceptive spinal pathways, thus modulating LEPs and increasing pain tolerance in healthy subjects.
... Energy densities were set between 50 and 79 mJ/mm 2 . These figures were within the normal values in our laboratory , and in accordance with published experimental data using Nd:YAP lasers (Leandri et al., 2006;Truini et al., 2007). ...
The autonomic nervous system (ANS) reacts to nociceptive stimulation during sleep, but whether this reaction is contingent to cortical arousal, and whether one of the autonomic arms (sympathetic/parasympathetic) predominates over the other remains unknown. We assessed ANS reactivity to nociceptive stimulation during all sleep stages through heart rate variability, and correlated the results with the presence of cortical arousal measured in concomitant 32-channel EEG. Fourteen healthy volunteers underwent whole-night polysomnography during which nociceptive laser stimuli were applied over the hand. RR intervals (RR) and spectral analysis by wavelet transform were performed to assess parasympathetic (HF(WV)) and sympathetic (LF(WV) and LF(WV)/HF(WV) ratio) reactivity. During all sleep stages, RR significantly decreased in reaction to nociceptive stimulations, reaching a level similar to that of wakefulness, at the 3rd beat post-stimulus and returning to baseline after seven beats. This RR decrease was associated with an increase in sympathetic LF(WV) and LF(WV)/HF(WV) ratio without any parasympathetic HF(WV) change. Albeit RR decrease existed even in the absence of arousals, it was significantly higher when an arousal followed the noxious stimulus. These results suggest that the sympathetic-dependent cardiac activation induced by nociceptive stimuli is modulated by a sleep dependent phenomenon related to cortical activation and not by sleep itself, since it reaches a same intensity whatever the state of vigilance.
... Recent experiments also suggest the importance of a mutual inhibitory interaction at spinal or supraspinal sites of A-and C-nociceptor activation affecting the brain activity induced by either fi ber system. 33,34 Enhanced C-nociceptor background activity following capsaicin sensitization may therefore have contributed to diminished A-nociceptor ER I/TR I activity. In contrast, the dominant feature of fi rst pain elicited by laser stimuli and the fact that it always precedes second pain may be important for the blocking of C-fi ber-related EEG-oscillations C-fi ber correlates in the evoked EEG by A-nociceptor input on normal skin. ...
Nociceptive input reaches the brain via two different types of nerve fibers, moderately fast A-delta and slowly conducting C-fibers, respectively. To explore their distinct roles in normal and inflammatory pain we used laser stimulation of normal and capsaicin treated skin at proximal and distal arm sites in combination with time frequency transformation of electroencephalography (EEG) data. Comparison of phase-locked (evoked) and non-phase-locked (total) EEG to laser stimuli revealed three significant pain-related oscillatory responses. First, an evoked response in the delta-theta band, mediated by A-fibers, was reduced by topical capsaicin treatment. Second, a decrease of total power in the alpha-to-gamma band reflected both an A- and C-nociceptor-mediated response with only the latter being reduced by capsaicin treatment. Finally, an enhancement of total power in the upper beta band was mediated exclusively by C-nociceptors and appeared strongly augmented by capsaicin treatment. These findings suggest that phase-locking of brain activity to stimulus onset is a critical feature of A-delta nociceptive input, allowing rapid orientation to salient and potentially threatening events. In contrast, the subsequent C-nociceptive input exhibits clearly less phase coupling to the stimulus. It may primarily signal the tissue status allowing more long-term behavioral adaptations during ongoing inflammatory events that accompany tissue damage.
... The influence of the context on the pain matrix response When a nociceptive stimulus is repeated at short and constant inter-stimulus interval, it elicits an ERP of smaller magnitude (e.g., Mouraux and Iannetti 2008). This effect of stimulus repetition is largely determined by the duration of the inter-stimulus interval: the shorter the interval, the more pronounced the response decrement (Bromm and Treede 1987; Raij et al. 2003; Truini et al. 2004; Truini et al. 2007). Previous studies have shown that the effect of stimulus repetition on the magnitude of nociceptive ERPs cannot be attributed to refractoriness of the afferent neural pathways or of the underlying cortical generators. ...
Pain is a conscious experience, crucial for survival. To investigate the neural basis of pain perception in humans, a large number of investigators apply noxious stimuli to the body of volunteers while sampling brain activity using different functional neuroimaging techniques. These responses have been shown to originate from an extensive network of brain regions, which has been christened the Pain Matrix and is often considered to represent a unique cerebral signature for pain perception. As a consequence, the Pain Matrix is often used to understand the neural mechanisms of pain in health and disease. Because the interpretation of a great number of experimental studies relies on the assumption that the brain responses elicited by nociceptive stimuli reflect the activity of a cortical network that is at least partially specific for pain, it appears crucial to ascertain whether this notion is supported by unequivocal experimental evidence. Here, we will review the original concept of the "Neuromatrix" as it was initially proposed by Melzack and its subsequent transformation into a pain-specific matrix. Through a critical discussion of the evidence in favor and against this concept of pain specificity, we show that the fraction of the neuronal activity measured using currently available macroscopic functional neuroimaging techniques (e.g., EEG, MEG, fMRI, PET) in response to transient nociceptive stimulation is likely to be largely unspecific for nociception.
The coherent perceptual experience of one's own body depends on the processing and integration of signals from multiple sensory modalities, including vision, touch, and proprioception. Although nociception provides critical information about damage to the tissues of one's body, little is known about how nociception contributes to own-body perception. A classic experimental approach to investigate the perceptual and neural mechanisms involved in the multisensory experience of one's own body is the rubber hand illusion (RHI). During the RHI, people experience a rubber hand as part of their own body (sense of body ownership) caused by synchronized stroking of the rubber hand in the participant's view and the hidden participant's real hand. We examined whether the RHI can be elicited by visual and “pure” nociceptive stimulation, ie, without tactile costimulation, and if so, whether it follows the basic perceptual rules of the illusion. In 6 separate experiments involving a total of 180 healthy participants, we used a Nd:YAP laser stimulator to specifically target C and Aδ fibers in the skin and compared the illusion condition (congruent visuonociceptive stimulation) to control conditions of incongruent visuonociceptive, incongruent visuoproprioceptive, and no nociceptive stimulation. The illusion was quantified through direct (questionnaire) and indirect (proprioceptive drift) behavioral measures. We found that a nociceptive rubber hand illusion (N-RHI) could be elicited and that depended on the spatiotemporal congruence of visuonociceptive signals, consistent with basic principles of multisensory integration. Our results suggest that nociceptive information shapes multisensory bodily awareness and contributes to the sense of body ownership.
Background:
Innocuous cooling of the skin activates cold-specific Aδ fibres, and hence, the recording of cold-evoked potentials (CEPs) may improve the objective assessment of human thermo-nociceptive function. While the feasibility of CEP recordings in healthy humans has been reported, their reliability and diagnostic use in clinical conditions have not been documented.
Methods:
Here, we report the results of CEP recordings in 60 consecutive patients with suspected neuropathic pain, compared with laser-evoked potentials (LEPs) which are the gold standard for thermo-algesic instrumental assessment.
Results:
CEP recording was a well-tolerated procedure, with only ~15 min of surplus in exam duration. The reproducibility and signal-to-noise ratio of CEPs were lower than those of LEPs, in particular for distal lower limbs (LLs). While laser responses were interpretable in all patients, CEPs interpretation was inconclusive in 5/60 because of artefacts or lack of response on the unaffected side. Both techniques yielded concordant results in 73% of the patients. In 12 patients, CEPs yielded abnormal values while LEPs remained within normal limits; 3 of these patients had clinical symptoms limited to cold sensations, including cold-heat transformation.
Conclusions:
CEPs appear as a useful technique for exploring pain/temperature systems. Advantages are low cost of equipment and innocuity. Disadvantages are low signal-to-noise ratio for LL stimulation, and sensitivity to fatigue/habituation. Joint recording of CEPs and LEPs can increase the sensitivity of neurophysiological techniques to thin fibre- spinothalamic lesions, in particular, when abnormalities of cold perception predominate.
Significance:
Recording of cold-evoked potentials is a well-tolerated, inexpensive and easy-to-use procedure that can be helpful in the diagnosis of abnormalities in the thin fibre- spinothalamic pathways. Supplementing LEPs with CEPs allows consolidating the diagnosis and, for some patients suffering from symptoms limited only to cold, CEPs but not LEPs may allow the diagnosis of thin fibre pathology. Optimal CEP recording conditions are important to overcome the low signal-to-noise ratio and habituation phenomena, which are less favourable than with LEPs.
To protect our body against physical threats, it is important to integrate the somatic and extra-somatic inputs generated by these stimuli. Temporal synchrony is an important parameter determining multisensory interaction, and the time taken by a given sensory input to reach the brain depends on the length and conduction velocity of the specific pathways through which it is transmitted. Nociceptive inputs are transmitted through very slow conducting unmyelinated C and thinly myelinated Aδ nociceptive fibers. It was previously shown that to perceive a visual stimulus and a thermo-nociceptive stimulus applied on the hand as coinciding in time, the nociceptive stimulus must precede the visual one by 76 ms for nociceptive inputs conveyed by Aδ fibers and 577 ms for inputs conveyed by C fibers. Since spatial proximity is also hypothesized to contribute to multisensory interaction, the present study investigated the effect of spatial congruence between visual and nociceptive stimuli. Participants judged the temporal order of visual and nociceptive stimuli, with the visual stimuli flashed either next to the stimulated hand or next to the opposite unstimulated hand, and with nociceptive stimuli evoking responses mediated by either Aδ or C fibers. The amount of time by which the nociceptive stimulus had to precede the visual stimulus for them to be perceived as appearing concomitantly was smaller when the visual stimulus occurred near the hand receiving the nociceptive stimulus as compared to when it occurred near the contralateral hand. This illustrates the challenge for the brain to process the synchrony between nociceptive and non-nociceptive stimuli to enable their efficient interaction to optimize defensive reaction against physical dangers.
Objective
In this clinical and neurophysiological study, we aimed to test trigeminal nerve fibre function in patients with trigeminal neuralgia, with and without concomitant continuous pain.
Methods
We enrolled 65 patients with a definite diagnosis of primary trigeminal neuralgia. Patients were grouped according to whether they experienced purely paroxysmal pain (36) or also had concomitant continuous pain (29). All participants underwent trigeminal reflex testing to assess the function of large non-nociceptive myelinated fibres and laser-evoked potentials to assess the function of small myelinated Aδ and unmyelinated C fibres. Neurophysiological examiners were blinded to the affected side.
Results
The only neurophysiological abnormality distinguishing the two groups of patients was the side asymmetry of C fibre-related laser-evoked potential amplitude (p =0.005), which was higher in patients with concomitant continuous pain than in patients with purely paroxysmal pain (indicative of a reduced C fibre-related laser-evoked potential amplitude in the affected side of patients with concomitant continuous pain).
Conclusions
Our clinical and neurophysiological study indicates that in patients with trigeminal neuralgia concomitant continuous pain is associated with unmyelinated C fibre damage as assessed with laser-evoked potentials.
Significance
Our findings suggest that concomitant continuous pain is related to unmyelinated C fibre loss, possibly triggering abnormal activity in denervated trigeminal second-order neurons.
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.
Objectives
We aimed to investigate the conduction velocity of the cold spinal pathway in healthy humans.
Methods
Using a cold stimulator consisting of micro‐Peltier elements that was able to produce steep cooling ramps up to ‐300°C/s we recorded cold‐evoked potentials after stimulation of the dorsal midline at C5, T2, T6, and T10 vertebral levels and calculated the conduction velocity of the cold spinal pathway. In all participants, we used laser stimulation to deliver painful heat (Aδ‐fibres mediated) and warm (C‐fibres mediated) stimuli to the same sites in order to compare the conduction velocity of the cold spinal pathway with that of the nociceptive and warm spinal pathways.
Results
Cold stimulation evoked large‐amplitude vertex potentials from all stimulation sites. The mean conduction velocity of the cold spinal pathway was 12.0 m/s, which did not differ from that of the nociceptive spinal pathway (10.5 m/s). The mean conduction velocity of the warm spinal pathway was 2.0 m/s.
Discussion
This study provides previously unreported findings regarding cold spinal pathway conduction velocity in humans, that may be useful in the assessment of spinal cord lesions, as well as in intraoperative monitoring during spinal surgery.
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.
Nonnoxious warmth reduces both perceived pain intensity and the amplitude of EEG markers of pain. However, the spatial properties of thermonociceptive interaction, and the level of sensory processing at which it occurs, remain unclear. We investigated whether interchannel warmth-pain interactions occur before or after intrachannel spatial summation of warmth. Warm stimuli were applied to the fingers of the right hand. Their number and location were manipulated in different conditions. A concomitant noxious test pulse was delivered to the middle finger using a CO 2 laser. We replicated the classical suppressive effect of warmth on both perceived pain intensity and EEG markers. Importantly, inhibition of pain was not affected by the location and the number of thermal stimuli, even though they increased the perceived intensity of warmth. Our results therefore suggest that the inhibitory effect of warmth on pain is not somatotopically organized. The results also rule out the possibility that warmth affects nociceptive processing after intrachannel warmth summation.
NEW & NOTEWORTHY We used spatial summation of warmth as a model to investigate thermonociceptive interactions. Painful CO 2 laser pulses were delivered during different thermal conditions. We found that warmth inhibited pain regardless of its location. Crucially, spatial summation of multiple warm stimuli did not further inhibit pain. These findings suggest that warmth-pain interaction occurs independently of or after spatial summation of warmth.
Although the most widely agreed neurophysiological tool for investigating small fibre damage is laser evoked potential (LEP) recording, no study has documented its diagnostic accuracy. In this clinical, neurophysiological and skin biopsy study we collected age-corrected LEP normative ranges, verified the association of LEPs with pinprick sensory disturbances in the typical diabetic mixed-fibre polyneuropathy and assessed the sensitivity and specificity of LEPs in diabetic small-fibre neuropathy.From 288 LEP recordings from the face, hand and foot in 73 healthy subjects we collected age-corrected normative ranges for LEPs. We then selected 100 patients with mixed-fibre diabetic neuropathy and 25 patients with possible small-fibre diabetic neuropathy. In the 100 patients with mixed-fibre neuropathy we verified how LEP abnormalities were associated with clinically evident pinprick sensory disturbances. In the 25 patients with possible pure small-fibre neuropathy, using the skin biopsy for assessing the intraepidermal nerve fibre density, as a reference standard, we calculated LEP sensitivity and specificity.In healthy participants, age strongly influenced normative ranges for all LEP variables. By applying age-corrected normative ranges for LEPs, we found that LEPs were strongly associated with pinprick sensory disturbances. In relation to the skin biopsy findings, LEPs yielded 78% sensitivity and 81% specificity in the diagnosis of diabetic small-fibre neuropathy.Our study, providing age-corrected normative ranges for the main LEP data and their diagnostic accuracy, helps to make LEPs more reliable as a clinical diagnostic tool, and proposes this technique as a less invasive alternative to skin biopsy for diagnosing diabetic small-fibre neuropathy.
Background
Individuals frequently show habituation to repeated noxious heat. However, given the defensive function of human pain processing, it is reasonable to assume that individuals anticipate that they would become increasingly sensitive to repeated thermal pain stimuli. No previous studies have, however, been addressed to this assumption. Therefore, in the current study, we investigated how healthy human individuals imagine the intensity of repeated thermal pain stimulations, and compared this with the intensity ratings given after physically induced thermal pain trials.
Methods
Healthy participants (N = 20) gave pain intensity ratings in two conditions: imagined and real thermal pain. In the real pain condition, thermal pain stimuli of two intensities (minimal and moderate pain) were delivered in four consecutive trials. The duration of the peak temperature was 20 s, and stimulation was always delivered to the same location. In each trial, participants rated the pain intensity twice, 5 and 15 s after the onset of the peak temperature. In the imagined pain condition, participants were subjected to a reference pain stimulus and then asked to imagine and rate the same sequence of stimulations as in the induced pain condition.
Results
Ratings of imagined pain and physically induced pain followed opposite courses over repeated stimulations: Ratings of imagined pain indicated sensitization, whereas ratings for physically induced pain indicated habituation. The findings were similar for minimal and moderate pain intensities.
Conclusions
The findings suggest that, rather than habituating to pain, healthy individuals imagine that they would become increasingly sensitive to repeated thermal pain stimuli.
Significance
This study identified opposite patterns of change in perception of imagined pain (sensitization) and physically induced pain (habituation). The findings show that individuals anticipate that they would become increasingly sensitive to repeated pain stimuli, which might also have clinical implications.
Neuropathic pain, ie, pain arising directly from a lesion or disease affecting the somatosensory afferent pathway, manifests with various symptoms, the commonest being ongoing burning pain, electrical shock-like sensations, and dynamic mechanical allodynia. Reliable insights into the mechanisms underlying neuropathic pain symptoms come from diagnostic tests documenting and quantifying somatosensory afferent pathway damage in patients with painful neuropathies. Neurophysiological investigation and skin biopsy studies suggest that ongoing burning pain primarily reflects spontaneous activity in nociceptive-fiber pathways. Electrical shock-like sensations presumably arise from high-frequency ectopic bursts generated in demyelinated, nonnociceptive, Aβ fibers. Although the mechanisms underlying dynamic mechanical allodynia remain debatable, normally innocuous stimuli might cause pain by activating spared and sensitized nociceptive afferents. Extending the mechanistic approach to neuropathic pain symptoms might advance targeted therapy for the individual patient and improve testing for new drugs.
Recent studies applied laser-evoked potentials (LEP) for the analysis of small nerve fibre function and focused on the detection of stable C-fibre-mediated potentials (C-LEPs); high technical requirements were needed. The diagnostic significance is still controversially discussed. So far, only few studies focused on the susceptibility of C-LEPs to distraction and other influences. We hypothesized that C-LEPs are altered by habituation processes and distraction.
Twelve subjects were tested with a C-fibre laser set-up (neodymium:yttrium-aluminium-perovskite laser with a 10-mm beam diameter and 10-ms stimulus time) at the left perioral area. In condition I, the subjects received repetitive painful laser stimuli at the right hand to induce habituation. In condition II, the subjects had to fulfil an auditory discrimination task (where the subjects had to estimate the pitch of different tones on a scale for 20 min). C-LEPs were retrieved before and after the habituation or distraction paradigm. C-LEPs were also measured in a control group who was not influenced by laser stimuli or other disturbances during a 23-min break between the two test sessions.
In both test conditions, there was significant C-LEP amplitude reduction. The LEP amplitudes of the control group remained unchanged.
In the approach of detecting C-fibre-mediated potentials with LEP, future studies should take the high susceptibility to distraction and habituation into account.
© 2015 European Pain Federation - EFIC®
The autonomic nervous system (ANS) reacts to nociceptive stimulation during sleep, but whether this reaction is contingent to cortical arousal, and whether one of the autonomic arms (sympathetic/parasym-pathetic) predominates over the other remains unknown. We assessed ANS reactivity to nociceptive stimulation during all sleep stages through heart rate variability, and correlated the results with the presence of cortical arousal measured in concomitant 32-channel EEG. Fourteen healthy volunteers underwent whole-night polysomnography during which nociceptive laser stimuli were applied over the hand. RR intervals (RR) and spectral analysis by wavelet transform were performed to assess parasympa-thetic (HF WV) and sympathetic (LF WV and LF WV /HF WV ratio) reactivity. During all sleep stages, RR significantly decreased in reaction to nociceptive stimulations, reaching a level similar to that of wakefulness, at the 3rd beat post-stimulus and returning to baseline after seven beats. This RR decrease was associated with an increase in sympathetic LF WV and LF WV /HF WV ratio without any parasympathetic HF WV change. Albeit RR decrease existed even in the absence of arousals, it was significantly higher when an arousal followed the noxious stimulus. These results suggest that the sympathetic-dependent cardiac activation induced by nociceptive stimuli is modulated by a sleep dependent phenomenon related to cortical activation and not by sleep itself, since it reaches a same intensity whatever the state of vigilance.
Emerging evidence associates fibromyalgia (FM) with pain system dysfunction. In this study, using laser evoked potentials (LEPs) and paired laser stimuli, we tested excitability in the pain matrices and sought possible changes in patients with FM.
In 20 patients with FM and 15 healthy subjects, after recording control nociceptive system-mediated Aδ- and C-fibre-related LEPs, we measured excitability in the pain matrices by testing the Aδ-LEP conditioned by a preceding C-LEP.
No difference was found in control LEP amplitudes for Aδ- or C-fibres between patients and healthy subjects. Conversely, the Aδ-LEP amplitude, conditioned by a preceding C-LEP, was significantly higher in patients than in healthy subjects (p<0.001).
Objective evidence from increased conditioned Aδ-LEP amplitudes reflecting hyperexcitability in the pain matrices in FM, provides diagnostically useful information and might help in developing new therapeutic approaches.
Introduction:
Contact heat evoked potentials (CHEPs) may be an objective, non-invasive diagnostic tool in small-fiber neuropathy (SFN). This study establishes normal CHEP values and examines their applicability in SFN patients.
Methods:
Standardized CHEPs were administered at the wrist and ankle. The N2 and P2 latencies and N2 -P2 peak-peak amplitude were recorded by electroencephalography. We examined healthy subjects (n = 97), stratified by age and gender, and SFN patients with abnormal intraepidermal nerve fiber density (n = 42). CHEP reproducibility and interobserver values were also investigated.
Results:
CHEP normative values were determined. There was a 9-16% increase in latency per centimeter of height with increasing age. Amplitudes were higher in women than men, and decreased (17-71%) with aging. Test-retest reproducibility and interobserver values were >0.61 and >0.96, respectively. CHEPs were abnormal in 73.8% of the patients.
Conclusion:
In this study we have established normal values, reliability, and clinical applicability of CHEPs in SFN.
For most clinical assessments, reporting perception of a painful event has relied on subjective ratings [e.g., the visual analog scale (VAS)]. A more quantifiable and objective method is desirable, preferably one that is directly related to the physiological processing of nociceptive stimuli. An
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.
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.
Neurophysiological techniques help in diagnosis, prognosis and treatment of chronic pain, and are particularly useful to determine its neuropathic origin. According to current standards, the diagnosis of definite neuropathic pain (NP) needs objective confirmation of a lesion or disease of somatosensory systems, which can be provided by neurophysiological testing. Lesions causing NP mostly concern the pain-temperature pathways, and therefore neurophysiological procedures allowing the specific testing of these pathways (i.e., A-delta and C-fibres, spino-thalamo-cortical tracts) are essential for objective diagnosis. Different techniques to stimulate selectively pain-temperature pathways are discussed. Of these, laser-evoked potentials (LEPs) appear as the easiest and most reliable neurophysiological method of assessing nociceptive function, and their coupling with autonomic responses (e.g., galvanic skin response) and psychophysics (quantitative sensory testing - QST) can still enhance their diagnostic yield. Neurophysiological techniques not exploring specifically nociception, such as standard nerve conduction velocities (NCV) and SEPs to non-noxious stimulation, should be associated to the exploration of nociceptive systems, not only because both may be simultaneously affected to different degrees, but also because some specific painful symptoms, such as paroxysmal discharges, may depend on specific alteration of highly myelinated A-beta fibres. The choice of techniques is determined after anamnesis and clinical exam, and tries to answer a number of questions: (a) is the pain-related to injury of somatosensory pathways?; (b) to what extent are different subsystems affected?; (c) are mechanisms and lesion site in accordance with imaging data?; (d) are results of use for diagnostic or therapeutic follow-up? Neuropathic pain (NP) affects more than 15 million people in Western countries, and its belated diagnosis leads to insufficient or delayed therapy. The use of neurofunctional approaches to obtain a "physiological photograph" of somatosensory function is therefore highly relevant, as it yields significant clues about the type and mechanisms of pain, thus prompting rapid and optimised therapy.
To examine changes in contact heat evoked potentials (CHEPs) and perceived pain intensity following acute sensitization with topical capsaicin.
CHEPs were recorded before and after 20 min of topical capsaicin application (200 μl, 5%) during skin warming in 22 healthy subjects. To evaluate the sequence effects and skin warming on CHEPs, 10 of these subjects also participated in a control study.
Topical capsaicin yielded an increase in contact heat evoked pain ratings (p < 0.0001) and a shortening in N2 latency from a mean 345.2 ± 37.2 ms to 310.2 ± 38.5 ms recorded from the vertex position (p = 0.003, paired t-test). No difference was found in the N2-P2 peak-to-peak amplitude (p = 0.83). These results were unchanged after controlling for sequence effects and skin warming. Following capsaicin, ultralate CHEPs (N2a latencies 970-1352 ms) were recorded in three subjects.
Our study showed a decrease in late CHEPs latencies and appearance of ultralate potentials compatible with sensitization of Aδ fibers and C fibers.
Contact heat may be a useful tool to assess sensitization of the pain system.
Although laser-evoked electroencephalographic (EEG) responses are increasingly used to investigate nociceptive pathways, their functional significance remains unclear. The reproducible observation of a robust correlation between the intensity of pain perception and the magnitude of the laser-evoked N1, N2, and P2 responses has led some investigators to consider these responses a direct correlate of the neural activity responsible for pain intensity coding in the human cortex. Here, we provide compelling evidence to the contrary. By delivering trains of three identical laser pulses at four different energies, we explored the modulation exerted by the temporal expectancy of the stimulus on the relationship between intensity of pain perception and magnitude of the following laser-evoked brain responses: the phase-locked N1, N2, and P2 waves, and the non-phase-locked laser-induced synchronization (ERS) and desynchronization (ERD). We showed that increasing the temporal expectancy of the stimulus through stimulus repetition at a constant interstimulus interval 1) significantly reduces the magnitudes of the laser-evoked N1, N2, P2, and ERS; and 2) disrupts the relationship between the intensity of pain perception and the magnitude of these responses. Taken together, our results indicate that laser-evoked EEG responses are not determined by the perception of pain per se, but are mainly determined by the saliency of the eliciting nociceptive stimulus (i.e., its ability to capture attention). Therefore laser-evoked EEG responses represent an indirect readout of the function of the nociceptive system.
To gain information on the topographical distribution of warmth, burning and itch sensations in healthy humans, we delivered laser stimuli to elicit sensations of warmth, applied capsaicin cream for burning, and pricked histamine for itch on the skin of the face, shoulder, hand, thigh and foot in 12 healthy subjects. We found that whereas warm and burning sensations progressively increased from foot to face, itch sensation increased from face to foot (P<0.0001). Hence our findings indicate that unlike thermal and pain receptors, itch receptors are denser at distal than at proximal body sites. Our psychophysical study provides new information supporting the idea that specific unmyelinated neuronal pathways mediate sensations of warmth, burning and itch.
In patients with distal symmetric polyneuropathy we assessed non-nociceptive Abeta- and nociceptive Adelta-afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 150 patients with distal symmetric polyneuropathy (68 with pain and 82 without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard nerve conduction study (NCS) to assess Abeta-fibre function, and laser-evoked potentials (LEPs) to assess Adelta-fibre function. Patients with pain had the same age (P>0.50), but a longer delay since symptom onset than those without (P<0.01). Whereas the LEP amplitude was significantly lower in patients with pain than in those without (P<0.0001), NCS data did not differ between groups (P>0.50). LEPs were more severely affected in patients with ongoing pain than in those with provoked pain (P<0.0001). Our findings indicate that the impairment of Abeta-fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that this type of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism-based grounds.
This paper reviews the literature on the Nl wave of the human auditory evoked potential. It concludes that at least six different cerebral processes can contribute to (he negative wave recorded from the scalp with a peak latency between 50 and 150 ms: a component generated in the auditory-cortex on the supratemporal plane, a component generated in the association cortex on the lateral aspect of the temporal and parietal cortex, a component generated in the motor and premotor cortices, the mismatch negativity, a temporal component of the processing negativity, and a frontal component of the processing negativity, The first three, which can be considered ‘true’ N1 components, are controlled by the physical and temporal aspects of the stimulus and by the general state of the subject. The other three components are not necessarily elicited by a stimulus but depend on the conditions in which the stimulus occurs. They often last much longer than the true N1 components that they overlap.
Feedback-controlled laser heat was used to stimulate the hairy skin of the hand dorsum and forearm, and heat-evoked cerebral potentials were recorded at midline (Fz, Cz, Pz) and temporal (T3, T4) scalp positions. Based on data from primary afferent electrophysiology a stimulus level (40 degrees C) was chosen, which is above C-fiber heat threshold, but clearly below A delta-nociceptor heat threshold in order to excite selectively C-fibers without concomitant excitation of A delta-fibers. Feedback-controlled stepped heat stimuli to 40 degrees C elicited ultralate laser evoked potentials (LEPs) at the vertex in a high proportion of experiments (90%). Estimates of conduction velocity calculated from latency shifts between the hand and forearm sites of ultralate LEPs (2.4 m/s) and of reaction times (2.8 m/s) confirmed mediation of ultralate potentials by unmyelinated nerve fibers (nociceptors and/or warm fibers). The ultralate LEP could be differentiated from resolution of contingent negative variation (CNV), an endogenous potential related to expectation and response preparation, by its scalp topography. Strong heat stimuli of 48 degrees C, which is suprathreshold for most A delta- and C-fiber nociceptors, elicited the well-known late LEPs mediated by nociceptive Adelta-fibers confirming previous studies. The LEP waveform to strong heat stimuli also contained an ultralate component reminiscent of an ultralate LEP following the late LEP. Ultralate and late LEP had identical scalp topography. In conclusion, the method of temperature-controlled laser heat stimuli allows the selective and reliable examination of A delta- and C-fiber-mediated afferent pathways and the related cortical processing without the complication of dissociating A-fiber nerve blocks.
We recorded laser-evoked cortical potentials (LEPs) in 54 consecutive patients presenting with unilateral neuropathic central pain (n = 42) or with lateralized pain of non-organic origin (n = 12). A number of cases in each group had superimposed hyperalgesia or allodynia. In patients with central pain, LEPs were significantly attenuated after stimulation over the painful territory, relative to stimulation of the homologous normal territory. LEP attenuation concerned not only patients with decreased pain/heat sensation, but also those with allodynia or hyperalgesia to laser pulses. In contrast, LEPs were never attenuated in patients with non-organic forms of pain, in whom LEPs could even be enhanced to stimulation of the painful territory. Increased responses in non-organic pain were a reminder of the cognitive modulation observed in normal subjects who direct attention to a laser stimulus. Enhanced LEPs never accompanied truly neuropathic hyperalgesia or allodynia. In central pain patients with exclusively spontaneous pain, LEP attenuation was more pronounced than that observed in those with allodynia and hyperalgesia. Patients with allodynia also presented occasionally ultra-late responses (>700 ms) to stimulation of the painful side. The hypothesis that such responses may reflect activation of a slow conducting 'medial' pain system is discussed. We conclude that, as currently recorded, LEPs essentially reflect the activity of a 'lateral' pain system subserved at the periphery by rapidly conducting A-delta fibres. They are useful to document the sensorial deficits (deafferentation) leading to neuropathic pain syndromes. Conversely, in the case of deafferentation, they fail to index adequately the affective aspects of pain sensation. On practical grounds, chronic pain coupled with reduced LEPs substantiates the diagnosis of neuropathic pain, whereas the finding of normal or enhanced LEPs to stimulation of a painful territory suggests the integrity of pain pathways, and does not support a neuropathic pathophysiology. In neuropathic cases, partial LEP preservation might increase the probability of developing provoked pain (allodynia/hyperalgesia). The possible predictive value of this phenomenon, when observed before the development of pain, remains to be demonstrated. In selected contexts (pain sine materia, non-organic anaesthesia), normal or enhanced LEPs may support a psychogenic participation in the syndrome.
Laser pulses excite superficial free nerve endings innervated by small-myelinated (Adelta) and unmyelinated (C) fibres. Whereas laser-evoked scalp potentials (LEPs) are now reliably used to assess function of the Adelta-fibre nociceptive pathways in patients with peripheral or central lesions, the selective activation of C-fibre receptors and recording of the related brain potentials remain difficult. To investigate trigeminal C-fibre function, we directed laser pulses to the facial skin and studied sensory perception and scalp evoked potentials related to Adelta- or C-fibre activation in healthy humans and patients--one having a bilateral facial palsy, two a trigeminal neuropathy, and two a Wallenberg syndrome. We also measured afferent conduction velocity and, with source analysis, studied the brain generators. Whereas laser pulses of low intensity and small irradiated area elicited pinprick sensations and standard Adelta-LEPs, laser pulses of very-low intensity and large irradiated area elicited warmth sensations and scalp potentials with a latency compatible with C-fibre conduction (negative wave 280 ms, positive wave 380 ms); the estimated conduction velocity was 1.2 m/s. The main waves of the scalp potentials originated from the anterior cingulate gyrus; they were preceded by activity in the opercular region and followed by activity in the insular region. The patient with bilateral facial palsy, who had absent trigeminal-facial reflexes, had normal Adelta- and C-related scalp potentials; the patients with trigeminal neuropathy, characterized by loss of myelinated and sparing of unmyelinated fibres, had absent Adelta- but normal C-related potentials; and the patients with Wallenberg syndrome had absent Adelta- and C-related potentials. We conclude that laser pulses with appropriate characteristics evoke brain potentials related to the selective activation of trigeminal nociceptive Adelta or thermal C fibres. The trigeminal territory yields rewarding LEP findings owing to the high density of thermal receptors and, because the short conduction distance, minimizes the problem of signal dispersion along slow-conducting unmyelinated afferents. The opercular-insular region and the cingulate gyrus are involved in the processing of C-fibre trigeminal inputs. The method we describe may prove useful in patients with lesions affecting the trigeminal thermal pain pathways.
We reviewed the recent progress in electrophysiological studies using electroencephalography (EEG), magnetoencephalography (MEG) and repetitive transcranial magnetic stimulation (rTMS) on human pain perception.
For recording activities following A delta fiber stimulation relating to first pain, several kinds of lasers such as CO2, Tm:YAG and argon lasers are now widely used. The activity is frequently termed laser evoked potential (LEP), and we reviewed previous basic and clinical reports on LEP. We also introduced our new method, epidermal stimulation (ES), which is useful for recording brain activities by the signals ascending through A delta fibers. For recording activities following C fiber stimulation relating to second pain, several methods have been used but weak CO2 laser stimuli applied to tiny areas of the skin were recently used.
EEG and MEG findings following C fiber stimulation were similar to those following A delta fiber stimulation except for a longer latency. Finally, we reviewed the effect of rTMS on acute pain perception. rTMS alleviated acute pain induced by intracutaneous injection of capsaicin, which activated C fibers, but it enhanced acute pain induced by laser stimulation, which activated A delta fibers.
One promising approach in the near future is to analyze the change of a frequency band. This method will probably be used for evaluation of continuous tonic pain such as cancer pain, which evoked response studies cannot evaluate.
Activity of single cells in cats immobilized with gallamine triethiodide was recorded with metal microelectrodes and displayed by an on?line dot display. Tone?burst, noise?burst, click, and swept?tone stimuli were presented through condensermicrophones at both ears. Spontaneous activity ranged from less than one spike per second to greater than 40 spikes per second. Almost all cells were affected by acoustic stimuli, either by enhancement of activity, reduction of activity, or a combination. Cells were affected at the onset and/or termination of a stimulus, throughout a stimulus, or a combination. Best frequency of cells ranged from less than 1 kHz to greater than 50 kHz. The pattern of response to tone bursts of some cells changed as the frequency of the stimulus was changed. The activity of some cells was closely related to the slow?wave potential at the electrode tip, but for others there was little relationship. Subsurgical doses of sodium pentobarbital greatly reduced both spontaneous and evoked unit activity. [Work supported in part by the Public Health Service, U. S. Department of Health, Education, and Welfare, and by the U. S. Air Force Office of Scientific Research.]
Central pain syndromes (CPS) could be caused by disinhibition of spinothalamic excitability or by other central nervous system (CNS) changes caused by reduced spinothalamic function. To examine these possibilities, we studied 11 patients (ages 51-82 years) with unilateral central pain and with reproducible cerebral evoked vertex potentials in response to cutaneous stimulation of the normal side with pulses from an infra-red CO2 laser. All patients had normal tactile and kinesthetic sensation; one had slightly decreased vibratory sense bilaterally. All showed, from the unaffected (asymptomatic) side, laser evoked potentials (LEPs) with negative (N) components ranging from 208 to 280 msec peak latency (av: 240 +/- 6 SE msec) and peak amplitudes of 1-7 mu V (av: 2.9 +/- 0. 5 SE mu V), followed, in all but 1 patient, by positive (P) potentials ranging from 288 to 370 msec peak latency (av: 319 +/- 7.7 SE msec) with peak amplitudes of 1-7 mu V (2.8 +/- 0.5 SE mu V). Laser stimulation of the affected (sympto
The necessary and sufficient condition to record brain responses to signals ascending through C-fibers seems to be avoidance of concomitant activation of Adelta-fibers. Several explanations are offered in the literature. One more is added, based on the phenomenon of post-event desynchronisation. Four methods, having in common the ability to selectively activate C-fiber afferents, are currently used to obtain ultralate-laser evoked potentials (LEPs) in a reliable way and with the appropriate latency. Exception made for the difference in latency, mainly due to the difference in peripheral conduction time, morphology and dynamic topography of the ultralate-LEPs (C-fibers), are similar to the late-LEPs (Adelta-fibers). These results suggest that both pathways have common cortical generators.
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.
We recorded laser-evoked cortical potentials (LEPs) in 54 consecutive patients presenting with unilateral neuropathic central pain (n = 42) or with lateralized pain of non-organic origin (n = 12). A number of cases in each group had superimposed hyperalgesia or allodynia. In patients with central pain, LEPs were significantly attenuated after stimulation over the painful territory, relative to stimulation of the homologous normal territory. LEP attenuation concerned not only patients with decreased pain/heat sensation, but also those with allodynia or hyperalgesia to laser pulses. In contrast, LEPs were never attenuated in patients with non-organic forms of pain, in whom LEPs could even be enhanced to stimulation of the painful territory. Increased responses in non-organic pain were a reminder of the cognitive modulation observed in normal subjects who direct attention to a laser stimulus. Enhanced LEPs never accompanied truly neuropathic hyperalgesia or allodynia. In central pain patients with exclusi
This chapter reviews physiological and biophysical aspects of the three most widely used techniques—namely electrical, contact heat, and laser pulsed stimulation. Standard neurophysiological techniques used for somatosensory assessment use low-intensity electrical stimuli, and therefore excite preferentially large-diameter, fast-conducting afferents, which have an electrical threshold lower than that of small-size, nociceptive fibers. Although increasing the intensity of electrical stimulation induces a growing aversive pain response, nociceptive afferents are excited “simultaneously” with non-nociceptive fibers, hence precluding the recording of specifically “nociceptive” evoked potentials (EPs). Standard thermodes such as those used in functional imaging studies do not allow temperature changes rapid enough to evoke EPs. New generations of fast-acting heat foil-thermodes allow temperature rise times up to 70°C/s and can evoke cortical responses. Radiant heat stimulation can circumvent most of the difficulties inherent in electrical or contact-heat stimuli, by providing selective activation of A-δ and C-thermosensitive nociceptors in the hairy skin, without concomitant activation of mechanoreceptors and A-β fibers.
Heat stimuli, applied to the skin by non-contact radiation pulses emitted by a CO2-laser, activate simultaneously both A-delta (mean conduction velocity 14 m/s) and C-fibres (0.8 m/s), which terminate in the most superficial skin layers. Correspondingly, brief heat stimuli elicit two pain sensations with mean reaction times of about 500 ms and 1400 ms. Similarly, two evoked potential waveforms were observed in the electroencephalogram: the late components N240/P370 and the ultralate components N1050/P1250. The shape of the two components was reproducible in independent samples of healthy volunteers. In patients with dissociated sensory loss, the laser evoked cerebral potentials are affected, depending on the kind of disturbed nerve and tracts. This is shown in patients with syringomyelia, encephalomyelitis disseminata, myelitis, Brown-Sequard syndrome, Wallenberg syndrome. In cases with hereditary motor and sensory neuropathy type I or with neurosyphilis, ultralate potentials are observed as correlates of delayed pain perception in the affected body areas. The laser evoked cerebral potentials reflected the clinical disorder of pain sensitivity in most cases, whereas somatosensory evoked potentials in response to conventional nerve stimuli failed in objectifying the diagnosis. As such, evoked cerebral potentials in response to laser heat stimuli applied to the hairy skin can be used for an overall examination of the functional integrity of peripheral small fibres, anterolateral tracts and thalamocortical projections.
Brief radiant heat pulses, generated by a CO2 laser, were used to activate slowly conducting afferents in the hairy skin in man. In order to isolate C-fibre responses a preferential A-fibre block was applied by pressure to the radial nerve at the wrist. Stimulus estimation and evoked cerebral potentials (EP), as well as reaction times, motor and sudomotor activity were recorded in response to each stimulus. With intact nerve, the single supra-threshold stimulus induced a double pain sensation: A first sharp and stinging component (mean reaction time 480 ms) was followed by a second burning component lasting for seconds (mean reaction time 1350 ms). Under A-fibre block only one sensation remained with characteristics and latencies of second pain. The heat pulse evoked potential consisted of a late vertex negativity at 240 ms (N240) followed by a prominent late positive peak at 370 ms (P370). Later activity was not reliably present. Under A-fibre block this late EP was replaced by an ultralate EP beyond 1000 ms, which in the conventional average looked like a slow halfwave of 800 ms duration. This potential was distinct from eye movements, skin potentials or muscle artefacts. With cross-correlation methods waveforms similar to the N240/P370 were detected in the latency range from 900 to 1500 ms during A-fibre block, indicating a much greater latency jitter of the ultralate EP. Latency corrected averaging with a modified Woody filter yielded a grand mean ultralate EP (N1050/P1250), the shape of which was surprisingly similar to the late EP (N240/P370). The similarity of these components indicates that both EPs may be secondary responses to afferent input into neural centers, onto which myelinated and unmyelinated fibres converge. Such convergence may also explain through the known mechanisms of short term habituation and selective attention, why ultralate EPs are not reliably present without peripheral nerve block.
Activity of single cells in cats immobilized with gallamine triethiodide was recorded with metal microelectrodes and displayed by an on‐line dot display. Tone burst, noise burst, click, and other stimuli at moderate intensities were presented through condensermicrophones at both ears. Spontaneous activity ranged from less than 1 spike/sec to greater than 40 spikes/sec. Almost all units were affected by acoustic stimuli, either by enhancement of activity, reduction of activity, or a combination. Units were affected at the onset and/or termination of a stimulus, throughout a stimulus, or a combination. Best frequency of units ranged from less than 1 kHz to greater than 50 kHz. Over half the units responding to tone bursts exhibited a response range greater than 1 2 oct. Some units had double response ranges. The pattern of response to tone bursts of some units changed as the frequency of the stimulus was changed. A minority of the units showed responses only to special stimuli such as swept tones or continuous noise or tones. It appears that the coding of acoustic stimuli by single units of the primary auditory cortex of the cat is performed in a highly individualistic and variegated manner.
Vertex evoked potentials (40--500 ms) elicited by painful dental stimulation were compared with those elicited by innocuous auditory stimuli across three rates of stimulus repetition: one second, four seconds, and eight seconds. In both modalities peak amplitude of the major waveform components increased linearly over log rate as stimulus repetition was slowed, and latency of the latest positive component was increased. No changes in subjective stimulus intensity across rate of repetition were reported. These observations demonstrate that the normally close relationship between subjective pain report and EP amplitude is not variant, and they suggest that the development of EP methodology in human pain research should proceed conservatively.
Thermal (laser) evoked responses were obtained from 13 male volunteers. A single trial analysis technique with a latency adjusting adaptive filter was used to analyze evoked response amplitudes. Significant and substantial within-subject linear correlations were found between the magnitude (A) of the primary waveform (RMS muV of the P200--N300-P400 complex ) and subjective pain response (R) as well as stimulus intensity (S). Since subjective pain response was strongly correlated with stimulus intensity, the partial correlation coefficients were calculated for R vs. A with S controlled, and S vs. A with R controlled, for each subject. The partial correlations revealed a much stronger relationship between subjective response and the evoked response amplitude, suggesting that the primary complex may measure neural events in the pain perception process rather than transduction and transmission of the stimulus event.
In this study, it is reported that CO2 laser heat stimulation of tiny skin surface area (0.15 mm2) provides a unique method to directly and selectively activate C-fibre as assessed by the ultra-late brain potentials (peak latencies: N810, P996) evoked consistently across a set of stimulus energy levels. On a larger surface area (15.5 mm2), low energy stimulation also resulted in minute ultra-late potential, while higher intensities induced only late potentials related to A-delta fibre activity (peak latencies: N247, P394). The selective activation of C afferent sensory terminals in the skin by stimulation of tiny surface area is explained by their relative high density and lower activation threshold.
Central pain syndromes (CPS) could be caused by disinhibition of spinothalamic excitability or by other central nervous system (CNS) changes caused by reduced spinothalamic function. To examine these possibilities, we studied 11 patients (ages 51-82 years) with unilateral central pain and with reproducible cerebral evoked vertex potentials in response to cutaneous stimulation of the normal side with pulses from an infra-red CO2 laser. All patients had normal tactile and kinesthetic sensation; one had slightly decreased vibratory sense bilaterally. All showed, from the unaffected (asymptomatic) side, laser evoked potentials (LEPs) with negative (N) components ranging from 208 to 280 msec peak latency (av: 240 +/- 6 SE msec) and peak amplitudes of 1-7 microV (av: 2.9 +/- 0.5 SE microV), followed, in all but 1 patient, by positive (P) potentials ranging from 288 to 370 msec peak latency (av: 319 +/- 7.7 SE msec) with peak amplitudes of 1-7 microV (2.8 +/- 0.5 SE microV). Laser stimulation of the affected (symptomatic) side in 5 patients evoked LEPs with N-P interpeak amplitudes that were within 20% of those evoked from the normal side. All but one of these patients had thresholds for warm, heat pain, and deep pain that were normal in comparison with the unaffected side. The excepted patient had the largest N-P interpeak amplitude asymmetry (18.5%) of this group. Ratings of laser pulse intensity were either symmetrical (n = 2) or increased on the affected side (n = 3) in these patients. In contrast, laser stimulation of the affected side failed to evoke either N or P potentials in 6 patients, all of whom had lateralized increased thresholds for warm, heat pain, or deep pain, or reduced ratings of laser pulse sensation. Although 1 patient had increased ratings of laser pulse sensation, the amplitude of the LEP was always reduced on the side of increased pain or heat threshold in these CPS patients (Fisher exact test: P = 0.015). These results reflect primarily a deficit in spinothalamic tract function and do not suggest excessive CNS responses to synchronous activation of cutaneous heat nociceptors in patients with CPS.
Nociceptive evoked potentials to laser stimuli (LEPs) are able to detect lesions of pain and temperature pathways at peripheral, spinal and supraspinal levels. It is commonly accepted that LEP attenuation correlates with the loss of pain and temperature sensations, while pathological heat-pain hypersensitivity has been associated with increased LEP amplitude. Here we present two patients in whom increased pain sensation (hyperalgesia) to laser stimuli was, on the contrary, associated to delayed, desynchronized and attenuated LEPs. Both patients experienced increased unpleasantness and affective reactions to laser, associated to poor ability to localize the stimulus. In both cases the results may be explained by an overactivation of the 'medial pain system', in one patient due to deafferentation of cortical sensory areas by a capsular lesion, and in the other to imbalance between A-delta and C fiber excitation due to peripheral nerve injury. Our results suggest that LEPs, as currently recorded, reflect the activity of a 'lateral' pain system subserved by rapidly conducting fibers. They may therefore, assess the sensory and cognitive dimensions of pain, but may not index adequately the affective-emotional aspects of pain sensation conveyed by the 'medial' pain system. The dissociation between pain sensation and cortical EPs deserve to be added to the current semiology of LEPs, as the presence of abnormal pain to laser on the background of reduced LEPs substantiates the neuropathic nature of the pain.
Laser evoked potentials (LEPs) are brain responses to activation of skin nociceptors by laser heat stimuli. LEPs consist of three components: N1, N2, and P2. Previous reports have suggested that in contrast to earlier activities (N1), LEPs responses after 230-250 ms (N2-P2) are modulated by attention to painful laser stimuli. However, the experimental paradigms used were not designed to specify the attentional processes involved in these LEP modulations. We investigated the effects of selective spatial attention and oddball tasks on LEPs. CO(2) laser stimuli of two different intensities were delivered on the dorsum of both hands of ten subjects. One intensity was frequently presented, and the other rarely. Subjects were asked to pay attention to stimuli delivered on one hand and to count rare stimuli, while ignoring stimuli on the other hand. Frequent and rare attended stimuli evoked enhanced N160 (N1) and N230 (N2) components in comparison to LEPs from unattended stimuli. Both components showed scalp distribution contralateral to the stimulus location. The vertex P400 (P2) was unaffected by spatial attention and stimulus location, but its amplitude increased after rare stimuli, whether attended or unattended. An additional parietal P600 component was induced by the attended rare stimuli. It is suggested that several attentional processes can modify nociceptive processing in the brain at different stages. LEP activities in the time-range of N1 and N2 (120-270 ms) showed evidence of processes modulated by the direction of spatial attention. Conversely, processes underlying P2 (400 ms) were not affected by spatial attention, but by the probability of the stimulus. This probability effect was not due to P3b-related processes that were observed at a later latency (600 ms). Indeed, P600 could be seen as a P3b evoked by conscious detection of rare targets.
There are two kinds of pain, a sharp pain ascending through Adelta fibers (first pain) and a second burning pain ascending though C fibers (second pain). By using a novel method, the application of a low intensity CO(2) laser beam to a tiny area of skin using a very thin aluminum plate with numerous tiny holes as a spatial filter, we succeeded in selectively stimulating unmyelinated C fibers of the skin in humans, and could record consistent and clear brain responses using electroencephalography (EEG) and magnetoencephalography (MEG). The conduction velocity (CV) of the C fibers of the peripheral nerve and spinal cord, probably spinothalamic tract (STT), is approximately 1-4 m/s, which is significantly slower than that of Adelta (approximately 10-15 m/s) and Abeta fibers (approximately 50-70 m/s). This method should be very useful for clinical application. Following C fiber stimulation, primary and secondary somatosensory cortices (SI and SII) are simultaneously activated in the cerebral hemisphere contralateral to the stimulation, and then, SII in the hemisphere ipsilateral to the stimulation is activated. These early responses are easily detected by MEG. Then, probably limbic systems such as insula and cingulate cortex are activated, and those activities reflected in EEG components. Investigations of the cortical processing in pain perception including both first and second pain should provide a better understanding of pain perception and, therefore, contribute to pain relief in clinical medicine.
In contrast to the function of the visual or auditory pathways which are electrophysiologically accessible by visual or auditory evoked potentials, the somatosensory pathway cannot be investigated as a whole by conventional somatosensory evoked potentials (SEP), because these only reflect function of large fibers, dorsal columns, medial lemniscus and their thalamo-cortical projections mediating sensations like touch and vibration. The other half of the somatosensory system, signaling temperature and pain perception, uses a different set of afferents and different central pathways, the function of which is accessible by laser-evoked potentials (LEPs). LEP can document lesions of the spinothalamic tract and (lateral) brainstem and of thalamo-cortical projections conveying thermo-nociceptive signals. In the peripheral nerve, LEP can help distinguish between large and small fiber neuropathies. The rapid heating of the skin by infrared laser pulses can easily be applied to non-glabrous skin in any dermatome. In recent years, many clinical studies have demonstrated that LEP can supply evidence for establishing clinical diagnoses when deficits of the nociceptive system are present. This review outlines principles and recording techniques for LEP in patients and compiles typical LEP findings in patients with lesions due to different diseases at various levels of the nociceptive pathways. Limitations for the use of LEP are pointed out, too, like the uncertainty of lesion location along these pathways and the fact that LEP can reliably show correlates of reduced nociceptive function but only rarely of enhanced transmission (like in hyperalgesia).
In this work we review data on cortical generators of laser-evoked potentials (LEPs) in humans, as inferred from dipolar modelling of scalp EEG/MEG results, as well as from intracranial data recorded with subdural grids or intracortical electrodes. The cortical regions most consistently tagged as sources of scalp LERs are the suprasylvian region (parietal operculum, SII) and the anterior cingulate cortex (ACC). Variability in opercular sources across studies appear mainly in the anterior-posterior direction, where sources tend to follow the axis of the Sylvian fissure. As compared with parasylvian activation described in functional pain imaging studies, LEP opercular sources tended to cluster at more superior sites and not to involve the insula. The existence of suprasylvian opercular LEPs has been confirmed by both epicortical (subdural) and intracortical recordings. In dipole-modelling studies, these sources appear to become active less than 150 ms post-stimulus, and remain in action for longer than opercular responses recorded intracortically, thus suggesting that modelled opercular dipoles reflect a "lumped" activation of several sources in the suprasylvian region, including both the operculum and the insula. Participation of SI sources to explain LEP scalp distribution remains controversial, but evidence is emerging that both SI and opercular sources may be concomitantly activated by laser pulses, with very similar time courses. Should these data be confirmed, it would suggest that a parallel processing in SI and SII has remained functional in humans for noxious inputs, whereas hierarchical processing from SI toward SII has emerged for other somatosensory sub-modalities. The ACC has been described as a source of LEPs by virtually all EEG studies so far, with activation times roughly corresponding to scalp P2. Activation is generally confined to area 24 in the caudal ACC, and has been confirmed by subdural and intracortical recordings. The inability of most MEG studies to disclose such ACC activity may be due to the radial orientation of ACC currents relative to scalp. ACC dipole sources have been consistently located between the VAC and VPC lines of Talairach's space, near to the cingulate subsections activated by motor tasks involving control of the hand. Together with the fact that scalp activities at this latency are very sensitive to arousal and attention, this supports the hypothesis that laser-evoked ACC activity may underlie orienting reactions tightly coupled with limb withdrawal (or control of withdrawal). With much less consistency than the above-mentioned areas, posterior parietal, medial temporal and anterior insular regions have been occasionally tagged as possible contributors to LEPs. Dipoles ascribed to medial temporal lobe may be in some cases re-interpreted as being located at or near the insular cortex. This would make sense as the insular region has been shown to respond to thermal pain stimuli in both functional imaging and intracranial EEG studies.
This review presents and discusses the leading arguments justifying the use of high power laser stimulators to explore the nociceptive system. To grasp the particularity of such stimulators, fundamentals concerning the interaction of low-energy radiation with the skin will be recalled and focused on the optimal match between the wavelength of the emitting source and the thermophysical properties of the skin. This knowledge shall allow us to discuss critical characteristics of laser stimulators. Study of the cutaneous spectrum of receptors showed that laser stimulators allow the selective activation of A(delta) and C-fiber nociceptors. We will present different methods, which increase the selectivity of the laser stimulation, restricting the activation to isolated C-fiber nociceptors. These methods open new perspectives in the study of the cerebral processing of signals ascending through A(delta) and/or C nociceptors and should contribute to a better understanding of their central interaction and integration in normal and pathological states.
To investigate the excitability of Adelta nociceptive pathways and the nature of the vertex laser evoked potentials (LEPs), we studied the recovery cycle of the P2-LEP component and compared it with that of the P200 of the somatosensory evoked potential (SEP). Using two identical CO(2)-laser stimulators, we delivered paired stimuli to two adjacent skin spots on the hand at interstimulus intervals ranging from 250 ms to 2 s. The test P2-LEP was strongly inhibited at the 250-ms interstimulus interval ( P<0.01) and progressively recovered by the 2-s interval. The P200-SEP, after paired stimuli to the median nerve, showed a time course even slower than the P2-LEP ( P<0.01). Besides providing the LEP recovery curve in normal subjects, our findings indicate that the P2-LEP relays through a number of synapses similar to (or even lower than) that for the P200-SEP, thus lending further support to the view that the nociceptive P2-LEP is not an endogenous potential equivalent to the P300.
To disclose a possible effect of duration of pulsed laser heat stimuli on Adelta nociceptor responses, skin temperature profiles, brain evoked potentials and pain perception.
We used a laser stimulator which works in the millisecond range and allows us to change the duration of the pulse while keeping the total energy of the stimulus constant. In 10 healthy volunteers, we measured the intensity of perceived pain with a 0-10 scale and the latency and amplitude of the early N1 and late N2 components of the scalp potentials evoked by laser pulses of equal energy and three different stimulus durations (2, 10, and 20 ms). Using a specifically developed pyrometer with a temporal resolution lower than 1 ms we also measured stimulus-induced changes of skin temperature.
Stimulus duration significantly influenced temperature rise times, pain perception, and brain potentials. Shorter stimulus durations yielded steeper slopes in the skin temperature profiles and higher pain ratings, shortened the latency of the N1 and N2 components, and increased the amplitude of N1.
The shorter stimulus duration shortens receptor activation times and yields a more synchronous afferent volley, thus providing a stronger spatial-temporal summation at central synapses that enhances intensity of first pain and brain potentials. This may prove useful in clinical applications.
Co-activation of Adelta- and C-fiber nociceptors by brief cutaneous laser heat stimuli may induce a dual sensation composed of first and second pain but evokes only a single, Adelta-fiber related, late laser-evoked potential (LEP). Yet, when concomitant activation of Adelta-nociceptors is avoided, C-nociceptor activation evokes an ultra-late LEP. As cumulating evidence indicates that late and ultra-late LEPs may share common generators, investigators have hypothesized that when Adelta-fibers trigger a late LEP, the later arriving C-fiber afferent volley cannot trigger an ultra-late LEP because underlying generators are in a 'refractory state'. Better understanding of these interactions could have important consequences regarding the functional significance of LEPs. Therefore, this hypothesis was tested by applying two consecutive laser stimuli to the hand dorsum such as to produce a second Adelta-nociceptor afferent volley arriving at generators during their expected 'refractory period'. Results showed that late LEPs evoked by the second stimulus were not altered and consequently that this hypothesis does not hold. In addition, when stimuli ended the sensory detection task, an ample P600 component was recorded. Studies have shown that this component is probably related to the P3b component described in other sensory modalities. This result provides support to the 'context closure' model hypothesizing that this component reflects the closure of information processing occurring when expectations are terminated. Altogether, these results suggest that late and ultra-late LEPs reflect very general processes, which are mainly related to detection and orientation and constitute only a fraction of the central processing of both nociceptive inputs.
Converging evidence from different functional imaging studies indicates that the intensity of activation of different nociceptive areas (including the operculoinsular cortex, the primary somatosensory cortex, and the anterior cingulate gyrus) correlates with perceived pain intensity in the human brain. Brief radiant laser pulses excite selectively Aδ and C nociceptors in the superficial skin layers, provide a purely nociceptive input, and evoke brain potentials (laser-evoked potentials, LEPs) that are commonly used to assess nociceptive pathways in physiological and clinical studies. Aδ-related LEPs are constituted of different components. The earliest is a lateralised, small negative component (N1) which could be generated by the operculoinsular cortex. The major negative component (N2) seems to be mainly the result of activation in the bilateral operculoinsular cortices and contralateral primary somatosensory cortex, and it is followed by a positive component (P2) probably generated by the cingulate gyrus.
This chapter focuses on the clinical utility of laser evoked potentials (LEP). Laser stimulators are able to deliver brief (1–100 ms) pulses that rapidly raise the temperature in the superficial layers of hairy skin and excite type II mechano-thermal nociceptors related to small diameter myelinated or unmyelinated fibers as well as thermal receptors innervated by unmyelinated fibers. Although the pathophysiological mechanisms are not completely understood, it is becoming increasingly clear that neuropathic pain is related to nociceptive pathway dysfunction. This supports the diagnostic use of LEP studies in patients with peripheral neuropathic pain. The severity of clinical pain on the affected side is also related to the magnitude of amplitude reduction in the LEP P2 wave. Thus, although LEPs in this condition reflect the loss of small myelinated fibers, rather than pain itself, the extent of this axonal loss is probably related to the development of neuropathic pain. LEPs have also been reported infrequently in radiculopathies or plexopathies.
Several types of lasers are available for eliciting laser evoked responses (LEPs). In order to understand advantages and drawbacks of each one, and to use it properly, it is important that the pattern of skin heating is known and duly considered. This study was aimed at assessing the skin temperature during and immediately after irradiation with pulses by Nd:YAP and CO(2) lasers.
The back of the non-dominant hand was irradiated in 8 subjects. Temperatures were measured by a fast analogical pyrometer (5 ms response time). Stimuli were tested on natural colour (white) and blackened skin.
Nd:YAP pulses yielded temperatures that were correlated with pulse energy, but not with pulse duration; much higher temperatures were obtained irradiating blackened skin than white skin (ranges 100-194 degrees C vs 35-46 degrees C). Temperature decay was extremely slow in white skin, reaching its basal value in more than 30 s. CO(2) pulses delivered with power of 3W and 6W yielded temperatures of 69-87 degrees C on white skin, and 138-226 degrees C on blackened skin. Temperature decay was very fast (4-8 ms).
Differences in peak temperatures and decay times between lasers and tested conditions depend on energy and volume of heated skin. The highest temperatures are reached with lesser degree of penetration, as in the case of CO(2) laser and blackened skin. Taking into account the temperature decay time of the skin, the minimum interstimulus interval to get reliable LEPs should be no less than 10 s for Nd:YAP and 100 ms for CO(2) laser. Another important practical consequence of the heating pattern is that the Nd:YAP pulses will activate warmth receptors more easily than CO(2).
By co-activating A delta- and C-nociceptors, a brief and intense infrared laser stimulus may produce a double sensation referred to as 'first' and 'second' pain, evoke late laser-evoked brain potentials (LEPs) related to the processing of A delta-fiber input, but fails to evoke any consistent activity related to C-fibers. Yet, ultra-late LEPs may be recorded if C-nociceptors are activated in isolation. Bromm and Treede (1985) reported that if a subject selectively focused his attention towards second pain, co-activation of A delta- and C-nociceptors could elicit both late and ultra-late LEPs (Bromm B, Treede RD. Electroencephalogr Clin Neurophysiol 1985;61). They hypothesized that for C-fiber input to elicit consistent ultra-late LEPs, attention must be specifically focused towards that sensory channel. However, the significance of this study was limited by the fact it relied on results of a single subject and used latency-correction algorithms. In an attempt to replicate these findings, this study examined LEPs recorded while trained subjects focused their attention either towards first pain or towards second pain. Whether or not subjects attended second pain, laser stimuli co-activating A delta- and C-nociceptors failed to elicit ultra-late LEPs, indicating that focusing attention towards C-fiber sensory input is not a sufficient condition for that input to evoke LEPs. However, selectively attending to first or second pain significantly modulated A delta-fiber related late LEPs. When subjects attended first pain, a late parietal P3 component was recorded, possibly related to task closure. When subjects attended second pain, a prefrontal positive enhancement of the P2 component was observed. Whether it could reflect brain processes related to response-inhibition is discussed.
Hyperalgesia with loss of laser EPs in neuropathetic pain
- Q Wu
- Mertens L P Garcia-Larrea
- A Beschet
- F Mauguière
- Sindou
Wu Q, Garcia-Larrea L, Mertens P, Beschet A, Mauguière F, Sindou M. Hyperalgesia with loss of laser EPs in neuropathetic pain. Pain 1999;80:209–14.
Hyperalgesia with loss of laser EPs in neuropathetic pain.
- Wu