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Are laser-evoked brain potentials modulated by attending to first or second pain?
Abstract
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.
... The heat penetration into the tissue is small and the tissue temperature reaches normal body temperature before less than 1 mm. intensity in combination with the long inter-stimulus interval and the rating task, (Becker et al., 2000;Becker et al., 1993;Kanda et al., 1996;Legrain et al., 2002;Mouraux and Plaghki, 2007;Siedenberg and Treede, 1996;Towell and Boyd, 1993). ...
... It is hypothesized, that as long as Aδ-fiber mediated potentials occur, no C-fiber evoked potential can be recorded (Bragard et al., 1996;Opsommer et al., 1999;Qiu et al., 2001). In contrast to the simultaneous appearance of Aδ-and C-fiber mediated evoked potentials in disease (Granot et al., 2001) this has not been confirmed in healthy subjects (Mouraux and Plaghki, 2007). ...
Physical disability following spinal cord injury (SCI) is the most striking problem noted
by the general public. But for the affected subjects urogenital difficulties or
depression and pain are often more burdensome. Pain after SCI can have various
reasons but only neuropathic pain below the level of lesion (bNP) is thought to be
caused by injury of the spinal nervous tissue. This type of pain is in the focus of this
thesis. Once bNP has established it is mostly chronic and medication is generally
ineffective. Currently, more and more treatments trying to restore function after SCI
enter the clinical trial phase. Besides improving function, however, treatments
increasing nerve growth in the spinal cord risk to induce or exacerbate bNP.
Therefore, observation of bNP is a crucial factor in such interventional studies. A
method to objectively supervise bNP has, however, not yet been established.
The spinothalamic tract (STT) mainly transmits nociceptive and temperature
information in the spinal cord. This tract was dysfunctional in SCI subjects suffering
from bNP in clinical examinations. Nevertheless, STT dysfunction was not predictive
for bNP and sensory differences between subjects with and without bNP could not be
detected. In contrast to clinical examination which is always subjective and only
offers limited resolution, electrophysiological measures allow for a more detailed and
objective investigation.
The novel electrophysiological method of contact heat evoked potentials (CHEP)
measures STT function. Establishment of this method was the goal of the first study.
The painful stimulation on locations along the spine allowed the calculation of the
conduction velocity of the STT in healthy subjects. Furthermore the CHEP latency
depended linearly on the heat pain threshold with 1° C higher threshold leading to
approximately 10 ms longer latency. It was hypothesized that the rather low heating
rate combined with the time-consuming passive heat spread from skin surface to
nociceptors was responsible for this.
The second study aimed at clarifying this dependence through comparison of the
results of study 1 with those of a theoretical heat transfer model. According to this
model, 1° C higher pain threshold leads to approximately 15 ms longer CHEP
latency. The close similarity between the experimentally determined (study 1) and the
computed dependence, proved the influence of the pain threshold on CHEP latency.
Summary
Electrophysiological markers for Neuropathic Pain in SCI Subjects 2
Subjects suffering from neuropathic pain (NP) in general and not only in SCI, have
lowered EEG peak frequency. It was hypothesized in literature that the reduced EEG
peak frequency emerged from thalamic deafferentiation and from the ensuing
dysrhythmia in thalamocortical feedback loops. Therefore, the third study
investigated EEG peak frequency in addition to STT function and compared both
between SCI subjects with and without bNP and controls. The STT function
(measured with CHEP) below the level of injury was distinctly impaired in SCI
compared to control subjects. Furthermore, the EEG peak frequency was generally
lower in the SCI subjects. While the CHEP measurements did not reveal differences
between subjects with and without bNP, the EEG peak frequency was lowered in
subjects with bNP. This difference, however, was only apparent after the linear
dependence of EEG peak frequency from the level of SCI was taken into account. In
consideration of this dependence, the EEG peak frequency could in future be helpful
to supervise bNP both in studies aiming at restoring function or reducing pain after
SCI.
Currently, the clinical read-out parameter for STT function is pinprick sensation. In
the fourth study this pinprick sensation was traced over the first year after SCI.
Comparison of this STT function with the bNP state of the same subjects 2-5 years
after SCI disclosed larger functional STT recovery in subjects suffering from bNP.
Despite the different STT functional recovery, the initial and end measurements did
not discriminate between subjects with and without bNP. This was in agreement with
earlier studies. The results corroborate the above mentioned hypothesis that new
therapies intending to promote sensorimotor recovery after SCI could simultaneously
induce bNP by boosting recovery of spinothalamic function.
... The reaction time was measured several times to confirm the stimulation of C-fibers. Quality of perception was assessed by asking subjects to choose one item among the following list of seven descriptors: 'not perceived', 'light touch', 'touch', 'tingling', 'warm', 'pricking', and 'burning' [25]. ...
... In a previous study, the sensations produced by IES were weak and painful, described as "flicking", "burning", or "long-lasting weak pricking" (50%), or light touch, described as a "faint touch" or "light pressure" (50%) [15]. Similarly, C-fiber stimulation by laser beams caused "warm" (20%), "tingling" (16%), or "light touch" (13%) sensations [25]. In studies that used contact thermal stimulation, the evoked sensation was usually "warm" [22]. ...
Intra-epidermal electric stimulation (IES) is an alternative to laser stimulation for selective activation of cutaneous Aδ-fibers. IES is based on the fact that nociceptive fiber terminals are located in the epidermis, whereas receptors of other fibers end deep in the dermis. IES can selectively stimulate C-fibers if the electrode structure and stimulation parameters are carefully selected. However, stable selective stimulation of C-fibers using IES has proven difficult and cannot currently be used in clinical settings. The purpose of the present study was to determine if IES performed using a modified electrode reliably stimulates C-fibers. Magnetoencephalographic responses to IES to the foot were measured in seven healthy subjects. IES elicited somatosensory evoked fields in all subjects. The mean peak latency was 1327±116ms in the opercular region contralateral to the stimulated side, 1318±90ms in the opercular region ipsilateral to the stimulated side, and 1350±139ms in the primary somatosensory cortex. These results indicate that IES performed using the modified electrode can selectively stimulate C-fibers and may be a useful tool for pain research as well as clinical evaluation of peripheral small fiber function.
... Most importantly, because of their very high power output, infrared lasers can generate the very steep heating ramps required to elicit time-locked responses such as reaction-times and event-related brain potentials [5], and are thus well suited to study the human nociceptive system. However, for reasons that remain a matter of debate, brain responses related to the activation of C-fibres can be identified only if the concomitant activation of Ad-fibres is avoided678. Therefore, in humans, the current research has focussed almost exclusively on characterizing the neural processes triggered by Adfibre input, simply because of the lack of reliable methods to study the responses triggered by the selective activation of C-fibres. ...
... Reaction time latencies were used to discriminate between detections triggered by C-fibre input and detections triggered by Ad-fibre input. This is justified by the fact that the nerve conduction velocity of unmyelinated C-fibres is much slower than the nerve conduction velocity of myelinated Adfibres (61 m/s vs. 610 m/s; [8,11,181920). Taking into account the peripheral conduction distance of afferent input originating from the hand, and taking into account the distribution of reaction times to laser stimuli after blocking the conduction of myelinated fibres [10,11], a criterion of 650 ms was chosen to discriminate between C-fibre responses (reaction time $650 ms) and Ad-fibre responses (reaction time ,650 ms) [11,20]. ...
Brief high-power laser pulses applied onto the hairy skin of the distal end of a limb generate a double sensation related to the activation of Aδ- and C-fibres, referred to as first and second pain. However, neurophysiological and behavioural responses related to the activation of C-fibres can be studied reliably only if the concomitant activation of Aδ-fibres is avoided. Here, using a novel CO(2) laser stimulator able to deliver constant-temperature heat pulses through a feedback regulation of laser power by an online measurement of skin temperature at target site, combined with an adaptive staircase algorithm using reaction-time to distinguish between responses triggered by Aδ- and C-fibre input, we show that it is possible to estimate robustly and independently the thermal detection thresholds of Aδ-fibres (46.9±1.7°C) and C-fibres (39.8±1.7°C). Furthermore, we show that both thresholds are dependent on the skin temperature preceding and/or surrounding the test stimulus, indicating that the Aδ- and C-fibre afferents triggering the behavioural responses to brief laser pulses behave, at least partially, as detectors of a change in skin temperature rather than as pure level detectors. Most importantly, our results show that the difference in threshold between Aδ- and C-fibre afferents activated by brief laser pulses can be exploited to activate C-fibres selectively and reliably, provided that the rise in skin temperature generated by the laser stimulator is well-controlled. Our approach could constitute a tool to explore, in humans, the physiological and pathophysiological mechanisms involved in processing C- and Aδ-fibre input, respectively.
... 55 For instance, perception of the second pain sensation to laser stimuli 6 may exist without a clear EP correlate even when attention is selectively focused on the stimulus. 44 Indeed, pain has a cognitiveevaluative component, requiring learning, recall of past experiences, and active decision making, 43 which should be borne in mind when assessing patients with pain complaints. ...
... A common method is to ask subjects to perform a simple reaction time at perception of the stimulus and record the EMG activity related to muscle contraction or the actual execution of the requested task. 30,44,45,57 However, this does not necessarily reflect that the stimulus has reached conscious perception. 26 The temporal profile of sensory perception can be estimated using several methods. ...
Unlabelled:
Evoked potentials (EPs) to radiant or contact heat pain stimuli reflect the synchronization of brain activity to noxious inputs. However, we do not know how they relate to conscious awareness (AW) of a sensation. In healthy volunteers, we determined the time of AW for thermal noxious and non-noxious sensory inputs and examined its correlation to parametric measures of vertex EPs. Subjects had to report the position of the hand of a Libet's clock at the moment they perceived either a laser or a thermode stimulus. AW was determined after subtracting the position of the clock hand at the moment of stimulus delivery from the one reported by the subject, in ms. Subjects estimated AW in all single trials, including those in which no EPs could be identified. Mean AW was estimated earlier than the corresponding EP latency for both types and intensities of stimuli. There was a weak but significant negative correlation of AW to EPs amplitude, which was higher than the correlation of AW to EPs latency. Our results indicate that the timing of AW is influenced by the subjective relevance of sensory inputs. This feature could be used for the analysis of cognitive aspects of pain processing.
Perspective:
This article presents a way to measure the subjective awareness of the sensation induced by a noxious heat stimulus, either radiant or contact, in healthy human subjects. This method could be used for the analysis of cognitive aspects of pain processing.
... Scores between 0 and 50 reflected the non-painful range, whereas scores between 50 and 100 reflected the painful range in line with previous studies. 59, [88][89][90][91] The unpleasantness of each stimulus was scored on a scale ranging from not at all unpleasant (0) to extremely unpleasant (100). The ratings of the 3 stimuli were averaged yielding 1 score for intensity and 1 for unpleasantness for each arm and time point. ...
The effect of cognition on the plasticity of the nociceptive system remains controversial. In this study, we examined whether working memory can buffer against the development of secondary hypersensitivity. Thirty-five healthy women participated in three experimental conditions. In each condition they underwent electrical stimulation of the skin for 2 minutes (middle-frequency electrical stimulation, MFS), which induces secondary hypersensitivity. During MFS, participants executed either an individually tailored and rewarded n-back task (working memory condition), a rewarded reaction-time task (non-working memory condition), or no task at all (control condition). Before and after MFS, participants rated the self-reported intensity and unpleasantness of mechanical pinprick stimuli. Fear of MFS was also assessed. Heart rate variability was measured to examine potential differences between the three conditions and steady-state evoked potentials to the electrical stimulation were recorded to investigate differences in cortical responses. We report no significant difference in hypersensitivity between the three conditions. Moreover, engaging in the cognitive tasks did not affect the heart rate variability or the steady-state evoked potentials. Interestingly, higher fear of MFS predicted greater hypersensitivity. In conclusion, we found no evidence that working memory affects the plasticity of the nociceptive system, yet pain-related fear plays a role.
... However, there are multiple techniques in which response time can be used. The following is based on the procedure described by Mouraux & Plaghki [105] in which response time was used for determination of individual threshold estimates, as well as to measure the response to co-activated Aδ and C-nociceptors to investigate early and ultralate LEPs. Heat stimuli were delivered to the dorsum of the left foot using a CO 2 laser in two conditions ("first pain" representing Aδ activation and "second pain" representing C-nociceptor activation). ...
Pain is defined as an inherently conscious multidimensional experience, which is traditionally studied using psychophysical methods. Pain threshold, rating, and tolerance are essential to the experimental and clinical assessment of pain. Yet, there is a long-standing tradition in physiological methods that complements the behavioral assessment, such as the study of spinal reflexes and brain activity. This chapter will focus on the quantitative assessment of pain experience using psychophysical as well as electrophysiological methods. We will review some of the main methodological approaches in the field and their advancements, both in healthy and clinical populations. We will also pinpoint some of the most relevant technical and ethical considerations. Moreover, researchers are invited to reflect on methodological demands and challenges that may be particularly relevant within the study of pain, such as confounding sampling variables (e.g., health status), design variables (e.g., motor arousal), and interpretational caveats (e.g., specificity of response measure) to ensure that the measurement is sufficiently robust and reliable as well as reproducible by other researchers and clinicians.Key wordsElectroencephalography Electromyography Electrophysiological methods Nociception Nociceptive withdrawal reflex Pain assessment Pain rating Pain tolerance Pain threshold Psychophysics
... Scores between 0 and 50 reflected the non-painful range, whereas scores between 50 and 100 reflected the painful range in line with previous studies. 59, [88][89][90][91] The unpleasantness of each stimulus was scored on a scale ranging from not at all unpleasant (0) to extremely unpleasant (100). The ratings of the 3 stimuli were averaged yielding 1 score for intensity and 1 for unpleasantness for each arm and time point. ...
The effect of cognition on the plasticity of the nociceptive system remains controversial. In this study, we examined whether working memory can buffer against the development of secondary hypersensitivity. Thirty-five healthy women participated in three experimental conditions. In each condition they underwent electrical stimulation of the skin for 2 minutes (middle-frequency electrical stimulation, MFS), which induces secondary hypersensitivity. During MFS, participants executed either an individually tailored and rewarded n-back task (working memory condition), a rewarded reaction-time task (non-working memory condition), or no task at all (control condition). Before and after MFS, participants rated the self-reported intensity and unpleasantness of mechanical pinprick stimuli. Fear of MFS was also assessed. Heart rate variability was measured to examine potential differences between the three conditions and steady-state evoked potentials to the electrical stimulation were recorded to investigate differences in cortical responses. We report no significant difference in hypersensitivity between the three conditions. Moreover, engaging in the cognitive tasks did not affect the heart rate variability or the steady-state evoked potentials. Interestingly, higher fear of MFS predicted greater hypersensitivity. In conclusion, we found no evidence that working memory affects the plasticity of the nociceptive system, yet pain-related fear plays a role.
... The rating of 50 constituted an anchor separating non-painful (0-50) to painful (50-100) sensations (e.g. [15,33,[36][37][38]). ...
Whether, how, and which cognitive factors modulate the development of secondary hypersensitivity/hyperalgesia following central sensitization is not fully understood. Here we tested, in three subsequent experiments, whether being engaged in non-pain related cognitive demanding tasks: i) lessens the amount of hypersensitivity developed after an experimental procedure sensitizing nociceptive pathways; ii) modulates cortical responses to somatosensory stimuli (measured by electroencephalography, EEG). In the first experiment we validated a novel model in humans using low frequency stimulation (LFS) of the skin and demonstrated that it was able to successfully induce hypersensitivity to mechanical pinprick stimuli in the area surrounding the sensitized site. In the second and third experiments we engaged participants in tasks of increasing difficulty (the Eriksen Flanker Task in experiment 2, and a modified N-back task in experiment 3). We observed that hypersensitivity to mechanical stimuli still developed in experiment 2, i.e. the pinprick stimuli applied on the sensitized arm were perceived as more intense after LFS. In contrast, no statistically significant enhancement of mechanical hypersensitivity was observed in experiment 3, indicating that, at the group level, being engaged in a difficult N-back task may interfere with the development of mechanical hypersensitivity. Contrary to previous studies, which have used different methods to induce sensitization, we did not observe any increase in the cortical response to somatosensory stimuli applied on the sensitized arm. We conclude that i) the development of pinprick hypersensitivity is modulated by the concomitant execution of a difficult N-back task, and ii) the enhancement of cortical responses to somatosensory stimuli is related to the method used to induce central sensitization.
... The rating of 50 constituted an anchor separating non-painful (0-50) to painful (50-100) sensations (e.g. [15,33,[36][37][38]). ...
Whether, how, and which cognitive factors modulate the development of secondary hypersensitivity/hyperalgesia following central sensitization is not fully understood. Here we tested, in 60 healthy volunteers, whether being engaged in non-pain related cognitive demanding tasks: i) lessens the amount of hypersensitivity developed after an experimental procedure sensitizing nociceptive pathways; ii) modulates cortical responses to somatosensory stimuli (measured by electroencephalography, EEG). In the first experiment we validated a novel model in humans using low frequency stimulation (LFS) of the skin and demonstrated that it was able to successfully induce hypersensitivity to mechanical pinprick stimuli in the area surrounding the sensitized site. In the second and third experiments we engaged participants in tasks of increasing difficulty (the Eriksen Flanker Task in experiment 2, and a modified N-back task in experiment 3). We observed that hypersensitivity to mechanical stimuli still developed in experiment 2, i.e. the pinprick stimuli applied on the sensitized arm were perceived as more intense after LFS. In contrast, no such effect was observed in experiment 3, indicating that, at the group level, being engaged in high-cognitive load task may interfere with the development of mechanical hypersensitivity. Contrary to previous studies, which have used different methods to induce sensitization, we did not observe any increase in the cortical response to somatosensory stimuli applied on the sensitized arm. We conclude that i) the development of hyperalgesia partly depends on attention, and ii) the enhancement of cortical responses to somatosensory stimuli is related to the method used to induce central sensitization
... mJ/mm 2 . Former studies used a stimulus intensity of 8.5 ± 1.8 mJ/mm 2 for C-fiber activation [14]. We find it remarkable that during stimulation block Th 12 grid and L 5 grid all subjects experienced a burning, long lasting sensation corresponding to C-fiber mediated 'second' pain. ...
... The T 2 temperatures ranged between 36 and 60°C following an adaptive up/down staircase algorithm based on RTs. This is justified by the fact that the nerve conduction velocity of unmyelinated C-fibres is much slower than that of myelinated Ad-fibres (AE1 m/s vs. AE10 m/s) Bjerring and Arendt-Nielsen, 1988;Mouraux et al., 2003;Mouraux and Plaghki, 2007). Opsommer and colleagues (Opsommer et al., 1999) showed that the time interval between the two peaks of the bimodal distribution of reaction times increases with peripheral distance. ...
Background:
We have recently shown that visual deprivation from birth exacerbates responses to painful thermal stimuli. However, the mechanisms underlying pain hypersensitivity in congenital blindness are unclear.
Methods:
To study the contribution of Aδ- and C-fibres in pain perception, we measured thresholds and response times to selective C- and Aδ-fibre activation in congenitally blind, late blind and normally sighted participants. Ultrafast constant-temperature heat pulses were delivered to the hand with a CO2 laser using an interleaved adaptive double staircase procedure. Participants were instructed to respond as quickly as possible when detecting a laser-induced sensation. We used a 650 ms cut-off criterion to distinguish fast Aδ- from slow C-fibre-mediated sensations.
Results:
Congenitally blind participants showed significantly faster reaction times to C- but not to Aδ-fibre-mediated sensations. In contrast, thresholds for Aδ- and C-fibre stimulation did not differ between groups. Late blind individuals did not differ from sighted controls in any aspect. A follow-up experiment using only suprathreshold stimuli for Aδ- and C-fibre activation confirmed these findings and further showed that congenitally blind individuals detected significantly more C-fibre-mediated stimuli than sighted controls. A decomposition analysis of the reaction times indicated that the faster response times in the congenitally blind are due to more efficient central processing of C-fibre-mediated sensations.
Conclusion:
The increased sensitivity to painful thermal stimulation in congenital blindness may be due to more efficient central processing of C-fibre-mediated input, which may help to avoid impending dangerous encounters with stimuli that threaten the bodily integrity. WHAT DOES THIS STUDY ADD?: Hypersensitivity to heat pain in congenital blindness is associated with faster responses to C-fibre activation, likely caused by more efficient central processing of C-fibre-mediated input.
... The thermal activation threshold of C-fibers is known to be lower (± 40 °C) than that of Aδ-nociceptors (± 46 °C) [3,4]. Mouraux and Plaghki showed the absolute detection threshold (7.6 ± 2.8 mJ/mm 2 ) can be assumed to reflect the detection threshold of C-fiber elicited sensations, whereas the average thermal activation threshold of Aδ-nociceptors was 10.0 ± 1.6 mJ/mm 2 [11]. Therefore, low intensity laser stimuli can be used to selectively activate C-fibers, whereas high intensity laser stimuli activate Aδ-fibers [3]. ...
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.
... The average energy density of the stimulus was 12.6 ± 2.1 mJ/mm 2 . This energy density was similar to the energy density used in our previous studies using single stimuli (e.g., Mouraux & Plaghki, 2007a, 2007b or trains of stimuli (e.g., Mouraux et al., 2011). Participants described the sensation elicited by these stimuli as a short-lasting pricking/burning sensation. ...
Whether the cortical processing of nociceptive input relies on the activity of nociceptive-specific neurons or whether it relies on the activity of neurons also involved in processing nonnociceptive sensory input remains a matter of debate. Here, we combined EEG "frequency tagging" of steady-state evoked potentials (SS-EPs) with an intermodal selective attention paradigm to test whether the cortical processing of nociceptive input relies on nociceptive-specific neuronal populations that can be selectively modulated by top-down attention. Trains of nociceptive and vibrotactile stimuli (Experiment 1) and trains of nociceptive and visual stimuli (Experiment 2) were applied concomitantly to the same hand, thus eliciting nociceptive, vibrotactile, and visual SS-EPs. In each experiment, a target detection task was used to focus attention toward one of the two concurrent streams of sensory input. We found that selectively attending to nociceptive or vibrotactile somatosensory input indistinctly enhances the magnitude of nociceptive and vibrotactile SS-EPs, whereas selectively attending to nociceptive or visual input independently enhances the magnitude of the SS-EP elicited by the attended sensory input. This differential effect indicates that the processing of nociceptive input involves neuronal populations also involved in the processing of touch, but distinct from the neuronal populations involved in vision.
... Both A␦-and C-fiber heat-sensitive afferents contribute to the perception elicited by nociceptive radiant heat stimuli (Mouraux and Plaghki 2007). Based on their responses to noxious heat, these afferents can be categorized as either slowly adapting (AMH-I and slowly adapting C-fibers, which respond gradually following the onset of a thermal stimulus and for which response exhibits little or no adaptation when the thermal stimulus is maintained over time) or rapidly adapting (AMH-II and quickly adapting C-fibers, which respond immediately after the onset of a thermal stimulus but quickly adapt if the thermal stimulus is maintained; Meyer and Campbell 1981;Treede et al. 1995). ...
High frequency electrical stimulation (HFS) of the human skin induces increased pain sensitivity in the surrounding unconditioned skin. The aim of the present study was to characterize the relative contribution of the different types of nociceptive and non-nociceptive afferents to the heterotopical hyperalgesia induced by HFS. In seventeen healthy volunteers (9 men and 8 women) we applied HFS to the ventral forearm. The intensity of perception and event-related brain potentials (ERPs) elicited by vibrotactile stimuli exclusively activating non-nociceptive low-threshold mechanoreceptors and thermonociceptive stimuli exclusively activating heat-sensitive nociceptive afferents were recorded before and after HFS. The previously-described mechanical hyperalgesia following HFS was confirmed by measuring the changes in the intensity of perception elicited by mechanical punctate stimuli. HFS increased the perceived intensity of both mechanical punctate and thermonociceptive stimuli applied to the surrounding unconditioned skin. The time course of the effect of HFS on the perception of mechanical and thermal nociceptive stimuli was similar. This indicates that HFS does not only induce mechanical hyperalgesia but also induces heat hyperalgesia in the heterotopical area. Vibrotactile ERPs were also enhanced after HFS, indicating that non-nociceptive somatosensory input could contribute to the enhanced responses to mechanical pinprick stimuli. Finally, the magnitude of thermonociceptive ERPs was unaffected by HFS, indicating that type II A-fibre mechanoheat nociceptors, thought to be the primary contributor to these brain responses, do not significantly contribute to the observed heat hyperalgesia.
... Because the nerve conduction velocity of unmyelinated C-fibres is markedly lower than that of Ad-fibres, these RTs were used to discriminate between responses triggered by Ad-and C-fibre input. Taking into account peripheral conduction distance, a cut-off of 650 ms was used to discriminate between Ad-and C-fibre responses when stimulating the hand dorsum [21], and a cut-off of 750 ms was used when stimulating the foot dorsum [23]. ...
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.
... These reflect mainly afferent input from small myelinated (Ad) fibres to the operculum and limbic system.While the intermediate peaks reflect how the afferent nociceptive signal activates supraspinal structures [24], late peaks around 300 ms may rather reflect discomfort or the emotionalmotivational aspect of the painful experience [27]. Ultralate peaks are difficult to record, but are thought to carry information from non-myelinated nociceptive C-fibre input [28]. Peaks are named according to their polarity (negative vs. positive) and their latency in milliseconds (e.g. ...
AIMS: To assess centrally mediated analgesic mechanisms in clinical trials with pain patients, objective standardized methods such as electroencephalography (EEG) has many advantages. The aim of this review is to provide the reader with an overview of present findings in analgesics assessed with spontaneous EEG and evoked brain potentials (EPs) in humans. Furthermore, EEG methodologies will be discussed with respect to translation from animals to humans and future perspectives in predicting analgesic efficacy. METHODS: We searched PubMed with MeSH terms "analgesics", "electroencephalography" and "evoked potentials" for relevant articles. Combined with a search in their reference lists 15 articles on spontaneous EEG and 55 papers on EPs were identified. RESULTS: Overall, opioids produced increased activity in the delta band in the spontaneous EEG, but increases in higher frequency bands were also seen. The EP amplitudes decreased in the majority of studies. Anticonvulsants used as analgesics showed inconsistent results. The N-Methyl-D-aspartate receptor antagonist ketamine showed an increase in the theta band in spontaneous EEG and decreases in EP amplitudes. Tricyclic antidepressants increased the activity in the delta, theta and beta bands in the spontaneous EEG while EPs were inconsistently affected. Weak analgesics were mainly investigated with EPs and a decrease in amplitudes was generally observed. CONCLUSIONS: This review reveals that both spontaneous EEG and EPs are widely used as biomarkers for analgesic drug effects. Methodological differences are common and a more uniform approach will further enhance the value of such biomarkers for drug development and prediction of treatment response in individual patients.
... Before analysis, it was expected that the interindividual variation would be mostly explained by the subject's ability to perceive the Bdouble-pain[ sensation classically induced by the CO 2 laser. 19 In fact, the main factor was the time spent in a closed-hand position, which may depend mainly on the subject's strength. Thus, a similar variability can also be expected in nonlaser pain models. ...
Transient pain in humans is usually quantified using visual analog or numeric rating scales, but no assessment method has yet been validated in real time during such stimulation.
To validate a transient pain monitor, healthy volunteers submitted to stimulations generated by a CO(2) laser at graded levels of stimulation were trained to close the dominant hand around a handgrip dynamometer as strongly as they felt the pain, and the signal was computerized.The parameters recorded for each response were the peak intensity, the area under the curve, and pain expressed on a visual analog scale as a control. The volunteers underwent a second session 1 week later to assess reproducibility.
The 3 parameters studied had a similar capacity to report the intensity of stimulation. The peak intensity showed many similarities with the visual analog scale, although a downward drift of the values throughout the session was observed. The area under the curve displayed a greater interindividual variability than other parameters, but it was better to assess low-intensity stimulation; a better fit for crossover designs was also suggested with the area under the curve.
This study validates in human volunteers under a laser stimulation of skin the metrological properties of an electronic handgrip device to assess the intensity of transient punctuate pain (compared with visual analog scale). The transient pain monitor validated here should now be tested in the clinical context.
... Electroencephalography (EEG), as a method of high temporal resolution, has been used in the past in combination with infrared laser stimuli to distinguish between A- and C-nociceptor activities. However, although psychophysical studies8 demonstrate a double sensation composed of first and second pain following laser stimuli, so-called ultralate components of laser-evoked potentials (LEP) that are related to C-fiber activity can only be elicited when the occurrence of late A-fiber mediated components is avoided, for example by applying a pressure blockade to the nerve.9 However, this method is complicated and can only be applied to small skin territories of distal nerve branches. ...
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.
... Laser stimuli of increasing or decreasing energy density were applied to the dorsum of the most strongly affected hand in patients and the non-dominant hand in controls. A-nociceptor and C-nociceptor activation were inferred from the reaction times of the subjects (5700 ms for A-nociceptor and !700 ms for C-nociceptor) (Towell et al., 1996;Mouraux and Plaghki, 2007). Thresholds were defined as the energy density eliciting a response in half the trials (Truini et al., 2005). ...
The present study aimed to investigate the relationship between neuropathic symptoms (i.e. pain and paraesthesia/dysaesthesia) and structural damage and functional alterations of spinal sensory tracts in patients with syringomyelia. Three-dimensional fibre tracking of the cervical spinal cord (at level C3-C4), electrophysiological assessments of nociceptive (laser-evoked potentials) and non-nociceptive (somatosensory-evoked potentials) pathways and quantitative sensory testing were carried out in 37 patients with syringomyelia, 27 with neuropathic pain and 21 controls. Four regions of the body (both hands and shoulders) were systematically examined with laser-evoked potentials and quantitative sensory testing, and somatosensory-evoked potentials were induced from both hands. The diffusion tensor imaging variables investigated included the mean fractional anisotropy, the mean apparent diffusion coefficient and the number of reconstructed nerve fibres of the tracts located within three volumes of interest (full spinal section, anterior cord and posterior cord). Consistent with the results of previous studies, patients with or without neuropathic pain were indistinguishable on the basis of quantitative sensory testing, laser-evoked and somatosensory-evoked potentials and three-dimensional fibre tracking analyses. However, in patients with neuropathic pain, higher average daily pain intensity was correlated with greater structural damage to the spinal cord, as assessed by fractional anisotropy (Spearman's ρ = -0.64, P = 0.020) and the number of reconstructed nerve fibres (r = -0.75; P = 0.020) of the full spinal cord. The number of reconstructed nerve fibres was negatively correlated with two neuropathic dimensions, i.e. 'deep spontaneous pain' (r = -0.59, P = 0.040) and 'paraesthesia/dysaesthesia' (i.e. pins and needles/tingling) (r = -0.67, P = 0.020), suggesting that various pain descriptors have distinct underlying mechanisms. Patients with both spontaneous and evoked pain clearly differed from patients with spontaneous pain only. Patients with spontaneous pain only had more severe spinal cord damage, and the correlation between average daily pain intensity and fractional anisotropy of the full spinal cord was particularly strong in this subgroup of patients (Spearman's ρ = -0.93, P = 0.008). By contrast, patients with both spontaneous and evoked pain had not only less structural spinal cord damage, but also better preserved spinothalamic and lemniscal tracts on quantitative sensory testing and electrophysiological testing. These data showed, for the first time, a direct relationship between central neuropathic pain and objective markers of spinal cord damage, and confirmed the clinical relevance of 3D fibre tracking for the sensory assessment of patients with a spinal cord lesion.
... Detection thresholds for IES, ES and LS were estimated using an adaptive staircase procedure. For LS, two distinct thresholds were estimated: the threshold for absolute detection, and the threshold for detection with reaction times (RT) < 650 ms [24]. Because RTs < 650 ms are compatible with the conduction velocity of small-diameter myelinated Ad-fibres, but not with the slower conduction velocity of unmyelinated C-fibres, and because the thermal activation threshold of C-nociceptors is lower than that of Ad-nociceptors , the absolute detection threshold reflected the detection threshold of C-fibre input (i.e. ...
In the past 30years, the study of nociception has relied mostly on thermal stimulation to activate nociceptors selectively. However, thermal stimulation suffers from some important limitations. For this reason, investigators have proposed intra-epidermal electrical stimulation (IES) as an alternative method to activate nociceptors selectively. This method relies on the fact that nociceptors are located mainly in the epidermis, while non-nociceptive fibres terminate more deeply in the dermis. Therefore, provided that the difference in receptor depth is sufficient, electric currents spatially restricted to the epidermal layers might activate nociceptors selectively. Here, we examined whether or not IES provides a fully selective nociceptive input. In a first experiment, we used capsaicin to induce a selective denervation of capsaicin-sensitive nociceptors, and thereby test whether the responses to IES are mediated by this population of afferent fibres. We found that capsaicin abolishes both the behavioural and the electrophysiological responses to IES applied at twice the perceptual threshold. In a second experiment, we applied a nerve pressure block to the superficial radial nerve to induce a temporally dissociated impairment of Abeta-, Adelta- and C-fibre afferents, and thereby determine the fibre populations contributing to the responses elicited by IES. We found that the time course of the blockade of the responses to IES follows closely the time course of the blockade of Adelta-fibres, but not of Abeta-fibres. Taken together, our results provide converging evidence that Adelta-nociceptors can be activated selectively using IES, provided that low intensities of stimulation are used.
Variability in pain sensitivity arises not only from the differences in peripheral sensory receptors, but also from the differences in central nervous system pain inhibition and facilitation mechanisms. Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation but is susceptible to confounding when elicited with the skin-contact thermode, which adds the responses of touch-related Aβ low-threshold mechanoreceptors (LTMR) to nociceptive receptors. In the present study, we evaluate an alternative method involving with the use contactless cutaneous laser for TSP assessment. We show that repetitive laser stimulations, 1-second inter-stimulus interval, evoked reliable TSP responses in a significant proportion of healthy subjects (N = 36). Female (N = 18) reported greater TSP responses than male subjects confirming earlier studies of sex differences in central nociceptive excitability. Furthermore, repetitive laser stimulations during TSP induction induced increased time-frequency EEG responses. The present study demonstrates that repetitive laser stimulation may be an alternative to skin-contact methods for TSP assessment in patients and healthy controls. PERSPECTIVE: Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation. We show that the contactless cutaneous laser stimulation is a reliable alternative to the skin contact approaches for evoking more pain-related neural responses during TSP assessment.
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.
The brain's response to external painful stimuli can be assessed through contact heat evoked cortical potentials that enable the evaluation of the integrity of pain pathways. This work aims to improve the reliability of this diagnostic procedure by decoupling the effects of heat transfer and nerve fiber conduction. It is herein shown experimentally that the latency of the N2 contact heat evoked cortical potentials component is the most stable diagnostic parameter. The contribution of heat transfer to N2 contact heat evoked cortical potentials latency was modeled as a function of the subject's pain threshold, allowing for the separation of nerve fiber pathology from thermodynamic influences.
Chronic fatigue following inflammatory diseases has been well documented. However, little is known about possible risk factors of chronic post-inflammatory fatigue. The aim of this study was to investigate whether chronic post-inflammatory fatigue after clinical remission of the disease sarcoidosis is associated with specific dimensions of personality, psychological symptoms and baseline levels of stress hormones.
Thirty-seven non-fatigued and 33 fatigued patients in clinical remission of sarcoidosis were evaluated with the Temperament and Character Inventory-short form (TCI); the Symptom CheckList-90 (SCL), and the Checklist Individual Strength (CIS). Baseline levels of ACTH and cortisol were measured in plasma. Principal component analysis with orthogonal rotation (varimax) was conducted on all personality, psychological and stress hormone data in order to obtain a smaller set of components. Logistic regression was performed to associate these components with chronic post-inflammatory fatigue.
Principal component analyses identified 5 components, of which two components were significantly associated with chronic post-inflammatory fatigue. The first component comprised the personality trait Harm Avoidance and all SCL-subscales except Sleep. The second component consisted of baseline levels ACTH and cortisol, and showed an inverse association with chronic post-inflammatory fatigue. The 3 other components, consisting of respectively SCL-Sleep, TCI-Novelty Seeking-Reward Dependence-Self Transcendence, and TCI-Persistence, were not significantly associated with chronic fatigue.
Chronic post-inflammatory fatigue after clinical remission of sarcoidosis is associated with a triad of risk factors: a specific personality profile with profound neurotic characteristics in combination with high levels of psychological distress, and decreased baseline ACTH/cortisol levels.
When the inflammatory phase of sarcoidosis has resolved, complaints of chronic fatigue frequently persist. Low-grade residual inflammatory activity may play a role in maintaining chronic fatigue. The aim of this study was to compare in vitro cytokine/chemokine production and plasma cytokine/chemokine levels between chronically fatigued and non-fatigued patients with sarcoidosis in clinical remission. Patients with sarcoidosis in clinical remission were assigned to a non-fatigued group (n=38) or a fatigued group (n=34) based on the standardized cut-off of the fatigue questionnaire Checklist Individual Strength. Cytokines/chemokines in plasma and in supernatants of whole blood cultures stimulated with either a T cell mitogen or lipopolysaccharide were quantified by multiplex analysis. Associations of cytokine/chemokine profiles with chronic fatigue were analyzed by multivariate analysis of variance and principal component analysis followed by logistic regression. Principal component analysis of T cell mitogen-induced cytokine/chemokine production identified three components that explained 76% of the variance in the cytokine/chemokine data. Logistic regression revealed that the 'Th2 cytokine'-component which mainly consists of interleukin (IL)-4, IL-5 and IL-10 was significantly and negatively associated with chronic fatigue. In addition, multivariate analysis revealed higher levels of LPS-induced IL-8 and lower levels of plasma monocyte chemoattractant protein (MCP)-1 in the fatigued group compared to the non-fatigued group. In chronically fatigued sarcoidosis patients in clinical remission, we found a cytokine/chemokine profile which is suggestive for a less competent Th2 counterbalancing capacity, that may contribute to the persistence of chronic fatigue.
To verify the possibility of selective activation of C-fibers by a 5-Hz transcutaneous electrical stimulus.
Because Aβ-, Aδ- and C-fibers have different conduction velocities, we verified the selective activation of A- and C-fibers on the basis of evoked potential latencies. We tested whether a 5-Hz sinusoidal electric stimulus could selectively activate C-fibers and consequently generate ultra-late N2/P2 components in the 750-1200 ms range.
We found that a 5-Hz sine wave stimulus, whether of high or low intensity, elicited N2/P2 complexes only in the late latencies (160-390 ms), suggesting that A-fibers were concomitantly activated along with C-fibers.
These findings are in agreement with those of previous simulation studies suggesting that activation of fibers of diameter less than 2.5 μm (i.e., C-fibers) at the 5-Hz frequency requires accompanying activity from Aβ- and Aδ-fibers.
Transcutaneous electrical stimulation with sine wave currents of different frequencies does not seem to be a reliable method for the selective assessment of somatosensory pathways.
Previous EEG studies reported the presence of synchronised 15-30 Hz oscillations in vertex electrodes following innocuous somatosensory stimulation and noxious laser stimulation. The purpose of the present study was to analyse the sources of poststimulus increases of 15-30 Hz oscillations during noxious laser stimulation of four different body regions and to compare the sources of the poststimulus synchronisation with the sources of the N2 component of laser-evoked potential (LEP). In 10 healthy subjects, moderately painful laser stimuli were applied to the dorsum of the right hand, dorsum of the right foot, right groin, and right side of the face. EEG data, recorded from 111 scalp sites, were analysed using event-related desynchronisation method and source dipole analysis. A profound amplitude increase of 15-30 Hz oscillations peaking 1-2 s after noxious laser stimulation was found during stimulation of each body part. The sources of these oscillations were located in the dorsal posterior cingulate cortex and showed no somatotopic arrangement. The sources of the N2-LEP component were located in the anterior mid-cingulate cortex 25-30 mm rostral to the sources of 15-30 Hz oscillations. The amplitude of the poststimulus synchronisation of 15-30 Hz oscillations correlated (P<0.05) with the amplitude of N2-LEP component. Results show that noxious laser stimuli induce bursts of 15-30 Hz oscillations in the posterior cingulate cortex. The poststimulus increases of 15-30 Hz oscillations may stand for transient cortical inhibition possibly aiding temporary suppression of motor programs that have been primed by noxious stimulation.
In the present study, we investigate the top-down centrifugal modulation of neural responses to a task-relevant noxious stimulation triggering voluntary movement by recording magnetoencephalography (MEG) and electroencephalography (EEG) simultaneously. An auditory warning signal was followed 2-3 s later by a noxious YAG laser stimulation as an imperative signal delivered to the left hand dorsum. Ten normal subjects performed three different conditions, Control, Movement, and Count. In Control, the subjects were asked to relax and rest quietly with no task. In Movement, the subjects extended the left index finger after imperative stimuli. In Count, the subjects counted the number of imperative stimuli silently. The amplitude of the N2 component recorded by EEG, which peaked about 220 ms after noxious stimulation, was significantly attenuated in Movement, but not in Count, compared to Control. The root-mean-square (RMS) from both hemispheres, and areal mean signal (AMS) amplitudes and the equivalent current dipole (ECD) strengths from SI/PPC and bilateral SII recorded at around 170 ms by MEG were not significantly different among the three conditions. In contrast, ECD strengths and AMS amplitudes from the anterior cingulate cortex (ACC), which showed a similar peak to the N2 component, were smaller in Movement than Control and Count. We therefore suspect that neural activities related to generator mechanisms of N2, especially including ACC, are inhibited by movement-related neural activities during the preparatory period. The present findings indicate a characteristic of pain-motor integration in a movement preparatory period.
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.
Although laser stimuli activate both Adelta- and C-fibres, the corresponding laser evoked potentials (LEPs) remain restricted to the Adelta-fibre input. Previous studies found C-LEPs after limb stimulation only in subjects with block or clinical impairment of Adelta-fibres. In this study, we aimed at verifying whether in the trigeminal territory the impairment of Adelta-fibres unmasks the C-LEP.
By collecting retrospectively LEPs recorded in 370 patients, we analyzed the results from 150 trigeminal divisions with absent Adelta-LEPs.
We found signals that were consistent with the C-fibre input in three patients only. In most patients with absent Adelta-LEPs, however, laser stimuli still elicited the Adelta-conveyed pinprick sensation.
The preserved pinprick sensation suggests that the Adelta-fibre volley, though weakened, reached the cortex. The C-LEP absence may be explained according to the first come first served hypothesis: the evoked potential related to an afferent volley reaching the cortex shortly after a preceding input (i.e. a C-fibre volley coming after an Adelta-fibre) will be suppressed.
In clinical studies using the standard laser pulses to evoke the Adelta-LEPs, the finding of absent signals does not indicate a concomitant impairment of C-fibres.
Primary somatosensory cortex (SI) and posterior parietal cortex (PPC) are activated by noxious stimulation. In neurophysiological studies using magnetoencephalography (MEG), however, it has been difficult to separate the activity in SI from that in PPC following stimulation of the upper limb, since the hand area of SI is very close to PPC. Therefore, we investigated human pain processing using MEG following the application of a thulium-YAG laser to the left thigh to separate the activation of SI and PPC, and to clarify the time course of the activities involved. The results indicated that cortical activities were recorded around SI, contralateral secondary somatosensory cortex (cSII), ipsilateral secondary somatosensory cortex (iSII), and PPC between 150-185 ms. The precise location of PPC was indicated to be the inferior parietal lobule (IPL), corresponding to Brodmann's area 40. The mean peak latencies of SI, cSII, iSII and IPL were 152, 170, 181, and 183 ms, respectively. This is the first study to clarify the time course of the activities of SI, SII, and PPC in human pain processing using MEG.
Notes that to understand the endogenous components of the event-related potential (ERP), data about the components' antecedent conditions to form hypotheses about the information-processing function of the underlying brain activity must be used. These hypotheses generate testable predictions about the consequences of the component. The application of this approach to the analysis of the P300 component is reviewed. Certain factors suggest that P300 is a manifestation of activity occurring whenever one's model of the environment must be revised. Tests of 3 predictions based on this "context updating" model are reviewed. Open peer commentary follows. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The P300 wave is a positive deflection in the human event-related potential. It is most commonly elicited in an "oddball" paradigm when a subject detects an occasional "target" stimulus in a regular train of standard stimuli. The P300 wave only occurs if the subject is actively engaged in the task of detecting the targets. Its amplitude varies with the improbability of the targets. Its latency varies with the difficulty of discriminating the target stimulus from the standard stimuli. A typical peak latency when a young adult subject makes a simple discrimination is 300 ms. In patients with decreased cognitive ability, the P300 is smaller and later than in age-matched normal subjects. The intracerebral origin of the P300 wave is not known and its role in cognition not clearly understood. The P300 may have multiple intracerebral generators, with the hippocampus and various association areas of the neocortex all contributing to the scalp-recorded potential. The P300 wave may represent the transfer of information to consciousness, a process that involves many different regions of the brain.
The shape (amplitude and latency) of single cortical responses to argon laser stimulation was found to match six perceptual classes: three pre-pain and three pain. The amplitude of the pain related single cortical responses correlated with the perceived feeling of pain. Easy detectable responses were obtained because habituation to the stimuli was reduced and a high degree of attention was given to each stimulus. Single cortical responses to argon laser stimuli are suggested as a new quantitative technique with application in the assessment of function in the thermal and nociceptive pathways.
The cortical organization of executive control was investigated using event-related potentials (ERPs). ERPs were collected while subjects performed a go/no go task that required response inhibition. First, around 260 ms after stimulus onset, an effect of response inhibition on ERPs was observed over inferior prefrontal areas. Generators in these regions were confirmed by source analysis. Later, between 300-600 ms after stimulus onset, a left lateralized fronto-central ERP effect was found which differed in topography from a non-specific effect of task difficulty. Source analysis indicated that generators in anterior cingulate and left premotor areas also contributed to this effect. Orchestrated activation of prefrontal areas and the anterior cingulate subserves executive function whereas relatively late activity of the left premotor cortex is involved in motor control.
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.
Neuroimaging and computational modeling studies have led to the suggestion that response conflict monitoring by the anterior cingulate cortex plays a key role in cognitive control. For example, response conflict is high when a response must be withheld (no-go) in contexts in which there is a prepotent tendency to make an overt (go) response. An event-related brain potential (ERP) component, the N2, is more pronounced on no-go than on go trials and was previously thought to reflect the need to inhibit the go response. However, the N2 may instead reflect the high degree of response conflict on no-go trials. If so, an N2 should also be apparent when subjects make a go response in conditions in which no-go events are more common. To test this hypothesis, we collected high-density ERP data from subjects performing a go/no-go task, in which the relative frequency of go versus no-go stimuli was varied. Consistent with our hypothesis, an N2 was apparent on both go and no-go trials and showed the properties expected of an ERP measure of conflict detection on correct trials: (1) It was enhanced for low-frequency stimuli, irrespective of whether these stimuli were associated with generating or suppressing a response, and (2) it was localized to the anterior cingulate cortex. This suggests that previous conceptions of the no-go N2 as indexing response inhibition may be in need of revision. Instead, the results are consistent with the view that the N2 in go/no-go tasks reflects conflict arising from competition between the execution and the inhibition of a single response.
Objective : We investigated the effects of a go/nogo task on event-related potentials (ERPs) evoked by somatosensory stimuli. Methods : ERPs following electrical stimulation of the second (go stimulus) or fifth (nogo stimulus) left-handed digit were recorded from 9 subjects. The recordings were conducted in 3 conditions: Control, Count and Movement. The subjects were instructed to count the go stimuli silently in Count, and respond to the go stimuli by grasping right hands in Movement. Go and nogo stimuli were presented at an even probability. Results : N140 was recorded in all conditions and P300 in Count and Movement. The mean amplitudes of the nogo stimuli in the interval 140–200 msec and nogo-N140 amplitude were significantly more negative than those of the go stimuli in Count or Movement. Nogo-P300 was larger in amplitude than go-P300 in Movement but not Count. The effect of P300 was applied to Fz and Cz, but not at Pz. Conclusions : In the present study, effects of a somatosensory go/nogo task on ERPs were investigated, and our findings were very similar to those of previous studies using visual and auditory go/nogo tasks. Therefore, we suggest that cortical activities relating to go/nogo tasks are not dependent on sensory modalities. Significance : The present study showed for the first time the go/nogo effects on somatosensory-evoked ERPs. These effects were similar to those in visual and auditory ERP studies.
Three experiments investigating the effects of response production and inhibition on the N2 and P3 components of the ERP are reported. In the first experiment, 12 young female volunteers were presented with the words 'push' and 'wait' (semantic stimuli). On a separate series of trials, they were presented with arbitrary symbols assigned the same meanings (symbolic stimuli). For each stimulus series half of the stimuli were degraded. To obtain an estimate of reliability of the data, each task was repeated. Data were collected from Fz, Cz and Pz electrode sites. The P3 amplitude had a parietal maximum when the stimuli instructed subjects to respond (Go). The P3 was equal at central and parietal sites when the stimuli instructed the subjects to withhold a response (No-Go). This topographic pattern was obtained for all stimulus manipulations, simple and degraded stimuli, words and symbols, and for the first and second runs. The N2 was a frontal maximum component that was larger to the No-Go than to the Go stimuli. This result was also robust to the manipulations. A second experiment investigated the dependency of these findings on an overt motor response. In this experiment, the symbolic and semantic stimulus series were each presented twice. The subjects counted the Go stimuli and did not count the No-Go stimuli for one presentation and pressed the reaction time button as in experiment 1 for the other presentation. While counting (compared to button pressing) delayed the N2 and P3 peaks, counting and pressing produced similar results, including the Go/No-Go P3 distribution effects. A third experiment investigated the sensitivity of these findings to the orientation of the symbols instructing the subjects to respond or withhold the response. Again the pattern of results was robust to this manipulation.
P3 is the most prominent of the electrical potentials of the human electroencephalogram that are sensitive to psychological variables. According to the most influential current hypothesis about its psychological significance [E. Donchin's], the “context updating” hypothesis, P3 reflects the updating of working memory. This hypothesis cannot account for relevant portions of the available evidence and it entails some basic contradictions. A more general formulation of this hypothesis is that P3 reflects the updating of expectancies. This version implies that P3-evoking stimuli are initially unexpected but later become expected. This contradiction cannot be resolved within this formulation. The alternative “context closure” hypothesis retains the concept of “strategic information processing” emphasized by the context updating hypothesis. P3s are evoked by events that are awaited when subjects deal with repetitive, highly structured tasks; P3s arise from subjects' combining successive stimuli into larger units. The tasks in which P3s are elicited can accordingly be classified in terms of their respective formal sequences of stimuli. P3 may be a physiological indicator of excess activation being released from perceptual control areas.
An adaptive filter system has been developed whereby variable latency neuroelectric signals may be detected and separated from associated noise. The system is based on correlation-averaging techniques which are described in detail. The adaptive property of the system derives from iterative correlation and averaging of the data signals and permits the recognition of signals the specific waveshapes of which are not known in advance.
The system consitutes a general pattern recognition device. It has been shown to be applicable to the analysis of evoked potentials of variable latency as well as to the analysis of patterns of EEG activity. Further applications include the analysis of multiple, complex signals such as miniature potentials from single motor units in the spinal cord. The use of an adaptive filter such as this with convergence properties based on broad statistical considerations appears to have greater analytic power than have previous methods.
CO2 laser emitted radiant heat pulses of 20 ms duration were used to activate predominantly slowly conducting nociceptive cutaneous afferents in man. Stimuli of two-fold individual pain threshold caused stinging and burning pain and elicited cerebral potentials with latencies consistent with Aδ-fibre activity. After preferential block of the myelinated nerve fibres by pressure only the burning pain remained with significantly increased reaction time (about 1433 ms). The Aδ-fibre-induced evoked potential components disappeared, and a marked ultralate positive component became visible with mean peak latency of 1260 ms, consistent with C-fibre activity.
The topography of averaged ERP to auditory and visual stimuli was evaluated employing an array of scalp electrodes overlying the left hemicranium in a sequential discrimination (Go-NoGo) task. The discriminanda (S1 and S2) were presented 1 sec apart and the subjects made a delayed motor response when S2 differed from S1 and withheld response when they were the same. Late positive components were associated with both S1 and S2 and slow negative shifts (CNV) occurred during the S1–S2 interval. The negative shifts terminated after the NoGo S2 but persisted after the Go stimuli until the motor response was performed.
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.
Short radiant heat pulses, emitted by a high power CO2 laser, were used to investigate single nociceptor activity, cerebral potentials and concomitant sensations. Stimuli of 20 and 50 ms duration with different intensities were randomly applied to the hairy skin of the hand. Microelectroneurography was performed from the radial nerve at the wrist; 26 stable recordings were evaluated. Pre- and post-stimulus EEG segments were recorded from vertex versus linked ear lobes. Sensation was assessed on an eight-step category scale, an adjective scale, and by reaction times. In some experiments an A-fibre block was applied in order to isolate C-fibre responses. The main results were: Short heat stimuli activate C-units. In addition one of two identified A delta-units responded. None of the 15 A beta-units investigated was activated by the heat pulses. Short heat stimuli evoked cerebral potentials having a main vertex positive component at about 400 ms. These potentials were ascribed to A delta-fibre input. Laser induced pain consisted of an immediate stinging component, followed by a burning pain which often lasted several seconds. Reaction time to first pain ranged from 400-500 ms. Weak laser stimuli induced non-painful sensations mostly of tactile character. High correlations were found between the number of spikes elicited by a given stimulus and the intensity of the evoked sensation. Intensity discrimination, as evaluated by measures of Signal Detection Theory, was better in the peripheral C-units than in the subjective ratings. If conduction of A-fibres was blocked by pressure, A delta-related cerebral potential components vanished.(ABSTRACT TRUNCATED AT 250 WORDS)
In many studies on the effect of selective attention and stimulus significance on evoked potentials, the target, or otherwise significant, stimuli were also infrequent stimuli. The present study aims at separating these two confounded effects. Repetitive homogeneous auditory stimuli were presented at short constant intervals. One of two deviant stimuli, one slightly lower and the other slightly higher in pitch than the repetitive stimulus (‘standard’), randomly replaced it at the same low probability. One at a time of these two physically equally deviant and equally infrequent stimuli was designated as a target and the subject's task was to count its number in a run and to ignore the other deviant stimulus.
This chapter discusses P300 in serial tasks which are an essential post-decision closure mechanism. It is now agreed that event-related potentials (ERPs) are composite phenomena made up of distinct components that can be differentially manipulated experimentally and reflect different cerebral processors engaged in the cognitive task. Middle range components such as N120 are elicited when the cognitive and speed overload exceed a certain value and present a somewhat restricted scalp topography that differs characteristically with the sensory modality of the target stimuli. Primary components in cortical receiving areas (clearly documented for the somatosensory evoked potentials only) are not modified by the task conditions and represent roughly a hard-wired response occurring irrespective of wide changes in N120 or P300. On the other hand the P300 occurs maximally or only for those stimuli having been designated as targets that correspond to a task-relevant category. The small P300 sometimes described for stimuli that the subject is told to ignore may result from a failure of the subject to follow instructions or to orienting.
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 an audio-visual Go/Nogo paradigm we studied whether the Go/Nogo difference, usually found in the time range of the visual N2, is also present after auditory stimuli, which bears on the common response inhibition hypothesis of this N2 effect. Moreover the possible presence and variation of P300 subcomponents were studied with the goal of clarifying the reasons for the commonly observed P300 topography changes between Go and Nogo trials. To disentangle possible P300 subcomponents we applied a crossmodal divided attention (DA) condition, in which the subcomponents are known to be separated after auditory stimuli in choice tasks. An N2 effect was found after visual but not after auditory stimuli, which is evidence against the response-inhibition hypothesis. After visual stimuli a positive complex (P400) was seen, whereas after auditory stimuli two dissociated components (P400 and P507) were found instead. The P507 had a parietal maximum for both Go and Nogo trials. It was larger and it peaked later in Go than in Nogo trials. The P400 showed topographic differences between Go and Nogo trials, which could be explained by the overlap of the two subcomponents. We assume that (i) both subcomponents have a stable topography across response type, and (ii) the first subcomponent is invariant with response type, whereas the second (which overlaps the first one) is larger and peaks later on Go than on Nogo trials.
Cerebral potentials evoked by CO2 laser stimulation were recorded in 22 normal volunteers. Substantial variability in latency, morphology and amplitude of the responses in individual trials was noted, and in some trials no response appeared to be present. Averaging after latency correction and removal of traces without clear responses was compared with conventional time-locked averaging. We found a greater amplitude and more consistent wave form in the former case, and better preservation of amplitude with increasing age and under conditions of impaired attention. Cross-correlation techniques and Minimum Mean Square Error (MMSE) filtering did not assist identification of responses. We conclude that with laser-evoked cerebral potentials visual identification of components is a simple and reliable way of obtaining an improved estimate of the average evoked potential.
We recorded CO2 laser evoked cerebral potentials in 6 healthy subjects using both a standard technique and an oddball paradigm. In the standard technique stimuli were aimed at the dorsum of the left hand with the subject passive; in the oddball paradigm, target infrequent stimuli (P = 0.15) were directed to one side of the dorsum of the left hand and the subject was instructed to count their occurrence, the frequent stimulus being delivered to the other side of the hand. In both standard and oddball frequent recordings, CO2 laser evoked potentials were a well-formed negative-positive complex with a peak latency and amplitude around 305 msec (to positivity) and 32 microV respectively. However, in the oddball target task a later potential was also recorded, with a mean latency and amplitude of 621 msec and 24 microV respectively which we believe to be a laser oddball potential. These results demonstrate that the CO2 potential is not altered by manipulations of attention to any significant extent and suggests that it is therefore closely related to the primary sensory input. They also provide further evidence of the non-specificity of the oddball potential across sensory modalities.
The present study was aimed at examining the specificity of the action of heterotopic nociceptive conditioning stimulation (HNCS) by comparing its effects of those induced by a mental task (MT). Five test stimuli made from short CO2 laser pulses (duration: 40 msec; diameter: 10 mm; intensity: 0.25-0.8 Joules) were delivered every 30 to 45 sec at random to 4 different spots on the skin of the upper lip in 3 groups of 10 healthy subjects. The two most intense stimuli were perceived as painful, the two least intense stimuli as warm, and the intermediate stimulus as hot or near painful. Perception (VAS), reaction time (T) and cerebral evoked potentials (CEPs) were monitored before, during and after conditioning stimulation consisting either of HNCS (hand submerged in cold water) or of MT (arithmetic subtraction). Pain perception (first pain) threshold was increased in both conditioning stimulations; however, the stimulus-response curve and the neurophysiological correlates were differently affected. During HNCS, the stimulus-response curve was depressed and T was increased mainly for the intermediate stimulus, whilst CEP power density was reduced for all stimulus intensities; discrimination performance near pain threshold was dramatically depressed. During MT, the stimulus-response curve was shifted down toward higher stimulus intensities, T was equally increased for all stimulus intensities, whereas CEP power density was not changed; discrimination performance remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
We recorded cortical potentials evoked by painful CO2 laser stimulation (pain SEP) employing an oddball paradigm in an effort to demonstrate event-related potentials (ERP) associated with pain. In 12 healthy subjects, frequent (standard) pain stimuli (probability 0.8) were delivered to one side of the dorsum of the left hand while rare (target) pain stimuli (probability 0.2) were delivered to the other side of the same hand. Subjects were instructed to perform either a mental count or button press in response to the target stimuli. Two early components (N2 and P2) of the pain SEP demonstrated a Cz maximal distribution, and showed no difference in latency, amplitude or scalp topography between the oddball conditions or between response tasks. In addition, another positive component (P3) following the P2 was recorded maximally at Pz only in response to the target stimuli with a peak latency of 593 msec for the count task and 560 msec for the button press task. Its scalp topography was the same as that for electric and auditory P3. The longer latency of pain P3 can be explained not only by its slower impulse conduction but also by the effects of task difficulty in the oddball paradigm employing the pain stimulus compared with electric and auditory stimulus paradigms. It is concluded that the P3 for the pain modality is mainly related to a cognitive process and corresponds to the P3 of electric and auditory evoked responses, whereas both N2 and P2 are mainly pain-related components.
The aim of this study was to distinguish the exogenous component (related to the physical properties of the stimulus) and the endogenous component (reflecting event-related cognitive processing) of the laser-evoked potential (LEP). Short painful radiant heat pulses generated by a CO2-laser were applied to the dorsum of the right and left foot. LEPs were recorded with 5 scalp electrodes in the midline versus linked earlobes in 26 healthy subjects. In order to identify the exogenous component, the LEP was recorded during a standardised distraction task (reading a short story). To identify the endogenous component P3 for the LEP, a 2-stimulus oddball paradigm was used (20% probability of targets). When the task of the oddball paradigm consisted of pressing a button, a movement-related long-latency negativity (N 1200) was recorded in frontal leads that was absent in a counting task. The LEP of targets, frequent non-targets and during distraction was dominated by a single large positivity. The amplitude of this positivity was task-dependent and increased the more attention the subject payed to the laser stimuli (distraction < neutral < non-target < target). The laser-evoked positivity during distraction had a peak latency of about 400 msec (P400) and a maximum amplitude at the vertex, which was independent of inter-stimulus interval. The P3 following laser stimulation had a significantly later peak at about 570 msec (P570) and a different scalp topography with a parietal maximum. Its amplitude decreased when the interstimulus interval was reduced from 10 to 6 sec. Under neutral instructions, the LEP positivity consisted of a superposition of both the exogenous P 400 and the endogenous P570.
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.
In visual Go/Nogo tasks the ERP usually shows a frontal negativity after Nogo stimuli ("Nogo-N2"), which possibly reflects an inhibition process. However, the Nogo-N2 appears to be very small after auditory stimuli, which is evidence against the inhibition hypothesis. In the present study we tested this hypothesis by evaluating performance differences between subjects. Assuming that for Ss with a high false alarm rate the inhibition process is weakened and/or delayed, they should reveal a smaller and/or later Nogo-N2 than Ss with a low false alarm rate. This prediction was confirmed, which supports the inhibition hypothesis. However, the Nogo-N2 was again much smaller and had a different topography after auditory than after visual stimuli despite similar performance in both modalities. This modality asymmetry was explained by assuming that the inhibitory mechanism reflected in the Nogo-N2 is located at a pre-motor rather than at the motor level. In the second part of the study we compared the Nogo-N2 with a similar phenomenon, the error negativity (Ne), which occurs in trials with commission errors (false alarms). Earlier work suggests that the Ne is a correlate of error detection or inhibition. This raises the possibility that the Ne is a delayed Nogo-N2, i.e., the Ne may reflect a late and hence unsuccessful attempt to inhibit the response after a nontarget. However, the Ne amplitude showed no difference between performance groups and stimulus modalities, as found for the Nogo-N2. Moreover, Ne and Nogo-N2 had different scalp topographies. This suggests that different mechanisms and generators underlie the Ne and the Nogo-N2.
This study was designed to estimate and compare nerve conduction velocity (NCV) of cutaneous heat-sensitive C-fibres obtained using two methods. The first is a method based on reaction times to different rates of temperature change produced by a large contact thermode (Thermotest). The second is a novel method based on ultra-late-evoked brain potentials to CO2 laser stimuli with tiny beam sections (< 0.25 mm2), allowing selective and direct activation of very slow conducting afferents. Both methods were applied on three sites of the right leg (foot, knee and thigh) of ten healthy subjects. When based on the reaction times to contact heat, NCV estimations were 0.4 +/- 0.22 m/s for the proximal segment (knee-thigh) and 0.6 +/- 0.23 m/s for the distal segment (foot-knee). When based on the difference in latency of the ultra-late positivity of laser-evoked brain potentials, NCV estimations were respectively 1.4 +/- 0.77 m/s and 1.2 +/- 0.55 m/s. For both methods, the difference in NCV between proximal and distal limb segments was not significant. Although both methods give NCV estimations within the range of C-fibres, the systematic difference between NCV obtained from each method may result from the activation of subpopulations of C-fibres with different NCV depending on the method of stimulation (low-threshold thermal receptors by the thermode and thermal nociceptors by the CO2 laser). Considering the difficulty of investigating peripheral fibres with slow conduction velocities (C-fibres) in humans, the methods used in the present study may be useful tools in both experimental and clinical situations.
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.
This study examined the relative capacity of Adelta- and C-fibers to encode non-painful and painful brief CO(2) laser stimuli by comparing the effects of Adelta/C-fiber activation versus C-fiber activation alone. In nine normal subjects, brief CO(2) laser pulses of four different intensities (range 5.8-10.6mJ/mm(2)) were delivered at random on the first intermetacarpal zone of the dorsum of the hand. A-fiber pressure block of the superficial radial nerve was performed to fully isolate the activity of C-fibers. Quality and intensity (VAS) of percepts, reaction time (RT) and laser-evoked potentials (LEPs) were examined in baseline and A-fiber block conditions. During A-fiber block, absolute detection threshold increased dramatically from 4.8+/-1.8 to 10.9+/-4.8mJ/mm(2), proportion of detected stimuli decreased from 87% to 47% and proportion of pain reports from 39% to 10%. The quality of sensations became mainly 'light touch' and the 'pricking' sensation almost vanished. The stimulus-VAS curve shifted to the right and the slope was reduced. Signal Detection Theory analysis revealed that discrimination performance (P(A)) was significantly depressed and that response bias (B) evolved from a neutral towards a stoical attitude. Median RT increased from 492 to 1355ms. The late LEPs, attributed to the activation of Adelta-fibers, disappeared and ultra-late LEPs were recorded at Cz with a positivity peaking around 800ms. Collectively, these observations lead to the conclusion that Adelta-fibers are the main peripheral mediators for the perception of brief CO(2) laser stimuli and that they provide more sensory information than C-fibers.
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).
Painful stimuli delivered by infrared laser stimulators elicit laser-evoked potentials (LEP) or magnetic fields in respective electroencephalogram (EEG) and magnetoencephalogram (MEG). Evidence is reviewed that LEP represent a series of event-related potentials (ERP) that depend on vigilance and arousal, selective spatial attention and contextual task variables. Paradigms adopted from other stimulus modalities in the assessment of attention and cognition in ERP and applied to LEP allow the view that middle-latency (N1) and long latency (N2-P2) components of LEP can be overlapped or supplemented by endogenous components such as the processing negativity and distinct members (P3a and P3b) of the "P300" activities, each of which is considered in detail in this review. This composite entity needs to be considered when LEP are experimentally or clinically used in the assessment of sensory and cognitive phenomena and abnormalities of pain sensation.
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.
We investigated the effects of a go/nogo task on event-related potentials (ERPs) evoked by somatosensory stimuli.
ERPs following electrical stimulation of the second (go stimulus) or fifth (nogo stimulus) left-handed digit were recorded from 9 subjects. The recordings were conducted in 3 conditions: Control, Count and Movement. The subjects were instructed to count the go stimuli silently in Count, and respond to the go stimuli by grasping right hands in Movement. Go and nogo stimuli were presented at an even probability.
N140 was recorded in all conditions and P300 in Count and Movement. The mean amplitudes of the nogo stimuli in the interval 140-200 msec and nogo-N140 amplitude were significantly more negative than those of the go stimuli in Count or Movement. Nogo-P300 was larger in amplitude than go-P300 in Movement but not Count. The effect of P300 was applied to Fz and Cz, but not at Pz.
In the present study, effects of a somatosensory go/nogo task on ERPs were investigated, and our findings were very similar to those of previous studies using visual and auditory go/nogo tasks. Therefore, we suggest that cortical activities relating to go/nogo tasks are not dependent on sensory modalities.
The present study showed for the first time the go/nogo effects on somatosensory-evoked ERPs. These effects were similar to those in visual and auditory ERP studies.
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.
Previous source analyses of event-related potential (ERP) data elicited in Go/NoGo tasks have suggested that the anterior cingulate cortex (ACC) plays an important role in response inhibition. So far, however, source models were derived for the difference wave Go stimulus minus NoGo stimulus. This difference wave is confounded with motor- and attention-related activity. To avoid these confounds, we alternatively derived source models for NoGo stimuli only. The problem of the NoGo-N2 being superimposed on a positive deflection was addressed in two ways. First, a baseline correction was applied using the time points just preceding and succeeding the NoGo-N2. Second, a separate source model was derived at the maximum amplitude of this positive deflection. Subjects were presented with a cued version of the continuous performance task (CPT; ABX). In a second study, the probability of the Go stimulus was gradually increased to heighten subjects' tendency to respond and, as a consequence, to enhance the amplitude of the NoGo-N2. The source models of the NoGo-N2 consistently indicated bilateral dipole pairs in medial frontal regions. This is in accordance with a generator in the anterior cingulate cortex.
By co-activating A partial partial differential- and C-fibre nociceptors, intense CO2 laser heat stimuli produce a dual sensation, composed of first and second pain, but induce only a single A partial partial differential-fibre related late laser evoked potential (LEP). However, when avoiding concomitant activation of A partial partial differential-fibres, C-fibre related ultra-late LEPs are recorded. This poorly understood phenomenon was re-investigated using a method which, unlike time-domain averaging, reveals electroencephalogram (EEG) changes whether or not phase-locked to stimulus onset.
CO2 laser stimuli were applied to the dorsum of the hand. Reaction-time was used to discriminate between A partial partial differential- and C-fibre mediated detections. Analyses were performed using a method based on the time-frequency wavelet transform of EEG epochs.
This study revealed: (1) a novel non-phase-locked component related to the activation of A partial partial differential-fibres occurring at similar latencies as the late LEP; and (2) a widespread post-stimulus event-related desynchronization (ERD) induced by both A partial partial differential- and C-fibres.
A partial partial differential- and C-fibre related LEPs could be electrophysiological correlates of similar brain processes, which, when already engaged by A partial partial differential-fibres, cannot or do not need to be reactivated by the later arriving C-fibre afferent volley. A partial partial differential-fibre related ERD could reflect a transient change of state of brain structures generating these responses.
Fonctions psychomé et mé psychophysiques adaptatives pour l'e ´tude de la douleur In: SFD-SOFRED Ed Evaluation de la douleur expé chez l'homme et l'animal Stimulus deviance and evoked potentials
- A Mouraux
- Plaghki
- R Naatanen
- M Simpson
- Loveless
Mouraux A, Plaghki L. Fonctions psychomé et mé psychophysiques adaptatives pour l'e ´tude de la douleur In: SFD-SOFRED Ed. Evaluation de la douleur expé chez l'homme et l'animal. Paris, 2000. Naatanen R, Simpson M, Loveless NE. Stimulus deviance and evoked potentials. Biol Psychol 1982;14:53–98.
Event-related brain potentials and cognition: a critique of the context updating hypothesis and an alternative interpretation Willis WD. The pain system. New York: Karger; 1985. Woody C. Characterization of an adaptive filter for the analysis of variable latency neuroelectric signals
- R Verleger
Verleger R. Event-related brain potentials and cognition: a critique of the context updating hypothesis and an alternative interpretation. Behav Brain Sci 1988;11. Willis WD. The pain system. New York: Karger; 1985. Woody C. Characterization of an adaptive filter for the analysis of variable latency neuroelectric signals. Med Biol Eng 1967;5:539–53.