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Human cerebral potentials evoked by CO2 laser stimuli causing pain
Abstract
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.
... CO 2 laser stimulation of the plantar side of the right hind paw (at least 3 s in between each stimulus; randomized skin sites) was used to selectively activate nociceptive afferents (figure 1(A)) [45,46]. Nociceptive evoked cortical responses and nociceptive withdrawal reflexes on CO 2 laser stimulation (wavelength, 10.6 µm; 5 W, unfocused beam, 3 mm in diameter, MedArt VariMed Diode Laser System, Denmark) were used to assess pain in the animal [34]. ...
... ECoGs were divided into 5 s epochs and their power spectral densities (PSD) were estimated and averaged for visualization. The relative powers (proportion of total signal power) contained within five different frequency bands (delta, 0.5-4 Hz; theta, 4-10 Hz; sigma, 10-15 Hz; beta, 15-30 Hz; gamma, [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45],) were estimated from the PSDs and used to detect potential differences in their shapes (indicating changes in brain state) between the control and stimulation conditions. ECoGs in which high-amplitude epochs were excluded by simple thresholding yielded equivalent results and validated by visual comparison of the original and cleaned signals. ...
... As can be seen in figure 6, the overall shape of PSDs of ECoGs recorded during the same sessions were very similar in the two conditions, in both cases dominated by low frequency components ( figure 6(A)). Quantitative comparison of the difference in relative band power showed a small, although significant (p < 0.05), difference in the theta (4-10 Hz) and gamma (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) Hz) bands (−3.1% and +1.4%, respectively, indicating a minor shift in PSD towards higher frequencies; figure 6(B)). This may suggest the induction of a slight shift in the level of wakefulness during stimulation, although not detected in the behavior (figure 5). ...
To clarify if an adaptive current stimulation protocol, in which current amplitude is modulated during continuous stimulation, provides better efficacy than constant current stimulation protocol with respect to analgesia caused by individualized stimulation in rat periaqueductal gray matter (PAG)/dorsal raphe nuclei (DRN).
Approach. Ultrathin microelectrodes adapted for recording (n=6) and stimulation (n=16) were implanted in rat primary somatosensory cortex and PAG/DRN, respectively. In each animal included (n=12), a subset of PAG/DRN microelectrodes (n=1-3 per animal) was selected that on simultaneous stimulation blocked nociceptive withdrawal reflexes in awake unrestrained animals without noticeable side effects. Analgesic effects were subsequently assessed from both nociceptive withdrawal reflexes and intracortical pain-related responses on CO2 laser hindpaw stimulation. The analgesic effects of adaptive current PAG/DRN stimulation comprising incremental increases of 5µA/microelectrode (initial median current 30µA/microelectrode) when effects declined were compared to the effects of constant current stimulation. Behavioral effects and brain state related changes were analyzed using quantitative movement analysis and electrocorticography (ECoG, recorded on top of the dura mater), respectively. Tissue reactions and probe placement in PAG/DRN were assessed with immunohistochemistry.
Main results. Powerful and sustained (4 hours) analgesia was achieved with the adaptive current protocol within a rather wide area of PAG/DRN. Analgesic after-effects were seen for up to 30 min. Behavioral and brain state related side effects were minimal. Moreover, 6 weeks after implantation, there were no traces of bleedings, only small glial reactions and small but not statistically significant loss of neurons nearby indicating that the 6 microelectrode stimulation employed is biocompatible.
Significance. The results indicate that sustained and powerful analgesia with minimal side effects can be achieved by granular and individualized stimulation in PAG/DRN using an adaptive current stimulation protocol. This microelectrode technology and stimulation 10 paradigm thus has the potential of providing a highly efficient and safe pain therapy.
... Scientific RepoRtS | (2018) 8:8265 | DOI: 10.1038/s41598-018-26604-0 A number of magnetoencephalography (MEG) and scalp electroencephalography (EEG) studies have shown that stimulus repetition at a constant ISI leads to a strong decrease in the amplitude of phase-locked responses, and in particular of laser-evoked potentials (LEPs) -a phenomenon defined as response habituation 5,[9][10][11][12][13][14][15][16][17] . Because this response habituation is not necessarily paralleled by a reduction in the intensity of perception, this can lead to a marked dissociation between the magnitude of these event-related potentials and perception 13 . ...
... Based on previous studies using scalp EEG and MEG 5,9,[11][12][13][15][16][17][18] , we hypothesized that (i) the intensity of stimulation would affect intensity ratings, as well as the magnitudes of both low-frequency phase-locked LFPs and GBOs elicited in the insula; (ii) that stimulus repetition at a constant and predictable ISI would decrease the magnitudes of low-frequency phase-locked LFPs recorded from the human insula, but would not affect intensity ratings nor the magnitudes of GBOs recorded at the same insular locations. ...
... This difference could be explained by a floor effect due to the much smaller responses elicited by low-intensity nociceptive and vibrotactile stimuli. In agreement with our findings, several scalp EEG and MEG studies have shown that the repeated presentation of a stimulus at a constant ISI leads to a habituation of the stimulus-evoked brain responses 5,[9][10][11][12][13][14][15][16][17]23 . These studies indicate that habituation takes place regardless of the modality of stimulation, as it was observed for thermonociceptive stimuli 5,9,[11][12][13][15][16][17] , as well as for innocuous somatosensory 11,14 and auditory 10,14,16,23 stimuli. ...
Salient nociceptive and non-nociceptive stimuli elicit low-frequency local field potentials (LFPs) in the human insula. Nociceptive stimuli also elicit insular gamma-band oscillations (GBOs), possibly preferential for thermonociception, which have been suggested to reflect the intensity of perceived pain. To shed light on the functional significance of these two responses, we investigated whether they would be modulated by stimulation intensity and temporal expectation - two factors contributing to stimulus saliency. Insular activity was recorded from 8 depth electrodes (41 contacts) implanted in the left insula of 6 patients investigated for epilepsy. Thermonociceptive, vibrotactile, and auditory stimuli were delivered using two intensities. To investigate the effects of temporal expectation, the stimuli were delivered in trains of three identical stimuli (S1-S2-S3) separated by a constant 1-s interval. Stimulation intensity affected intensity of perception, the magnitude of low-frequency LFPs, and the magnitude of nociceptive GBOs. Stimulus repetition did not affect perception. In contrast, both low-frequency LFPs and nociceptive GBOs showed a marked habituation of the responses to S2 and S3 as compared to S1 and, hence, a dissociation with intensity of perception. Most importantly, although insular nociceptive GBOs appear to be preferential for thermonociception, they cannot be considered as a correlate of perceived pain.
... This seemed like a good explanation as even though the C fiber receptors have a lower threshold than the A∂ receptors and are therefore more easily excited, they require more spatial and temporal summation than do the A∂ receptors, making the timing of their afferent volleys less synchronized. Bromm and Treede (1987) found that the intra-and inter-individual peak latency standard deviation was 150 ms, which would cause significant jitter, and thus the peak could be 'smeared' ...
... Because the N2P2 resulting from A∂ excitation is similar in morphology and topology to the ultra-late potential (Bragard et al., 1996, Opsommer et al., 2003 visualized when Aδ fibers are blocked, it is a possibility that they result from the same cortical generator (Bromm and Treede, 1987, Mouraux and Plaghki, 2006. Thus, it was proposed by several researchers that the reason the ultra-late potential was not visualized without A∂ suppression was that the generator was in a refractory period . ...
... In humans, neurophysiological research has identified the laser-evoked potential (LEP) as a useful tool for studying nociception and, by extension, pain (Chen et al., 1979, Arendt-Nielsen and Bjerring, 1988, Arendt-Nielsen, 1994, Bromm and Lorenz, 1998. The LEP has proven useful for testing the patency of the pain pathway (Bromm and Treede, 1987), and has been used as a method of assessing the efficacy of analgesics , Beydoun et al., 1997, Garcia-Larrea, 2006. Researchers have additionally demonstrated that there are LEP features, the magnitude of which correlate to a human subject's perception of pain. ...
PhD Dissertation from Neuro and Cognitive Sciences Program, University of Maryland
... In addition, studies in adult humans using surface 101 , and intracortical recording of LEPs 100 , and magnetoencephalography following laser stimulation 106 , have shown that the specificity of laser stimulation in activating Ad fibres 96,97,101,105,107 enables observation of the sequence of Ad fibre activation of primary (SI) and secondary (SII) somatosensory cortices. All three studies demonstrated that contralateral SII has a substantial role in the processing of small diameter afferent input, possibly through direct thalamocortical projections 100,101,106 . ...
... Nothing is known about small fibre connectivity in infants and young children. However, studies in adults haveshown that it is possible to gain information concerning the contributions of Aβ, Aδ, and C sensory nerve fibres, and the functional integrity of the pathways in which they are involved using mechanical, electrical, and laser stimulation to elicit SEPs[96][97][98][99][100][101][102][103][104] . ...
There is still much to be discovered about the structural and functional development of the components of the nervous system concerned with pain processing in the human. Although there have been elegant studies on developing animals which have elucidated some of the elements underlying pain mechanisms, particularly at the level of the spinal cord, very little is known of how signals from painful stimuli are processed at higher levels, up to and including the cerebral cortex, in either animals or humans when they are very young. Neurophysiological studies on human neonates and infants are technically difficult to perform, and ethically it is totally unacceptable to give children painful stimuli of any kind except through clinical necessity, such as a heel lance for required blood sampling. Therefore, as in the studies from our research group, inference has to be drawn by recording responses that are modulated by the presence of ongoing pain, but that can be elicited using non-painful stimuli, such as the flexion withdrawal reflex and the abdominal skin reflex.
... A recent study using a pain conditioning paradigm did not find evidence for a modulation of the VP by expectations and prediction errors, suggesting that the VP mostly reflects the sensory processing of a stimulus (13). However, other studies have shown that the amplitude of the VP is modulated by the history and unpredictability of previous stimuli and can be decoupled from perceived intensity (14)(15)(16)(17)(18). ...
... To ensure that the effects of confidence on EEG signals were not driven by confounding factors related to the prediction itself (p(I 1 |y 1:n , M i , ω i ) := p n ) (20), we first computed the residual confidence c r n from the confidence c n by regressing out the predicted probability, its logarithm, and its square as: c n = β r 0,k +β r 1 ·p n +β r 2 ·p 2 n +β r 3 ·log(p n )+β r 4 ·log(1−p n )+c r n , [14] where k denotes the testing block index, n the trial index, and β r the regression coefficients. The first coefficient β r 0,k is a fixed intercept grouped by testing condition k (i.e., generative probabilities of the sequences). ...
Pain typically evolves over time, and the brain needs to learn this temporal evolution to predict how pain is likely to change in the future and orient behavior. This process is termed temporal statistical learning (TSL). Recently, it has been shown that TSL for pain sequences can be achieved using optimal Bayesian inference, which is encoded in somatosensory processing regions. Here, we investigate whether the confidence of these probabilistic predictions modulates the EEG response to noxious stimuli, using a TSL task. Confidence measures the uncertainty about the probabilistic prediction, irrespective of its actual outcome. Bayesian models dictate that the confidence about probabilistic predictions should be integrated with incoming inputs and weight learning, such that it modulates the early components of the EEG responses to noxious stimuli, and this should be captured by a negative correlation: when confidence is higher, the early neural responses are smaller as the brain relies more on expectations/predictions and less on sensory inputs (and vice versa). We show that participants were able to predict the sequence transition probabilities using Bayesian inference, with some forgetting. Then, we find that the confidence of these probabilistic predictions was negatively associated with the amplitude of the N2 and P2 components of the vertex potential: the more confident were participants about their predictions, the smaller the vertex potential. These results confirm key predictions of a Bayesian learning model and clarify the functional significance of the early EEG responses to nociceptive stimuli, as being implicated in confidence-weighted statistical learning.
... We tested this hypothesis by focusing on the N2 and P2 ERP components during heat-evoked pain responses; The N2 and P2 components arise respectively 200-400 and 300-500 ms after the stimulation of Aδ fibers (Bromm & Treede, 1987) and originates from brain areas also involved in PA (Apkarian et al., 2005; see for reviews Benedetti, 2014;Wager & Atlas, 2015). These early components are sensitive to nociceptive stimulation (Wager et al., 2006) and are associated with the magnitude of pain perception Garcí-Larrea et al., 1997;Iannetti et al., 2005; for reviews see Colloca, 2014;Legrain et al., 2002). ...
... As specified in the ERP analyses section, the Period of Interest (POI) for each of the investigated ERP component was determined as the average of individual GFP peaks AE1SD for each group (Table 3). While the N2 and P2 components were expected to occur respectively 200-400 and 300-500 ms post-stimulus onset (Bromm & Treede, 1987), they actually manifested in the 408-to 500-and 541-to 634-ms intervals (Figures S10 and S11). ...
Placebo analgesia is defined as a psychobiological phenomenon triggered by the information surrounding an analgesic drug instead of its inherent pharmacological properties. Placebo analgesia is hypothesized to be formed through either verbal suggestions or conditioning. The present study aims at disentangling the neural correlates of expectations effects with or without conditioning through prior experience using the model of placebo analgesia (PA). This article is protected by copyright. All rights reserved. We addressed this question by recruiting two groups of individuals holding comparable verbally-induced expectations regarding morphine analgesia but either (i) with or (ii) without prior experience with opioids. We then contrasted the two groups' neurocognitive response to acute heat-pain induction following the injection of sham morphine using electroencephalography (EEG). Topographic ERP analyses of the N2 and P2 pain evoked potential components allowed to test the hypothesis that PA involves distinct neural networks when induced by expectations with or without prior experience. First, we confirmed that the two groups showed corresponding expectations of morphine analgesia (Hedges' gs < 0.4 positive control criteria, gs = 0.37 observed difference), and that our intervention induced a medium-sized PA (Hedges' gav >= 0.5 positive control, gav = 0.6 observed PA). We then tested our hypothesis on the recruitment of different PA-associated brain networks in individuals with vs without prior experience with opioids and found no evidence for a topographic N2 and P2 ERP components difference between the two groups. Our results thus suggest that in the presence of verbally-induced expectations, modifications in the PA-associated brain activity by conditioning is either absent or very small.
... We tested this hypothesis by focusing on the N2 and P2 ERP components during heat-evoked pain responses; The N2 and P2 components arise respectively 200-400 and 300-500 ms after the stimulation of Aδ fibers (Bromm & Treede, 1987) and originates from brain areas also involved in PA (Apkarian et al., 2005; see for reviews Benedetti, 2014;Wager & Atlas, 2015). These early components are sensitive to nociceptive stimulation (Wager et al., 2006) and are associated with the magnitude of pain perception Garcí-Larrea et al., 1997;Iannetti et al., 2005; for reviews see Colloca, 2014;Legrain et al., 2002). ...
... As specified in the ERP analyses section, the Period of Interest (POI) for each of the investigated ERP component was determined as the average of individual GFP peaks AE1SD for each group (Table 3). While the N2 and P2 components were expected to occur respectively 200-400 and 300-500 ms post-stimulus onset (Bromm & Treede, 1987), they actually manifested in the 408-to 500-and 541-to 634-ms intervals (Figures S10 and S11). ...
Placebo analgesia (PA) is defined as a psychobiological phenomenon triggered by the information surrounding an analgesic drug instead of its inherent pharmacological properties. PA is hypothesized to be formed through either verbal suggestions or conditioning. The present study aims at disentangling the neural correlates of expectations effects with or without conditioning through prior experience using the model of PA.
We addressed this question by recruiting two groups of individuals holding comparable verbally‐induced expectations regarding morphine analgesia but either (i) with or (ii) without prior experience with opioids. We then contrasted the two groups' neurocognitive response to acute heat‐pain induction following the injection of sham morphine using electroencephalography (EEG). Topographic ERP analyses of the N2 and P2 pain evoked potential components allowed to test the hypothesis that PA involves distinct neural networks when induced by expectations with or without prior experience.
First, we confirmed that the two groups showed corresponding expectations of morphine analgesia (Hedges' g s < .4 positive control criteria, g s = .37 observed difference), and that our intervention induced a medium‐sized PA (Hedges' g av ≥ .5 positive control, g av = .6 observed PA). We then tested our hypothesis on the recruitment of different PA‐associated brain networks in individuals with versus without prior experience with opioids and found no evidence for a topographic N2 and P2 ERP components difference between the two groups. Our results thus suggest that in the presence of verbally‐induced expectations, modifications in the PA‐associated brain activity by conditioning are either absent or very small.
... Prior to experimentation on hens, the thermal laser stimulus was tested on the medial aspect of the forearm of the researchers. This confirmed that in humans the sensations provoked by thermal stimulation using this type of laser were comparable to those described by Willer et al., (1979) and Bromm and Treede (1987). Initially, there was a short-lasting pain, which was comparable to a localised pinprick. ...
... This was followed by a burning wave, which was a less severe pain, less localised, longer lasting and instilled was a sense of tissue injury. The initial pain is probably due to Aδ plus C-fibre activation, and the later pain to C-fibre activation alone (Bromm and Treede, 1987;Bromm and Lorenz, 1998;Ringkamp et al., 2013). In the chicken trials during baseline recordings the birds responded within 1.5 s, which would have corresponded to the initial pricking pain experienced by humans. ...
The study assesses the effectiveness of reversible head-only and back-of-the-head electrical stunning of chickens using 130–950 mA per bird at 50 Hz AC.
Three trials were conducted to compare both stunning systems: (a) behavioural assessment of return of consciousness, (b) insensibility to thermal pain, and (c) assessment of return of brain activity with visually evoked potentials (VEPs).
Assessment of behaviour suggested that the period of unconsciousness following head-only electrical stunning was shorter in hens compared to broilers.
Stunning across the back-of-the-head delayed the time to return of brainstem function compared to stunning with standard head-only electrodes. Additionally, back-of-the-head stunning produced a more prolonged period of electroanalgesia compared to head-only.
Based on examination of return of brain function with VEPs in hens, back-of-the-head stunning produced a shorter-lasting stun than standard head-only. However, even for standard head-only, the stun was notably shorter than previously reported. In some birds, brain function had returned within 9 s after the end of stunning.
The results suggest that some birds may recover consciousness prior to or during the neck cut. Based on these findings, back-of-the-head stunning and standard head-only stunning of hens should not be recommended without further development.
... A slowly modifying thermal stimulus has been used only scarcely with clinical purposes [23,44,48]. However, we considered that it would reflect the processes of activation and inactivation of receptors for heat and cold in the skin under the thermode, albeit filtered through subjective perception and conduction time in the thermoalgesic fibers [5]. ...
... Baseline temperature of the thermode was set at 32°C and increased at a rate of 70°C/s, to reach a peak temperature of 53°C. Contact heat-evoked potentials (CHEPs) were recorded from Cz (vertex potentials) referenced to linked earlobes (A1-A2), which is where CHEPs have their maximal amplitude [5]. Impedance was kept below 5 kX. ...
... 31,39,49 As markers of cortical nociceptive processing, we recorded the laser-evoked brain potentials (LEPs), a response generated by a set of cortical areas activated by the ascending Ad-and C-fiber input. 6,7,15 If LBR was suppressed by concomitant touch, then supraspinal mechanisms alone are unlikely to be sufficient to drive touch-induced analgesia, which would therefore be mediated by a subcortical gating of the ascending nociceptive volley. ...
... Laser-generated radiant heat pulses selectively activate both Adand C-fiber free nerve endings in the epidermis. 6,7,15 However, because of the different conduction velocity of thinly myelinated Ad fibers and unmyelinated C fibers, laser pulses elicit a typical double sensation: an initial Ad-fiber-related pricking pain is followed by a C-fiber-related burning pain. 32 Laser-evoked potentials show clear components at latencies compatible with the conduction velocity of Ad fibers. ...
The neural mechanisms of the powerful analgesia induced by touching a painful body part are controversial. A long tradition of neurophysiological studies in anaesthetized, spinal animals indicate that touch can gate nociceptive input at spinal level. In contrast, recent studies in awake humans have suggested that supra-spinal mechanisms can be sufficient to drive touch-induced analgesia. To investigate this issue, we evaluated the modulation exerted by touch on established electrophysiological markers of nociceptive function at both subcortical and cortical levels in humans. Aδ and C skin nociceptors were selectively activated by high-power laser pulses. As markers of subcortical and cortical function, we recorded the Laser-Blink Reflex (LBR), which is generated by brainstem circuits prior to the arrival of nociceptive signals at the cortex, and Laser-Evoked Potentials (LEPs), which reflect neural activity of a wide array of cortical areas. If subcortical nociceptive responses are inhibited by concomitant touch, supraspinal mechanisms alone are unlikely to be sufficient to drive touch-induced analgesia. Touch induced a clear analgesic effect, suppressed the LBR, and inhibited both Aδ-fibre and C-fibre LEPs. Thus, we conclude that touch induced-analgesia is likely to be mediated by a subcortical gating of the ascending nociceptive input, which in turn results in a modulation of cortical responses. Hence, supra-spinal mechanisms alone are not sufficient to mediate touch-induced analgesia.
... Similar to previous studies, 22,34 we have mainly focused on vertex potentials in the above analyses, which are the most prominent deflections evoked by transient sensory stimuli. 35,36 However, focusing only on vertex potentials can be an important limitation in the present study. We thus conducted new control analyses to assess the possible relationship between other components (especially the early components) and sensory discriminability. ...
Neural indicators of pain discriminability have far-reaching theoretical and clinical implications but have been largely overlooked previously. Here, to directly identify the neural basis of pain discriminability, we apply signal detection theory to three EEG (Datasets 1–3, total N = 366) and two fMRI (Datasets 4–5, total N = 399) datasets where participants receive transient stimuli of four sensory modalities (pain, touch, audition, and vision) and two intensities (high and low) and report perceptual ratings. Datasets 1 and 4 are used for exploration and others for validation. We find that most pain-evoked EEG and fMRI brain responses robustly encode pain discriminability, which is well replicated in validation datasets. The neural indicators are also pain selective since they cannot track tactile, auditory, or visual discriminability, even though perceptual ratings and sensory discriminability are well matched between modalities. Overall, we provide compelling evidence that pain-evoked brain responses can serve as replicable and selective neural indicators of pain discriminability.
... Complementary to QST, nociception research has made extensive use of event-related potentials (ERPs) elicited by thermonociceptive laser stimulations, which have proven to be a validated, alternative method to probe the functional integrity of the nociceptive system (from peripheral nociceptors, spinothalamic transmission up to cortical projections) [67,68]. Although laser-ERPs are not entirely specific to nociception and might also reflect a certain degree of psychological artefacts [68], the combined use of both QST and somatosensory evoked-ERPs might help increase our understanding of the observed subjective responses [69]. ...
Background
Transcutaneous auricular Vagal Nerve Stimulation (taVNS) is a non-invasive neurostimulation technique with potential analgesic effects. Several studies based on subjective behavioral responses suggest that taVNS modulates nociception differently with either pro-nociceptive or anti-nociceptive effects.
Objective
This study aimed to characterize how taVNS alters pain perception, by investigating its effects on event-related potentials (ERPs) elicited by different types of spinothalamic and lemniscal somatosensory stimuli, combined with quantitative sensory testing (detection threshold and intensity ratings).
Methods
We performed 3 experiments designed to study the time-dependent effects of taVNS and compare with standard cervical VNS (cVNS). In Experiment 1, we assessed the effects of taVNS after 3 hours of stimulation. In Experiment 2, we focused on the immediate effects of the duty cycle (OFF vs. ON phases). Experiments 1 and 2 included 22 and 15 healthy participants respectively. Both experiments consisted of a 2-day cross-over protocol, in which subjects received taVNS and sham stimulation sequentially. In addition, subjects received a set of nociceptive (thermonociceptive CO 2 laser, mechanical pinprick) and non-nociceptive (vibrotactile, cool) stimuli, for which we recorded detection thresholds, intensity of perception and ERPs. Finally, in Experiment 3, we tested 13 epileptic patients with an implanted cVNS by comparing OFF vs. ON cycles, using a similar experimental procedure.
Results
Neither taVNS nor cVNS appeared to modulate the cerebral and behavioral aspects of somatosensory perception.
Conclusion
The potential effect of taVNS on nociception requires a cautious interpretation, as we found no objective change in behavioral and cerebral responses to spinothalamic and lemniscal somatosensory stimulations.
... IMI2-PainCare-BioPain-RCT3 will thus focus on biomarkers derived from non-invasive EEG measurements. Specifically, it will evaluate laser-evoked brain potentials (LEPs) which are brain responses related to the selective activation of heat-sensitive cutaneous nociceptors [1][2][3], pinprick-evoked brain potentials (PEPs) which are brain responses related to the preferential activation of mechano-sensitive nociceptors [4,5], and ongoing EEG whose oscillations have been shown to be sensitive to changes in brain network function, to relate to perceived pain intensity, to correlate with variations in vigilance and attentional states, and to be sensitive to the effects of several analgesic drugs acting at the level of the central nervous system [6][7][8]. ...
Background
IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity.
Methods
This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory.
Discussion
LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.
Trial registration
This trial was registered 25/06/2019 in EudraCT ( 2019%2D%2D001204-37 ).
... Thresholds may also vary (Churyukanov et al., 2012;Treede et al., 1995). As an example, intense short-lasting phasic heat stimuli such as those generated by a high power infrared laser pulse directed onto the skin have been shown to generate responses almost exclusively related to the activation of one specific type of heat-sensitive afferent, so-called A-fibre Type 2 nociceptors, with very little contribution of other types of heat-sensitive nociceptors such as Type 1 A-fibre nociceptors and C-fibre nociceptors (Bromm & Treede, 1987). Because the respective contribution of these different types of nociceptive afferents to clinical pain remains largely unknown, this raises questions about the translatability to patients of results obtained using transient experimental stimuli in healthy volunteers. ...
For decades, basic research on the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need. In this opinion paper bringing together pain researchers from very different disciplines, the opportunities and challenges of translational pain research are discussed. The many factors that may prevent the successful translation of bench observations into useful and effective clinical applications are reviewed, including interspecies differences, limited validity of currently available preclinical disease models of pain, and limitations of currently used methods to assess nociception and pain in non‐human and human models of pain. Many paths are explored to address these issues, including the backward translation of observations made in patients and human volunteers into new disease models that are more clinically relevant, improved generalization by taking into account age and sex differences, and the integration of psychobiology into translational pain research. Finally, it is argued that preclinical and clinical stages of developing new treatments for pain can be improved by better preclinical models of pathological pain conditions alongside revised methods to assess treatment‐induced effects on nociception in human and non‐human animals.
Significance:
For decades, basic research of the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need.
... In consideringtime as arelevant factor,the psychological and neural differences across pain experiencesb ecome even more salient.S mall differences in psychological properties can be recognizedb yc omparing pains thatl astm illiseconds,s econds,o rm inutes.M ost prominent is the difference between socalled first and secondp ain. The subject first experiencesapreciselyl ocalized sharp and stinging pain followed by al onger-lastingd ull and predominately burning pain that is more diffusei ni ts location ( Broom and Treede, 1987;Melzack, 1973). First pain is associatedwith an increasing activity in the primary somatosensory cortex whereas second pain is associated with an increasing activity in the anterior cingulate cortex (Ploner et al., 2002). ...
Although pain is one of the most fundamental and unique experiences we undergo in everyday life, it also constitutes one of the most enigmatic and frustrating subjects for many scientists. This book provides a detailed analysis of why this issue is grounded in the nature of pain itself. It also offers a philosophically driven solution of how we may still approach pain in a theoretically compelling and practically useful manner. Two main theses are defended: (i) Pain seems inscrutable because there exists no property that is commonly shared by all types of pain and that is at the same time particular to pain, setting it apart from other bodily sensations. This applies irrespective of whether we consider the psychological dimensions, neural networks, causal relations or biological functions of pain. Consequently, it is impossible to refer to ideal far-reaching and ideal distinct generalizations on the matter of pain. (ii) Despite this challenge, by focusing on the resemblance relations that hold across pains, we can generate scientific progress in explaining, predicting and treating pain. In doing so, the book aims to provide a clear conceptual basis for interdisciplinary communication and a useful heuristic for future research.
... The earliest response detected by LEPs is a small negative component (N1) wave, peaking at ~160 ms and maximal over the temporal region contralateral to the stimulated side [46]. The largest part of LEPs is a negative-positive biphasic wave (N2-P2), peaking at ~200-350 ms after stimulus onset and maximal at the scalp vertex [47]. Source analyses showed that these LEP components could be modeled by a combination of brain areas composing the "pain matrix" [48], which were further confirmed by consistent results obtained using subdural [49][50][51] and intracerebral recordings [52][53][54]. ...
Developing an objective biomarker for pain assessment is crucial for understanding neural coding mechanisms of pain in the human brain as well as for effective treatment of pain disorders. Neuroimaging techniques have been proven to be powerful tools in the ongoing quest for a pain signature in the human brain. Although there is still a long way to go before achieving a truly successful pain signature based on neuroimaging techniques, important progresses have been made through great efforts in the last two decades by the Pain Society. Here, we focus on neural responses to transient painful stimuli in healthy people, and review the relevant studies on the identification of a neuroimaging signature for pain.
... Several studies already aimed at preferentially activating specific types of thermosensitive afferents, mainly using electroencephalography (EEG) and the recording of event-related brain potentials (ERPs) [9]. For example, brief laser heat stimuli applied onto the skin generate laser-evoked brain potentials (LEPs) that are thought to mainly result from the activation of one class of polymodal nociceptors: so-called 'Type 2' (quickly-adapting) mechano-and heatsensitive Aδ fiber nociceptors (AMH-2) [10,11]. Although such stimuli are also expected to activate quickly-adapting C fiber thermonociceptors, co-activation of these unmyelinated afferents does not elicit any evident brain activity compatible with their slow conduction velocities [12,13]. ...
Thermosensation is crucial for humans to probe the environment and detect threats arising from noxious heat or cold. Over the last years, EEG frequency-tagging using long-lasting periodic radiant heat stimulation has been proposed as a means to study the cortical processes underlying tonic heat perception. This approach is based on the notion that periodic modulation of a sustained stimulus can elicit synchronized periodic activity in the neuronal populations responding to the stimulus, known as a steady-state response (SSR). In this paper, we extend this approach using a contact thermode to generate both heat- and cold-evoked SSRs. Furthermore, we characterize the temporal dynamics of the elicited responses, relate these dynamics to perception, and assess the effects of displacing the stimulated skin surface to gain insight on the heat- and cold-sensitive afferents conveying these responses. Two experiments were conducted in healthy volunteers. In both experiments, noxious heat and innocuous cool stimuli were applied during 75 seconds to the forearm using a Peltier-based contact thermode, with intensities varying sinusoidally at 0.2 Hz. Displacement of the thermal stimulation on the skin surface was achieved by independently controlling the Peltier elements of the thermal probe. Continuous intensity ratings to sustained heat and cold stimulation were obtained in the first experiment with 14 subjects, and the EEG was recorded in the second experiment on 15 subjects. Both contact heat and cool stimulation elicited periodic EEG responses and percepts. Compared to heat stimulation, the responses to cool stimulation had a lower magnitude and shorter latency. All responses tended to habituate along time, and this response attenuation was most pronounced for cool compared to warm stimulation, and for stimulation delivered using a fixed surface compared to a variable surface.
... Painful laser stimuli were generated by a Thulium-YAG laser (Themis, StarMedTec Starnberg, Germany) with a wavelength of 2.01 m, a beam diameter of 5 mm, and a pulse duration of 1 ms. It was shown in previous studies that such laser stimuli activate selectively A-delta and C fiber nociceptors in the most superficial skin layers and are therefore an adequate stimulus to elicit nociceptive responses (Bromm and Treede 1987;Iannetti et al. 2006;Mouraux et al. 2010;Plaghki and Mouraux 2003;Treede et al. 2003). The hand piece was equipped with a visible laser, to indicate the area where the infrared laser beam was transmitted. ...
Recent studies put forward the idea that stimulus-evoked gamma-band oscillations (GBOs; 30-100 Hz) play a specific role in nociception. So far, evidence for the specificity of GBOs for nociception, their possible involvement in nociceptive sensory discriminatory abilities and knowledge regarding their cortical sources is just starting to grow. To address these questions, we used electroencephalography (EEG) to record brain activity evoked by phasic nociceptive laser stimuli and tactile stimuli applied at different intensities to the right hand and foot of 12 healthy volunteers. The EEG was analyzed in the time domain to extract phase-locked event-related brain potentials (ERPs), and in three regions of interest in the time-frequency domain (delta/theta, 40 Hz gamma, 70 Hz gamma) to extract stimulus-evoked changes in the magnitude of non-phase locked brain oscillations. Both nociceptive and tactile stimuli, matched with respect to subjective intensity, elicited phase locked ERPs of increasing amplitude with increasing stimulus intensity. In contrast, only nociceptive stimuli elicited a significant enhancement of GBOs (65-85 Hz, 150-230 ms after stimulus onset), whose magnitude encoded stimulus intensity, whereas tactile stimuli led to a GBO decrease. Following nociceptive hand stimulation, the topographical distribution of GBOs was maximal at contralateral electrode C3, whereas maximum activity following foot stimulation was recorded at the midline electrode Cz, compatible with generation of GBOs in the representations of the hand and foot of the primary sensorimotor cortex, respectively. The differential behavior of high frequency GBOs and low frequency 40 Hz GBOs is indicating different functional roles and regions in sensory processing.
... Laser-induced heat has been used as noxious thermal stimulation to observe cor- tical activity (EEGs) 97,[101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119] ; and since lesions causing neuropathic pain mostly con- cern the pain-temperature pathways, it has been considered the easiest and most reliable neurophysiological method of assessing nociceptive function in health and disease 120,121 . ...
Noxious heat is a natural stimulus that activates peripheral sensory neurons expressing heat-gated ion channels. Recently, the TRPM3 channel emerged as a noxious heat sensor independent of TRPV1, which is also sensitive to the neurosteroid Pregnenolone sulphate (PS). Recently, evidence of a direct mechanism that controls the agonist-induced TRPM3 channel activity by activation of the µ-opioid receptor (MOR) has been described, through direct binding of the G-beta-gamma subunit to TRPM3. The submitted thesis investigated mechanisms of heat-induced nociception using near-infrared laser stimulation as a rapid and accurate way to apply noxious heat. Responses to laser-heat were analyzed: in vitro by functional assays on heterologous expression systems and primary culture of sensory neurons, and in vivo by behavioral experiments and electrophysiological recordings at the dorsal horn of the spinal cord. Laser-heat activates TRPV1 and TRPM3 channels in heterologous expression systems with activation thresholds of about 574 µJ and 615 µJ. The response amplitudes of TRPM3 upon activation with PS exceeded those of maximum laser stimulation (1.5 ± 0.003 of the ratio 340/380 versus 0.66 ± 0.011). Chemical- and thermal- induced activity of the TRPM3 channel co-expressing the MOR was reduced with DAMGO by 63.4% and 44.5%. In DRGs, 15-25% of all neurons analyzed (n= 550) functionally co-expressed TRPV1 and TRPM3, 38% expressed TRPV1 independent of TRPM3, 7-8% expressed TRPM3 but not TRPV1. DRG neurons displayed a direct inhibition by 18 ± 4.1% and 23 ± 3% when co-applying the MOR agonist DAMGO with PS. In the dorsal horn of the spinal cord, the processing of peripheral laser stimulation was carried out by a subset of WDR and HTM neurons, which were found at all depths of the dorsal horn (range: 120-820 µm). Laser-heat stimuli induced pain-behavior in vivo. All neurons that responded to suprathreshold laser-heat were nociceptive, including one third of WDR neurons and half of HTM neurons investigated. No laser-heat responses of LTM neurons were found. The peripheral input of the laser sensitive neurons was composed of C- and A- fibers; however, responses to laser-heat were transmitted by C-fibers. The sizes of the heat receptive fields ranged 10% - 60% of the mechanical receptive field and they located always inside them. The number of AP following laser stimulation was higher in HTM neurons compared to WDR neurons (14 ± 0.7 vs 9 ± 4.3), however not significant, and the latencies after onset of the laser stimulation were 266 ± 16 ms and 308.3 ± 55. The estimated temperature threshold for laser sensitive WDR neurons and HTM neurons (40.1 °C and 43.3 °C) was comparable to the mean heat withdrawal threshold in awake rats (41 °C). Differences in the proportions of neurons expressing TRPM3 and/or TRPV1 could be responsible for those differences in receptive field sizes. Since the threshold for laser-heat activation of the TRPM3 channel was higher than the threshold for TRPV1, a greater proportion of peripheral neurons containing TRPM3 might converge in dorsal horn laser sensitive HTM neurons than for laser sensitive WDR neurons.
... In adults, cortical SEP latencies are compatible with the conduction velocity of the peripheral fibers stimulated, which in turn depends on their diameter and myelination (Mauguiere, 2004). Selective electrical stimulation of large diameter myelinated Ab fibers (30-65 m/s (Vallbo et al., 1979)) evokes a faster response (20 msec when stimulating the medial nerve (Mauguiere, 2004)) compared to painful laser stimulation of small myelinated Ad fibers (4-30 m/s; response at 160 ms (Treede et al., 1988)) or unmyelinated C fibers (0.4-1.8 m/s; response at 1000 msec (Bromm and Treede, 1987)). The decrease in latency and sharpening (and consequently increase in amplitude) of the SEPs during development is therefore likely to mirror the increase in myelination and the decreased synaptic delay throughout the somatosensory nervous system (Gutrecht and Dyck, 1970;Cracco et al., 1979;Brody et al., 1987). ...
This review addresses the fundamental question of how we first experience pain, at the beginning of our lives. The brain is activated by peripheral tissue damaging stimulation from birth, but unlike other sensory systems, the pain system in healthy individuals cannot rely upon a prolonged activity dependent shaping through repeated noxious stimulation. Considering the importance of pain, remarkably little is known about when and how the nociceptive cortical network activity characteristic of the mature adult brain develops. We begin this review by considering the underlying framework of connections in the infant brain. Since this developing brain connectome is necessary, if not sufficient, for pain experience, we discuss the structural and functional development of cortical and subcortical networks that contribute to this network. We then review specific information on the development of nociceptive processing in the infant brain, considering evidence from neurophysiological and haemodynamic measures separately, as the two are not always consistent. Finally we highlight areas that require further research and discuss how information gained from laboratory animal models will greatly increase our understanding in this area.
... Special techniques have been proposed to improve the selectivity of electrical stimuli for pain pathways, such as selective blocks of large fibres [11][12] and intra-neural or intra-epidermal stimulation. [13][14] However, all of these techniques have significant technical limitations, are confined to restricted territories and whether they provide a reliable specific correlate of the nociceptive input is controversial. ...
... Die frühe Fragestellung der physiologischen Schmerzforschung, ob die Impulse von nozizeptiven C-Fasern die kortikalen Projektionsareale S1 und S2 erreichen, wurde mithilfe evozierter Potenziale in elektroenzephalographischen (EEG) Ableitungen untersucht. Durch kurze Hitzeimpulse von CO 2 -Lasern konnte man "late" (von Aδ-Fasern) und "ultra-late potentials" unterscheiden [117]. ...
Pain research is based broadly on physiological disciplines and its development follows the methodological progress of the era, from classical psychophysiology to electrophysiological investigations at peripheral and central nociceptive systems, single cells and ion channels to modern imaging of nociceptive processing. Physiological pain research in Germany has long been part of an interdisciplinary research network extending beyond all political boundaries, and this situation has continued since molecular techniques started to dominate all biomedical research. Current scientific questions, such as intracellular nociceptive signal mechanisms, interactions with other physiological systems including the immune system, or the genetic basis of epidemic and chronic pain diseases can only be solved interdisciplinary and with international collaboration.
... To study the neural correlates of pain perception neurophysiological investigations rely on experimental stimuli (e.g. laser, heat, electrical) to evoke synchronized cortical responses, which can be detected by event-related potentials (ERPs; Carmon et al., 1978;Bromm and Scharein, 1982;Bromm and Treede, 1987;Baumg€ artner et al., 2010;Brock et al., 2010). ...
Pain perception is typically assessed using subjective measures; an objective measure of the response to pain would be valuable. In this study, Brain Network Activation (BNA), a novel multivariate pattern analysis and scoring algorithm, was applied to event-related potentials (ERPs) elicited by cortical responses to brief heat stimuli. Objectives of this study were to evaluate the utility of BNA as a quantitative and qualitative measure of cortical response to pain.
Contact Heat Evoked Potentials (CHEPs) data were collected from 17 healthy, right-handed volunteers (10 M, 7F) using 5 different temperatures (35, 41, 46, 49 and 52 °C). A set of spatio-temporal activity patterns common to all the subjects in the group (Reference Brain Network Model; RBNM) was generated using the BNA algorithm, based on evoked responses at 52 °C.
Frame by frame 'unfolding' of the brain network across time showed qualitative differences between responses to painful and non-painful stimuli. Brain network activation scores were shown to be a better indicator of the individual's sensitivity to pain when compared to subjective pain ratings. Additionally, BNA scores correlated significantly with temperature, demonstrated good test-retest reliability, as well as a high degree of sensitivity, specificity and accuracy in correctly categorizing subjects who reported stimuli as painful.
These results may provide evidence that the multivariate analysis performed with BNA may be useful as a quantitative, temporally sensitive tool for assessment of pain perception.
© 2015 European Pain Federation - EFIC®
... This generally involves the use of an infrared light source focused on a skin site. A more recent modification employs a CO 2 laser as the heat source (Bromm and Treede, 1987). The laser-induced thermal stimulation produces a double pain sensation: an initial pinprick sensation attributable to Adelta fiber activity, and a second, diffuse burning sensation due to C-afferent activity. ...
... It has been reported that the compression over nerves could block A-delta fiber activity 27 . The study showed that elderly individuals exhibited a stable pain threshold throughout the study, but younger patients exhibited an increase in pain threshold during superficial nerve compression (A-Delta fiber block). ...
Data from clinical studies suggest that there is an overall decrease in pain sensitivity with advancing age. Evidence indicates that aging is associated with the degeneration of nociceptive pathways. Specifically, primary afferent fibers undergo degenerative changes including decreased trophic support and decreased expression of several ion channels. Significantly, aged primary afferents (in humans or experimental animals) show axonal involution, Wallerian degeneration and decreased neurotransmitter content, which are alterations that represent a defective pain transmission in elderly people. These observations suggest that clinicians must predict a greater level of underlying pathology when elderly persons make a report of pain and that the standard pain management needs to be modified to meet the special needs of elderly people. The elderly population is growing Because life expectancy continues to rise, a major shift in the age distribution of the world's population is expected. In 2003, nearly 36 million people age 65 and over (elderly) lived in the United States, accounting for just over 12 percent of the total population 1 . Worldwide, the elderly population is growing by an unprecedented 800,000 persons/month, according to a report issued by the U.S. Census Bureau and the National Institute on Aging 2 . Pain as an early warning system In the absence of disease, pain is a key mechanism utilized by the body to warn of impending tissue damage. Compromises or failures of this warning system can have catastrophic effects, as seen in patients with leprosy and diabetes. Children with congenital insensitivity to pain (recently shown to be a genetic disorder) experience accidents and injuries more frequently and die of infection at an early age. Patients with diabetic neuropathy provide another example of the value of pain. These patients often lose the sense of touch, pain and temperature in their lower extremities due to polyneuropathy and are subject to severe infections and wounding. Unrecognized burns, puncture wounds, and bone fractures are common in such individuals. Thus, normal pain perception plays a crucial role in the survival of an organism. Pain sensitivity in aging This early warning system appears to be altered in elderly persons since, as a group, they show an increased pain threshold (or decreased pain sensitivity) in the absence of any disease. Pain threshold is defined as the lowest stimulus value at which the person reports pain. The quantitative sensory testing to measure pain thresholds, therefore, offers an approach for evaluation of functional integrity of the entire neural pathway. The measurement of pain threshold and suprathreshold sensitivity in healthy volunteers of various ages has been performed in over 40 separate research studies to date (for review, see 3). These studies have employed controlled electrical, mechanical and noxious heat stimulation applied to different sites on the body, including the hand, forearm, forehead and sole of the foot. Although there were marked technical and methodologic differences between the various studies, and the mean age of the
The coherent perceptual experience of one's own body depends on the processing and integration of signals from multiple sensory modalities, including vision, touch, and proprioception. Although nociception provides critical information about damage to the tissues of one's body, little is known about how nociception contributes to own-body perception. A classic experimental approach to investigate the perceptual and neural mechanisms involved in the multisensory experience of one's own body is the rubber hand illusion (RHI). During the RHI, people experience a rubber hand as part of their own body (sense of body ownership) caused by synchronized stroking of the rubber hand in the participant's view and the hidden participant's real hand. We examined whether the RHI can be elicited by visual and “pure” nociceptive stimulation, ie, without tactile costimulation, and if so, whether it follows the basic perceptual rules of the illusion. In 6 separate experiments involving a total of 180 healthy participants, we used a Nd:YAP laser stimulator to specifically target C and Aδ fibers in the skin and compared the illusion condition (congruent visuonociceptive stimulation) to control conditions of incongruent visuonociceptive, incongruent visuoproprioceptive, and no nociceptive stimulation. The illusion was quantified through direct (questionnaire) and indirect (proprioceptive drift) behavioral measures. We found that a nociceptive rubber hand illusion (N-RHI) could be elicited and that depended on the spatiotemporal congruence of visuonociceptive signals, consistent with basic principles of multisensory integration. Our results suggest that nociceptive information shapes multisensory bodily awareness and contributes to the sense of body ownership.
The clinical evaluation of spinal afferents is an important diagnostic and prognostic marker for neurological and functional recovery after spinal cord injury (SCI). Particularly important regarding neuropathic pain following SCI is the function of the spinothalamic tract (STT) conveying nociceptive and temperature information. Here, we investigated the added value of neurophysiological methods revealing discomplete STT lesions, i.e., residual axonal sparing in clinically complete STT lesions. Specifically, clinical pinprick testing and thermal thresholds were compared to objective contact heat-evoked potentials (CHEPs) and a novel measure of pain-autonomic interaction employing heat-induced sympathetic skin responses (SSR). The test stimuli (i.e., contact heat, pinprick) were applied below the lesion level in 32 subjects with thoracic SCI while corresponding heat-evoked responses (i.e., CHEPs and SSR) were recorded above the lesion (i.e., scalp and hand, respectively). Readouts of STT function were related to neuropathic pain characteristics. In subjects with abolished pinprick sensation, measures of thermosensation (10%), CHEPs (33%) and SSR (48%) revealed residual STT function. Importantly, SSRs can be used as an objective readout and when abolished, no other proxy indicated residual STT function. No relation was found between STT function readouts and spontaneous neuropathic pain intensity and extent. However, subjects with clinically preserved STT function presented more often with allodynia (54%) than subjects with discomplete (13%) or complete STT lesions (18%). In individuals with absent pinprick sensation, discomplete STT lesions can be revealed employing pain-autonomic measures. The improved sensitivity to discern STT lesion completeness might support revealing the interference with neuropathic pain following SCI.
Objective
To explore the so-called “structure-function paradox” in individuals with focal spinal lesions by means of tract-specific MRI coupled with multi-modal evoked potentials and quantitative sensory testing.
Methods
Individuals with signs and symptoms attributable to cervical myelopathy (i.e., no evidence of competing neurological diagnosis) were recruited in the Balgrist University Hospital, Zurich, Switzerland between February 2018 and March 2019. We evaluated the relationship between the extent of structural damage within spinal nociceptive pathways (i.e., dorsal horn, spinothalamic tract, anterior commissure) assessed with atlas-based MRI , and 1) the functional integrity of spinal nociceptive pathways measured with contact heat-, cold-, and pinprick- evoked potentials and 2) clinical somatosensory phenotypes assessed with quantitative sensory testing.
Results
Sixteen individuals (mean age 61 years) with either degenerative (N=13) or post-traumatic (N=3) cervical myelopathy participated in the study. Most individuals presented with mild myelopathy (modified Japanese Orthopaedic Association score (mJOA)>15; N=13). 71% of individuals presented with structural damage within spinal nociceptive pathways on MRI. Yet, 50% of these individuals presented with complete functional sparing (i.e., normal contact heat-, cold-, and pinprick- evoked potentials). The extent of structural damage within spinal nociceptive pathways was neither associated with functional integrity of thermal (heat: p=0.57; cold: p=0.49) and mechano-nociceptive pathways (p=0.83) nor with the clinical somatosensory phenotype (heat: p=0.16; cold: p=0.37; mechanical: p=0.73). The amount of structural damage to the spinothalamic tract did not correlate with spinothalamic conduction velocity (p>0.05; rho=-0.11).
Conclusions
Our findings provide neurophysiological evidence to substantiate that structural damage in the spinal cord does not equate to functional somatosensory deficits. This study recognizes the pronounced structure-function paradox in cervical myelopathies and underlines the inevitable need for a multi-modal phenotyping approach to reveal the eloquence of lesions within somatosensory pathways.
Laser evoked potentials (LEPs) – the EEG response to temporally-discrete thermal stimuli – are commonly used in experimental pain studies in humans. Such stimuli selectively activate nociceptors and produce EEG features which correlate with pain intensity. The rodent LEP has been proposed to be a translational biomarker of nociception and pain, however its validity has been questioned because of reported differences in the classes of nociceptive fibres mediating the response. Here we use a machine learning, trial by trial analysis approach on wavelet-denoised LEPs generated by stimulation of the plantar hindpaw of rats. The LEP amplitude was more strongly related to behavioural response than to laser stimulus energy. A simple decision tree classifier using LEP features was able to predict behavioural responses with 73% accuracy. An examination of the features used by the classifier showed that mutually exclusive short and long latency LEP peaks were clearly seen in single-trial data, yet were not evident in grand average data pooled from multiple trials. This bimodal distribution of LEP latencies was mirrored in the paw withdrawal latencies which were preceded and predicted by the LEP responses. The proportion of short latency events was increased after intradermal application of high dose capsaicin (to defunctionalise TRPV1 expressing nociceptors), suggesting they were mediated by Aδ-fibres (specifically AMH-I). These findings demonstrate that both C- and Aδ-fibres contribute to rodent LEPs and concomitant behavioural responses, providing a real-time assay of specific fibre function in conscious animals. Single-trial analysis approaches can improve the utility of LEPs as a translatable biomarker of pain.
Objectives
In clinical neurophysiology practice, various methods of stimulation can be used to activate small-diameter nociceptive cutaneous afferents located in the epidermis. These methods include different types of laser and intraepidermal electrical stimulation techniques. The diffusion of the stimulation in the skin, inside or under the epidermis, depends on laser wavelength and electrode design, in particular. The aim of this study was to compare several of these techniques in their ability to selectively stimulate small nerve fibers.
Methods
In 8 healthy subjects, laser stimulation (using a CO2 or Nd:YAP laser) and intraepidermal electrical stimulation (using a micropatterned, concentric planar, or concentric needle electrode), were applied at increasing energy or intensity on the dorsal or volar aspect of the right hand or foot. The subjects were asked to define the perceived sensation (warm, pinprick, or electric shock sensation, corresponding to the activation of C fibers, Aδ fibers, or Aβ fibers, respectively) after each stimulation. Depending on the difference in the sensations perceived between dorsal (hairy skin with thin stratum corneum) and volar (glabrous skin with thick stratum corneum) stimulations, the diffusion of the stimulation inside or under the epidermis and the nature of the activated afferents were determined.
Results
Regarding laser stimulation, the perceived sensations turned from warm to pinprick with increasing energies of stimulation, in particular with the Nd:YAP laser, of which pulse could penetrate deep in the skin according to its short wavelength. In contrast, CO2 laser stimulation produced only warm sensations and no pricking sensation when applied to the glabrous skin, perhaps due to a thicker stratum corneum and the shallow penetration of the CO2 laser pulse. Regarding intraepidermal electrical stimulation using concentric electrodes, the perceived sensations turned from pinprick to a combination of pinprick and electrical shocks with increasing intensities. Using the concentric planar electrode, the sensations perceived at high stimulation intensity even consisted of electric shocks without concomitant pinprick. In contrast, using the micropatterned electrode, only pinprick sensations were produced by the stimulation of the hairy skin, while the stimulation of the glabrous skin produced no sensation at all within the limits of stimulation intensities used in this study.
Conclusions
Using the CO2 laser or the micropatterned electrode, pinprick sensations were selectively produced by the stimulation of hairy skin, while only warm sensation or no sensation at all were produced by the stimulation of glabrous skin. These two techniques appear to be more selective with a limited diffusion of the stimulation into the skin, restricting the activation of sensory afferents to the most superficial and smallest intraepidermal nerve fibers.
Background
In clinical practice, small myelinated sensory fibers, Aδ-fibers, conveying mainly pain and temperature sensations, cannot be examined with available nerve conduction study techniques. Currently, these fibers can only be examined with experimental or very specialized and not commonly available nerve conduction techniques, or only indirectly with cerebral evoked potentials.
New Method
This study uses equipment and methods available in clinical neurophysiology laboratories to record from human sensory nerves ≥1000 averaged responses to focal, non-painful stimuli applied by a special electrode to epidermal nerves. The averaged responses to odd numbered stimuli are compared to the averaged responses to even numbered stimuli. An algorithm identifies potentials common in both averages. The 99th and 99.9th percentiles for this algorithm are obtained from control records without stimulation and applied to records with stimulation to identify potentials resulting from stimulation of intraepidermal nerves.
Results
The algorithm identifies numerous negative and positive potentials as being different from controls at the 99th and 99.9th percentile levels. The conduction velocities of the potentials range from of 1.3 to 29.9 m/s and are compatible with conduction velocities of Aδ-fibers.
Comparison with existing Method(s)
No existing methods.
Conclusions
The stimulation, recording and data analysis methods used in this study can be applied in the clinical EMG laboratory to identify Aδ-fibers in human sensory nerves.
Clinical neurophysiologic investigation of pain pathways in humans is based on specific techniques and approaches, since conventional methods of nerve conduction studies and somatosensory evoked potentials do not explore these pathways. The proposed techniques use various types of painful stimuli (thermal, laser, mechanical, or electrical) and various types of assessments (measurement of sensory thresholds, study of nerve fiber excitability, or recording of electromyographic reflexes or cortical potentials). The two main tests used in clinical practice are quantitative sensory testing and pain-related evoked potentials (PREPs). In particular, PREPs offer the possibility of an objective assessment of nociceptive pathways. Three types of PREPs can be distinguished depending on the type of stimulation used to evoke pain: laser-evoked potentials, contact heat evoked potentials, and intraepidermal electrical stimulation evoked potentials (IEEPs). These three techniques investigate both small-diameter peripheral nociceptive afferents (mainly Aδ nerve fibers) and spinothalamic tracts without theoretically being able to differentiate the level of lesion in the case of abnormal results. In routine clinical practice, PREP recording is a reliable method of investigation for objectifying the existence of a peripheral or central lesion or loss of function concerning the nociceptive pathways, but not the existence of pain. Other methods, such as nerve fiber excitability studies using microneurography, more directly reflect the activities of nociceptive axons in response to provoked pain, but without detecting or quantifying the presence of spontaneous pain. These methods are more often used in research or experimental study design. Thus, it should be kept in mind that most of the results of neurophysiologic investigation performed in clinical practice assess small fiber or spinothalamic tract lesions rather than the neuronal mechanisms directly at the origin of pain and they do not provide objective quantification of pain.
Nonnoxious warmth reduces both perceived pain intensity and the amplitude of EEG markers of pain. However, the spatial properties of thermonociceptive interaction, and the level of sensory processing at which it occurs, remain unclear. We investigated whether interchannel warmth-pain interactions occur before or after intrachannel spatial summation of warmth. Warm stimuli were applied to the fingers of the right hand. Their number and location were manipulated in different conditions. A concomitant noxious test pulse was delivered to the middle finger using a CO 2 laser. We replicated the classical suppressive effect of warmth on both perceived pain intensity and EEG markers. Importantly, inhibition of pain was not affected by the location and the number of thermal stimuli, even though they increased the perceived intensity of warmth. Our results therefore suggest that the inhibitory effect of warmth on pain is not somatotopically organized. The results also rule out the possibility that warmth affects nociceptive processing after intrachannel warmth summation.
NEW & NOTEWORTHY We used spatial summation of warmth as a model to investigate thermonociceptive interactions. Painful CO 2 laser pulses were delivered during different thermal conditions. We found that warmth inhibited pain regardless of its location. Crucially, spatial summation of multiple warm stimuli did not further inhibit pain. These findings suggest that warmth-pain interaction occurs independently of or after spatial summation of warmth.
A fundamental function of nociception is to trigger defensive motor responses to threatening events. Here, we explored the effects of phasic pain on the motor excitability of ipsilateral and contralateral arms. We reasoned that the occurrence of a short-lasting nociceptive stimulus should result in a specific modulation of motor excitability for muscles involved in the withdrawal of the stimulated limb. This was assessed using transcranial magnetic stimulation (TMS) of the left and right primary motor cortex to elicit motor-evoked potentials (MEPs) in three flexor and two extensor muscles of both arms. To assess the time-course of nociception-motor interactions, TMS pulses were triggered 50-2000 ms after delivering short-lasting nociceptive laser stimuli to the left or right hand. We made three main observations. First, nociceptive stimuli induced an early-latency (100 ms) enhancement of MEPs in flexor muscles of the stimulated hand. Considering its latency, this modulation is likely consequent to nociceptive-motor interactions at spinal level. This early and lateralized enhancement was followed by a later (150-400 ms) MEP reduction in extensor muscles of the stimulated hand and flexor muscles of both hands, predominant at the stimulated hand. Finally, we observed a long-lasting (600-2000 ms) MEP enhancement in muscles of the non-stimulated hand. These later effects of the nociceptive stimulus could reflect nociception-motor interactions occurring at cortical level.
Advances in electrophysiology occurring in the middle of the twentieth century provided a nonintrusive means of studying the bioelectrical activity associated with behavior in humans and the first method for assessing the activity of the brain. Early psychophysiological research was typically crude and plagued with methodological problems related to various technical limitations (e.g., Angell and Thompson [1]). Nevertheless, a foundation was established for the investigation of the physiological manifestations of cognition. Although methodological complexities continue to present an interpretive problem in experiments, there is now abundant evidence that both central and peripheral bioelectrical activity reflect behavioral and cognitive processes. The observation of this physiological activity led to the concept of arousal, which became an important part of many theories of attention.
Background and objectivesSearch strategyDefinitionsClinical examination and psychophysiological measuresLaboratory tests
In this chapter, we summarize the neurocognitive processes underlying acute pain and the impact of emotions on these processes. First, we briefly introduce the neural substrates of nociception and pain, as well as emotions, and potential shared networks. Then, we focus on the emotional modulation of experimentally induced acute pain by affective visual stimuli, both affective scenes and emotional faces. Thus we review literature investigating the influence of emotions on subjective, peripheral, and cerebral correlates of pain perception. A special section thereby deals with the effect of facial expressions of pain perception and on the mutual influences. Overall, a viewpoint emerges that emotions can exert their effects at multiple levels of pain processing (supraspinal and spinal). However, it also becomes clear that pain reversely influences emotion perception, although future research needs to probe the effects of pain at various levels of emotion processing by using different psychophysiological methods. Furthermore, the emotion–pain interactions and their neural substrates, which potentially are characterized by multiple feedback mechanisms, still need to be clarified more precisely.
Acute pain arises from activation of myelinated (A delta) and unmyelinated (C) nociceptive afferents, leading to first (A-fiber) or second (C-fiber) pain sensations. The current study sought to investigate first and second pain within glabrous and hairy skin sites in human upper limbs. Fifty healthy adults (25 male/25 female, 18-30 years old, mean = 20.5 ± 1.4 years) participated in a psychophysical study investigating electronically rated, thermal first and second pain sensations within the glabrous skin at the palm and hairy skin of the forearm. Repeated measures analysis of variance indicated that the threshold for first pain was lower (more sensitive) than for second pain (P = .004), for glabrous as well as hairy skin, and thresholds at glabrous skin were higher than for hairy skin (P = .001). Hairy skin presented a steeper slope for testing, whereas there were no differences in slope between first and second pain. The study findings support assumptions associated with mechanistic differences between first and second pain sensations, while offering a novel method for producing first and second pain with the same thermal stimulus. Efforts to understand abnormalities among people with clinical pain and development of new therapeutic agents will benefit from specific psychophysical methods.
Perspective:
This article presents a novel method for directly comparing first and second pain within the same thermal stimulus. The ability to directly compare first and second pain sensations can aid in understanding pain abnormalities in clinical pain and development of therapeutic aids.
This chapter reviews the literature on cerebral evoked potentials following cutaneous thermal stimulation in humans. To date, two thermal stimulation techniques have been employed: water circulated thermodes and laser beams.
Modern history of clinical somatosensory evoked potentials (SEPs) testing began fifty years ago with George Dawson's recordings, in patients with myoclonus, of what is known today as a “giant” somatosensory cortical response. Thus, the first clinical application of SEP was to elucidate the mechanism of a movement disorder. Cortical SEPs were the first studied in normal subjects and patients, while spinal and sub-cortical far-field potentials were identified in the seventies and early eighties. Recent advances in the knowledge of cortical responses to somatosensory stimulation are issued from development of multichannel recordings of SEPs and somatosensory evoked magnetic fields (SEFs) coupled with source localization in the 3D images of brain volume, as provided by magnetic resonance imaging (MRI). Studies based on electro-clinical correlations in patients with focal lesions have identified a single generator for each SEP component, a view compatible with the concept that the processing of somatosensory inputs by the nervous system is based on a sequential activation of fibers and synaptic relays. Source localization studies rather suggest that the evoked field recorded on the scalp surface at a given moment often results from activities of multiple distributed sources overlapping in time. This model fits better with the parallel activation and feedback loops characterizing the process of sensory inputs at the cortical level. This chapter discusses the early SEP components that can be helpful for analyzing the somatosensory control of movement in normal subjects.
We propose a blade as a non-injurious nociceptive stimulus modelling sharp mechanical pain and yielding acute pain and hyperalgesia responses with closer proximity to incision-induced pain/hyperalgesia than punctate or blunt pressure mechanical pain models.Twenty-six healthy men and women each were investigated to compare a small incision in the left forearm with non-invasive stimuli of different shape and modality to the right forearm. Magnitude and time course of incisional and blade-induced pain were assessed by numerical rating scales. Affective vs. sensory components of pain experience were differentiated using a pain sensation questionnaire (SES). Magnitude and time course of the axon reflex vasodilator response and of secondary hyperalgesia following a 7 sec blade application were assessed.The maximum blade or incisional pain was similar (VAS: blade 32.9 ± 22.5 vs. incision 33.6 ± 29.8, mean ± SD), and both time courses matched closely in the first ten seconds (paired t-test; p = 0.5 to 1.0), while incision but not blade was followed by a second phase of pain, probably related to the tissue injury (decrease to half-maximum pain 8 ± 2 vs. 33 ± 35 seconds; p<0.01). Affective pain scores were significantly lower than sensory scores for all stimuli (p<0.001). Comparing blade and incision, patterns of affective and sensory pain descriptors exhibited a remarkably similar pattern. Hence, we suggest the blade as novel model of sharp mechanical pain which will be useful in investigating post-operative/mechanical pain and the role of self-injurious behavior in, e.g., patients with borderline personality disorder (BPD).
It has been 15 years since the original publication of Neuropsychology of Attention. At the time of its publication, attention was a construct that had long been of theoretical interest in the field of psychology and was receiving increased research by cognitive scientists. Yet, attention was typically viewed as a nuisance variable; a factor that needed to be accounted for when assessing brain function, but of limited importance in its own right. There is a need for a new edition of this book within Neuropsychology to present an updated and integrated review of what is know about attention, the disorders that affect it, and approaches to its clinical assessment and treatment. Such a book will provide perspectives for experimental neuropsychological study of attention and also provide clinicians with insights on how to approach this neuropsychological domain. © Springer Science+Business Media New York 2014. All rights reserved.
Sleep deprivation induces hyperalgesia. However, this pronociceptive effect is not reflected at the electrophysiological level, since sleep restricted subjects show amplitude reduction of Laser-evoked Potentials (LEP). We aimed to explore the contribution of habituation to this paradoxical LEP amplitude decline.
We compared LEP's of 12 healthy students (23.2 ± 1.1 years) after habitual sleep (HS) and a night of total sleep deprivation (TSD). Twelve repetitive laser stimulus blocks (each comprising twenty stimuli) were applied under three attention conditions ('focusing' - 'neutral' - 'distraction' condition). Stimulus blocks were split in part 1 (stimulus 1-10) and part 2 (stimulus 11-20). The contribution of habituation to the TSD-induced LEP amplitude decline was studied by calculating the percentage amplitude reduction of part 2 as compared to part 1. Individual sleepiness levels were correlated with (1) averaged LEP's and (2) the degree of habituation.
TSD induced hyperalgesia to laser stimuli (p < 0.001). In contrast, depending on the attention condition, the P2 amplitude of the N2P2-complex was significantly reduced ('focusing': p = 0.004; 'neutral': p = 0.017; distraction: p = 0.71). Habituation of the P2 amplitude to radiant heat was increased after TSD ('focusing': p = 0.04; 'neutral': p < 0.001; distraction: p = 0.88). TSD had no significant effect on N1 amplitudes (p > 0.05). Individual sleepiness correlated negatively with averaged P2 amplitudes (p = 0.02), but not with the degree of habituation (p = 0.14).
TSD induces hyperalgesia and results in attention-dependent enhanced habituation of the P2 component. Increased habituation may - to a substantial degree - explain the TSD-induced LEP-amplitude decline.
© 2015 European Pain Federation - EFIC®
Die evozierten Potentiale nach schmerzhaften Reizen sind eine Sonderform somatosensorisch evozierter Potentiale (SEP). Gegenüber den Standard-SEP zeichnen sie sich durch andere periphere und zentrale Leitungsbahnen aus (zur Übersicht s. Willis 1985): Schmerzhafte Reize aktivieren A3- und C-Fasern in peripheren Nerven. Diese primären Afferenzen werden bereits im Hinterhorn des Rückenmarks auf sekundäre Neurone umgeschaltet, deren Axone im kontralateralen Tractus spinothalamicus nach rostral projizieren. Diese Bahn verläuft weit lateral bis in den unteren Hirnstamm hinein und trifft erst kurz unterhalb des Thalamus auf den Lemniscus medialis. Deshalb können durch schmerzhafte Reize evozierte Potentiale in der neurologischen Topodiagnostik eine wichtige Ergänzung zu den SEP liefern.
Intense radiant heat pulses concomitantly activate Aδ- and C-fiber skin nociceptors, and elicit a typical double sensation: an initial Aδ-related pricking pain is followed by a C-related prolonged burning sensation. It has been repeatedly reported that C-fiber laser-evoked potentials (C-LEPs) become detectable only when the concomitant activation of Aδ-fibers is avoided or reduced. Given that the saliency of the eliciting stimulus is a major determinant of LEPs, one explanation for these observations is that the saliency of the C-input is smaller than that of the preceding Aδ-input. However, even if the saliency of the C-input is reduced because of the preceding Aδ-input, a C-LEP should still be visible even when preceded by an Aδ-LEP response. Here we tested this hypothesis by applying advanced signal processing techniques (peak alignment and time-frequency decomposition) to electroencephalographic data collected in two experiments conducted in 34 and 96 healthy participants. We show that, when using optimal stimulus parameters (delivering >80 stimuli within a small skin territory), C-LEPs can be reliably detected in most participants. Importantly, C-LEPs are observed even when preceded by Aδ-LEPs, both in average waveforms and single trials. By providing quantitative information about several response properties of C-LEPs (latency jitter, stimulus-response and perception-response functions, dependency on stimulus repetitions and stimulated area), these results define optimal parameters to record C-LEPs simply and reliably. These findings have important clinical implications for assessing small-fiber function in neuropathies and neuropathic pain.
Compared volleys induced by artifical stimuli can be recorded from peripheral nerves of human subjects with extraneural electrodes. In contrast, the study of the normal traffic of impulses requires other methods. A powerful technique for recording this type of activity with percutaneously inserted intraneural electrodes was introduced in 1966. The development of the technique was promoted by interest in studying somatosensory and proprioceptive mechanisms in organisms with an intact sensorium and intact volition, particularly human subjects. This method opened up the possibility of investigating a number of neural mechanisms and is has been used mainly for studies of proprioceptive mechanism, tactile and nociceptive cutaneous activity, and efferent sympathetic discharges. In addition, cutaneous thermosensitive activity and oral mechanosensitive activity have been analyzed. Single-unit activity has been recorded from large myelinated nerve fibers and from unmyelinated nerve fibers, whereas rather few recordings from small myelinate fibers have been reported. In addition, multiunit activity from myelinated and unmyelinated fibers has been studied. Pathological mechanisms as well as normal conditions have been analyzed. Our aim here is to review findings extracted by recording impulses in human nerves with emphasis on the implications these findings may have on current theories within a number of fields. As far as it is feasible, the findings from human subjects are related to knowledge based on studies in other species. This review is based on reports published or known to be in the process of publication when the article was being written.
A surface-negative transepidermal steady potential of approximately 30 mV exists in all areas of cephalic skin. Positive deflections of up to 2.5 mV may be superimposed upon this resting potential following sensory stimulation and probably reflect sweat gland activity. These phasic potential shifts may contaminate the scalp-recorded electroencephalogram markedly. Electrodermal potentials may be eliminated by puncturing the skin at the electrode site.RésuméUn potentiel stable surface négative trans-épidermique d'approximativement 30 mV existe sur toutes les régions du cuir chevelu. Des déflexions positives supérieures à 2.5 mV peuvent se superposer à ce potentiel de repos après stimulation sensorielle et reflètent probablement l'activité des glandes sudoripares. Ces déflexions phasiques de potentiel peuvent contaminer de façon importante l'électroencéphalogramme enregistré sur le scalp. Les potentiels électrodermaux peuvent être éliminés en ponctionnant la peau au siège de l'électrode.
This chapter discusses the component structure of the human event-related potentials (ERPs). Several years ago the world of human event-related potentials (ERPs) was a simple and comfortable place. There were evoked potentials related to sensation (N1), perception (P3), expectancy (CNV), and intention (BP). A variety of rather innocent theories held these components loosely together. Recently, however, there has been a proliferation of new components. The “exogenous” or stimulus-dependent components of the event-related potential can now be recorded from all levels of the afferent pathways. The “endogenous” components — those that can occur independently of external stimuli — have particularly multiplied. The late vertex potential following sensory stimuli consists of a series of waves — most prominently the N1-P2 components—that occur 50 and 250msec after a stimulus. This complex of waves is at first considered to be a non-specific response of frontal association cortex to incoming sensory information. Recent evidence has suggested that this response may consist of multiple subcomponent processes.
The dorsal horn is a nexus of many inputs and outputs. Afferents arrive both from the periphery and from many parts of spinal cord, brain stem and cortex. Efferents pass to the ventral horn, other spinal segments, brain stem, thalamus and cerebellum. In writing on the physiology of such a structure or in assessing an experimental paper or especially in designing an experiment, it is necessary to keep in mind that the scientists’ intellectual activities will be based on some conceptual model of the structure. One model sees the dorsal horn as a road intersection with rotary and flyover systems entered by independent units of traffic which pass through and proceed to their proper destinations except in pathological circumstances of collision, breakdown or collapse. A second analogy is that of the railway marshalling yard where units arrive and leave with theii origin and destination labelled but a central control may accelerate or slow them and may dispatch them in mixed trains. My own bias is towards a model which would add to the first two the possibilities of not only controlled collections and dispatch but also of local abstraction, integration, selection and decision. We shall review the available facts on dorsal horn physiology but before doing so it is essential to list the conceptual and technical factors which limit our knowledge.
A polarizing current applied transiently to a nerve selectively blocks conduction in the A-fibers, whereas the C-fibers remain unaffected. The block is reversible. Stimulation of A-fibers by the polarizing current is prevented by appropriately adjusting its slope of rise.Ein kurzdauernder polarisierender Strom blockiert die Impulsfortleitung in den A-Fasern eines Nerven, bleibt dagegen ohne Wirkung auf die C-Fasern. Der Block der A-Fasern ist reversibel. Bei hinreichend niedriger Anstiegsgeschwindigkeit werden durch den Blockstrom selbst keine A-Fasern gereizt.
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.
In normal subjects, cerebral potentials were evoked by brief, passive extension of the wrist joint at various interstimulus intervals (ISIs). The resulting somatosensory evoked potentials (SEPs) were found to decrease during repetitive stimulation. The greatest decrement occured between the first and second responses of each series. After cessation of stimuli, the SEP amplitude returned to control values over a prolonged, exponential time course. The authors postulate that the observed response decrement may be a form of habituation, which provides a model for studying the neuronal substrates of behavior.RésuméChez des sujets normaux, des potentiels cérébraux ont été évoqués par de brèves extensions passives du poignet, l'intervalle entre chaque stimulation étant variable. Les potentiels évoqués somatosensoriels obtenus ont présenté une diminution au cours de la stimulation répétitive. La diminution la plus importante apparaissait entre la première et la deuxième réponse de chaque série. Après arrêt des stimulations, l'amplitude du potentiel évoqué somatosensoriel revenait à sa valeur contrôle avec un long décours temporel exponentiel. Les auteurs suggèrent que la diminution observée de la réponse pourrait être une forme d'habituation, ce qui procure un modèle pour l'étude des substrats neuronaux du comportement.
The inter-relationship between stimulus intensity and inter-stimulus interval (ISI) on pain-related evoked vertex potentials was studied. Sixteen subjects were tested with 4 stimulus intensities at 4 different ISIs forming 16 averaged event-related potentials for each subject. Data were analyzed in 2 ways: first by multiple regression analysis of peak-to-peak amplitudes and secondly by single-trial analysis for each subject based on a linear model employing principal component loadings as basis functions, from which were derived separate time-dependent functions describing the contributions of intensity and ISI. Peak-to-peak amplitudes of the averaged waves increased with increases in either intensity or ISI. There are no significant interactions. However, single-trial analysis revealed subtle, but consistent, differences in the peak latencies between stimulus and ISI components, suggesting that the components arise from distinct sources.
Peak latency variation and the temporal interrelationships of the auditory event-related potential were investigated in 12 normal adults (ages 28-42). Measures of variation were based on both conventional averages and single trials. Estimates of N1, P2, N2 and P3 latencies were made on a trial-by-trial basis to target stimuli recorded from Fz, Cz and Pz scalp locations. Results showed that single-trial latency variability of the auditory ERP differed both among the various components and between subjects. Larger standard deviations were measured for the later N2 and P3 components than the earlier N1 and P2 components. Regression analyses between various component latencies indicated a strong covarying relationship between N2 and P3, with N2 accounting for up to 61% of the variance of P3 latency at Pz. Earlier N1 and P2 components added little to the overall prediction of either P3 or N2. For the other components, P2 accounted for 9-16% of the variance of N2, while N1 accounted for approximately 1% of the variance of N2; N1 accounted for 8-10% of the latency variation of P2. The correlations between single-trial peak latencies and RTs were positive but of low magnitude. The highest correlations between peak latency and RT were found for N2 (r = 0.33) and P3 (r = 0.24). The low correlations between the single-trial latencies of N1 and P3 suggest that the processes reflected by these components are independent and support a distinction between the earlier and the later components of the ERP. The close temporal coupling between N2 and P3 suggests that N2 may reflect cognitive properties in common to P3 in stimulus evaluation processes.
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 effect of interaction between large and small diameter fiber systems on the somatosensory evoked potential (SEP) was studied in anesthetized cats. Activation of large diameter fibers of the peroneal or radial nerves eliminates the late components of the SEP produced by stimulation of all fibers in the contralateral median or radial nerves. The inhibitory effects of a selective conditioning stimulus to the large diameter fibers of the peroneal nerve on the radial nerve evoked SEP was eliminated by bilateral transection of the dorsal column and spino-cervical tracts. However, interaction could still be obtained following transection when both large and small diameter fibers in the peroneal nerve were stimulated. The results of this study support the hypothesis that a correlation exists between activity in different fiber groups in afferent nerves, their conduction pathways through the cord, and the components of the cortical evoked potential.
1. Impulses in cutaneous nerve fibres were recorded percutaneously with tungsten micro-electrodes from the superficial radial nerve of adult human subjects. 2. Eight units studied had conduction velocities below 1.5 m/sec, and thus belong to the class of C fibres. On the basis of their responsiveness to mechanical and to thermal stimuli the units were classified as 'polymodal nociceptors'. 3. Units were tested with 12 sec heat pulses starting from a base line temperature of 43.0-43.5 degrees C. Heat stimuli reaching three different maximal levels were applied in randomized order, the subjects being blind with respect to stimulus size. Each of the eight units studied was tested with more tha 20 stimuli and with four of them were 80-125 stimulus repetitions. 4. After each stimulus the subjects had to rate his sensations on a six-point rating scale extending from 'just noticeable' to 'very hot, painful'. 5. Discrimination between the three stimulus levels by the integtated spike discharges and by the ratings of the subject was compared using the P(A) measure of the Signal Detection Theory. It was found that both the neurophysiological and the psychophysical measurements provided about equal discrimination. 6. In addition it has been found that spike discharges and ratings share a common variance beyond their common dependence on the stimulus level. Among the factors contributing to this interdependence a 'temporal position effect' was the most significant. 7. In spite of this interdependence between discharge rates and subjective ratings, the latter gave a better estimation of the stimulus size than of the discharge rates of the individual C fibre under study. 8. It was concluded that the polymodal C-nociceptors might be instrumental for the quantitative aspects of heat pain sensation. The hypothesis was derived from the present results that, under the conditions of cour experiments, the loss of information in the course of central processing might be about equal to the gain by the parallel processing in a population of nociceptors excited by a stimulus.
The relationships between different parameters of the evoked cerebral response to noxious thermal stimulation, stimulus intensity, and subjective pain were investigated in seven normal human volunteers. The evoked response was characterized by late events: a small negative peak at 164--180 ms, followed by a high amplitude positive peak at 372--391 ms. The only correlation found in this study was between the amplitude of the positive component and the qualitative and quantitative aspects of the verbal report of pain. This was manifested by a linear trend of association: an increase in the evoked response amplitude was accompanied by an increase in the magnitude of the subjective sensation. The findings suggest that the evoked response to noxious heat reflects not a mere transduction of the physical parameters of the stimulus, but rather a complex interpretative action at the cerebral level.
Psychophysical experiments were carried out on 6 huma subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4-8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51-5% C). The magnitude of first and second pain sensations was estimated using cross-modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in Adelta and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of Adelta heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of singlt Adelta heat nociceptive afferents, C polymodal nociceptive afferents, and "warm" afferents of rhsus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers (greater than 1/3 sec). These spinal cord summation mechanisms could account for the summation of second pain.
Peak latency variation and the temporal interrelationships of the auditory event-related potential were investigated in 12 normal adults (ages 28-42). Measures of variation were based on both conventional averages and single trials. Estimates of N1, P2, N2 and P3 latencies were made on a trial-by-trial basis to target stimuli recorded from Fz, Cz and Pz scalp locations. Results showed that single-trial latency variability of the auditory ERP differed both among the various components and between subjects. Larger standard deviations were measured for the later N2 and P3 components than the earlier N1 and P2 components. Regression analyses between various component latencies indicated a strong covarying relationship between N2 and P3, with N2 accounting for up to 61% of the variance of P3 latency at Pz. Earlier N1 and P2 components added little to the overall prediction of either P3 or N2. For the other components, P2 accounted for 9-16% of the variance of N2, while N1 accounted for approximately 1% of the variance of N2; N1 accounted for 8-10% of the latency variation of P2. The correlations between single-trial peak latencies and RTs were positive but of low magnitude. The highest correlations between peak latency and RT were found for N2 (r = 0.33) and P3 (r = 0.24). The low correlations between the single-trial latencies of N1 and P3 suggest that the processes reflected by these components are independent and support a distinction between the earlier and the later components of the ERP. The close temporal coupling between N2 and P3 suggests that N2 may reflect cognitive properties in common to P3 in stimulus evaluation processes.
Brief CO2 laser radiant heat pulses activate both A delta- and C-fibres. In the evoked potential (EP) late and ultralate components can be seen as correlates of first and second pain. Usually the ultralate EP appears to be suppressed. It could be uncovered by a preferential A-fibre block, and in two neurological patients with tabes dorsalis and with a polyneuropathy involving myelinated fibre loss. Due to a strong latency jittering the shape of the ultralate component is distorted in the conventional average. Latency corrected averaging, adaptive filters or parametric spectral estimators are needed to analyze these EP components. As a result the filtered ultralate waveforms look very similar to the late EP components. Clinical application of CO2 laser EPs promises to nonivasively assess A delta- and C-fibre function.
Event-related brain potentials measured with scalp electrodes are always corrupted by unrelated electrical discharges occurring in the brain. These unrelated electrical discharges, generally referred to as noise, have temporal and spectral characteristics similar to evoked potential waveforms, and they greatly increase the difficulty of detecting and estimating the parameters of the evoked potential waveforms themselves. This problem has been analyzed by computing the probability distributions for measured amplitudes and latencies of ERP components measured in the presence of the ongoing EEG. The analytical results have been verified over a wide range of signal-to-noise ratios by computer simulation. Comparisons of theoretical results to measured data indicate that the latency variations found experimentally greatly exceed what would be expected if they were due only to additive noise. It may be concluded, therefore, that the single ERP is not a signal whose components are deterministically related to the stimulus, but is made up of components that shift significantly in both amplitude and latency from one stimulus application to the next. Using the expressions developed in the paper, it is possible to separate the contributions to the variance due to interference from the ongoing EEG and that inherent in the ERP.
In 19 cats anesthetized with 75% nitrous oxide/25% oxygen, two types of cortical activity have been demonstrated to respond to repetitive stimulation of small myelinated and unmyelinated peripheral nerve fibers. One is a rhythmic 3–4 c/sec high voltage activity seen most prominently in the cortical association areas. The other is a 20–40 c/sec small amplitude train of brief discharges appearing most prominently in the primary somatosensory area. This latter response is related to the activity of smaller peripheral nerve fibers. The two responses differ in that the 20–40 c/sec activity is not evoked by epinephrine, appears shortly after the stimulus, and has a shorter duration of activity than the higher voltage 3–4 c/sec theta activity. The slow rhythm is evoked by epinephrine, is delayed in onset and outlasts an evoking stimulus train. Neither response is evoked by optic stimulation or by stimulation of the larger peripheral afferent fibers. Both varieties of cortical activity are suppressed by intravenous phenobarbital.
Characteristics of first and second pain (human subjects) and flexion reflexes (spinal cats) were studied to assess their consistency with dorsal horn cell responses to cutaneous A and C fiber stimulation. For both experiments, two percutaneous electrical shock intensities were used to activate only A fibers and both A and C fibers. Selective block of ulnar nerve impulses necessary for first (pricking) pain was achieved by pressure to the ventral forearm. During blockade, sensation thresholds to shock and graded von Fry hairs increased progressively. After about 40 min, touch, first pain, and pinprick were no longer perceived, but long-latency (> 1 sec) burning sensations due to intense shocks and strong pinch persisted. Differences in reaction time to first and second pain indicated that second pain was related to impulses conducting between 0.8 and 1.6 m/sec (mean = 1.3 m/sec). Sensations of second pain increased with each successive shock if stimulus frequencies were greater than 0.3/sec. These progressive increases occurred both before and after blockade of first pain but not with shock intensities sufficient only to produce first pain. Second pain could be selectively suppressed by mildly painful clamping of adjacent or contralateral digits. A similar analysis applied to flexion reflexes showed that late (or second) flexion reflexes increased progressively when C fibers were activated and when shock frequency exceeded 0.3/sec. The stimulus intensities and frequencies of shocks producing progressively more intense second pain and late flexion reflexes are consistent with previously observed increases in dorsal horn responses to iterative C fiber stimulation.
Microelectroneurographic studies in man allow the comparison of stimulus induced activity in the single peripheral nerve unit with the subject's ratings of sensation. Relationships between stimulus intensity, single unit discharges, and pain ratings were investigated using a CO2 laser stimulator which delivers radiant heat pulses of 50 ms duration. Recordings were performed percutaneously from the radial nerve at the wrist. Receptor types were identified by their response to different stimulus modalities and by their reaction delay to electrical test stimuli within the receptive field. Receptive fields of identified units were stimulated with randomised series of different radiant heat intensities between half and double the individual pain threshold (5 to 20 W; stimulation area 64 mm2).
The largest receptor class observed to be activated by CO2 laser stimuli were polymodal C-nociceptors. None of them was spontaneously active. High discharge rates up to 75/s were not necessarily associated with pain but, if pain was felt, the impulse trains usually lasted for more than 60 ms. Inter-spike intervals were distributed over a wide range between 8 and 145 ms with a peak at about 25 ms. This peak was only slightly shifted by increasing the stimulus intensity. Higher correlations were found between the number of spikes and stimulus intensity. Measures of Signal Detection Theory indicated that the single unit discharges discriminated stimulus intensities better than the subjects' ratings. These findings underline the importance of temporal summation in the processing of C-fibre input with a considerable loss of information in the nociceptive system.
In cats anesthetized with alpha-chloralose, somatic evoked potentials (SEP) were recorded in response to electrical stimulation of surgically isolated peripheral nerves. Selected surgical lesions were made at T9-L1 spinal cord and were histologically verified. Two stimulus magnitudes were used to activate peripheral nerves, one only exciting the large fibers and another exciting the small fibers as well. Control SEPs were recorded in response to stimulation of both large and small fibers of the radial nerve. The later components (latencies greater than 40 msec) of this SEP were suppressed when evoked 100 msec after application of a conditioning stimulus (CS) to the large fibers of either peroneal nerve. Bilateral transection of the dorsal columns and spinocervical tracts eliminates these effects. Increasing the CS intensity to include small diameter fibers again resulted in reduction of the later components of the SEP. This interaction was largely eliminated if the transection was extended to include mid-lateral cord tracts. These results suggest that the SEP can be influenced by small fiber afferent activity conducted in mid-ventrolateral spinal cord in the absence of the dorsal columns and spinocervical tracts. Alterations in the forelimb-evoked SEP by a conditioning hindlimb stimulus is a sensitive indicator of spinal cord integrity. This method may be used to assess whether low spinal injury spares ventrolateral columns.
To determine whether or not knowledge of stimulus timing influences the amplitude and latency of evoked cortical potentials, we have studied the evoked potentials of 24 adults under two contrasting conditions in which people knew or did not know the timing of tone stimuli by means of numerical perceptual cuing. Results demonstrated markedly smaller amplitude and significantly faster latency for the late components of vertex potentials evoked by stimuli whose timing subjects knew in advance. The cognitive act of knowing when auditory stimuli will occur attenuates the amplitude and facilitates the poststimulus timing of cortical evoked potentials.
Contralateral and ipsilateral cortical somatosensory evoked potentials to selective activation of different diameter sural nerve fiber groups were recorded in cats. Activation of alpha fibers evoked a well defined positive-negative primary potential at the contralateral somatosensory area II. Activation of delta fibers in addition to alpha fibers resulted in another positive-negative wave of comparable amplitude with a latency approximately twice that of the early component. Isolation of the peripheral input to the delta fibers alone, by blocking the alpha fiber activity with the use of triangular pulses, caused the complete disappearance of the initial wave, leaving the second with no latency or amplitude changes. This demonstrated that the latter potential was evoked by delta fibers. Ipsilateral responses followed the same pattern, however with higher peripheral thresholds, longer latencies and smaller amplitudes. No cortical potentials could be recorded to activation of C fibers. The results of this study are at variance with previous observations about the cortical responses to small myelinated nerve fiber activity. The rationale of the use of triangular pulses for selectively activating nerve fiber groups is also discussed.
In monkeys anesthetized with 70% N2O-30% O2, alterations in the configuration of the somatosensory evoked potential (SEP) were observed to follow specific spinal cord lesions. The SEPs were recorded in response to stimulation of the exposed superficial peroneal nerve after bilateral dorsal or anterolateral column transection, right or left hemisection, or central cord lesions. Stimulus intensities were sufficient to stimulate large nerve fibers or all nerve fibers. Small nerve fibers were selectively stimulated by blocking large fibers, using a combination of cooling and electrical polarization, while applying maximal stimulus intensities. The results indicate that large-diameter peripheral nerve fibers and the dorsal columns contribute primarily to early wave components (less than 40 ms). Small-diameter peripheral nerve fibers and the anterolateral columns appear to contribute primarily to later wave components (greater than 70 ms). Both large- and small-diameter peripheral nerve fibers and both dorsal and anterolateral columns appear to contribute to components with latencies between 35 and 70 ms.
Minimal conduction velocities of peripheral nerves contributing to acute thermal pain sensation in human volunteer subjects were calculated. Purely thermal stimulation was administered by a low power laser beam directed at the subjects' fingers, and subjective pain responses correlated with a peak in the event-related brain potential (ERBP). These cerebral responses were found to preclude C fiber peripheral activity from this phenomenon.
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)
Thesis (M.S.)--University of Washington, 1983. Includes bibliographical references (leaves [39]-54).
Cerebral potentials evoked by noxious CO2 laser stimuli in man have been referred to nociceptive A delta units. This paper shows 1) that ultra short (5 - 50 ms) high power (less than or equal to 50 W) CO2 laser skin stimuli are able to activate nociceptive C units in man, and 2) that these C nociceptors have to be assumed to terminate in the very superficial skin layer (less than or equal to 300 microns depth).
The application of localized noxious heat stimuli to the skin, generated by brief infrared radiation pulses emitted by a CO2 laser, is a relatively new experimental technique for the thermal induction of pain in humans and in experimental animals. This study proposes a model for the spatial (3-dimensional) and temporal distribution of the skin temperature during and following a radiation pulse. The heat equation is written and solved, using thermal and optical constants of human skin reported in the literature. The solution is approximated, with a very small error, by a closed form expression, having a simple physical interpretation. This model is applied to analyze a typical set-up currently in use in our laboratory. The results show a significant difference between the temperature of the surface of the skin and that of the border between the epidermis and the dermis, which is the location of the most superficial receptive nerve ends. It is shown that, for the set-up examined, these nerve ends reach a temperature of 45 degrees C, known to be the human pain threshold, 30-40 ms after pulse onset. Moreover, it is also shown that they may remain above threshold temperature for up to a few hundreds of milliseconds (considerably outlasting pulse cessation). In addition, it is shown that the area in which nerve ends reach this threshold is a circle with a very small radius (1-2.5 mm). The implications of the results on the double sensation experienced by humans, and on the extremely powerful EEG correlates, are discussed.
Pain estimation (E), evoked cerebral potential (EP), electrooculogram (EOG), electromyogram of withdrawal reflex activity (EMG) and skin conductance reaction (SCR) were measured in response to electrical skin stimuli in 11 male volunteers (age 21-31 years). Constant current stimuli (20 msec; 2, 3, 6, 10 mA) were applied to a finger tip (averaged pain threshold at 5.1 mA). Interstimulus intervals (20-40 sec) and stimulus intensities were delivered in quasi-randomized order, each intensity appearing 40 times per session. Four sessions were repeated with intervals of two days between sessions. With randomized stimulus intensities, power spectral density functions of the prestimulus EEG indicated a stable non-specific arousal level between and within sessions. Under these conditions no significant response plasticity was found for E and EP, not in the prepain or the pain range, and also not between or within sessions. In contrast, the amplitudes of EOG, EMG and SCR decreased drastically with time, especially between the first and second session, and between the first 10 and second 10 stimuli of equal intensity in each session. EP and E remained highly correlated in repeated sessions. A EOG-EP contamination could be ruled out because of their different time course to repeated stimuli.
Thermal stimulation with intense pulses of CO2 laser radiation has recently come into use as a method for generating robust cerebral evoked responses in man. Because the heat transient involved (at least 200°C/s) is at least an order of magnitude greater than that of most conventional thermal stimulators, we checked whether or not there might be anomalous activation of fiber types other than the well known cutaneous thermoreceptors. Recordings were made from primary afferent fibers in the rat sciatic nerve and second order somatosensory cells in the dorsal horn. Most of the laser-sensitive afferent fibers sampled were C polymodal nociceptors with lesser representation of other thermoreceptor types. There were no instances in which low threshold mechanoreceptors or other nonthermal afferent fibers were engaged. We conclude that the advantages of infrared laser stimulation are not compromised by a loss of receptor specificity.
The problem of estimating an unknown transient signal, given an ensemble of waveforms, in which this signal appears as a nonrandom component in the presence of additive noise is considered. This problem is solved by generalizing the method of "a posteriori 'Wiener' filtering". In the new method, the ensemble average is filtered by a time-varying system which is based on estimated time-varying power spectra of signal and noise. The nature of this system, and the computational procedures involved, are discussed in detail. A software package for time-varying filtering is briefly described. Application of the method is illustrated by a simulation example, which also provides a comparison to time-invariant a posteriori "Wiener" filtering.
Sensation, perception and attention: analysis using ERPs Event related brain potentials in man
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Hillyard SA (1978) Sensation, perception and attention: analysis using ERPs. In: Callaway E, Tueting P, Koslow SH (eds) Event related brain potentials in man. Academic Press, New York, pp 223-321
Cortical evoked responses upon selective stimulations of cutaneous group III fibers and the mediating spinal pathways Are cerebral evoked potentials reliable indices of first or second pain? In: Bonica JJ (ed) Advances in pain research and therapy
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Handwerker HO, Zimmermann M (1972) Cortical evoked responses upon selective stimulations of cutaneous group III fibers and the mediating spinal pathways. Brain Res 36: 43%440 Harkins SW, Price DD, Katz MA (1983) Are cerebral evoked potentials reliable indices of first or second pain? In: Bonica JJ (ed) Advances in pain research and therapy, Vol 5. Raven Press, New York, pp 185-191
Dorsal horn electrophysiology In: Iggo A (ed) Handbook of sensory physiology
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Wall PD (1973) Dorsal horn electrophysiology. In: Iggo A (ed) Handbook of sensory physiology, Vol II. Somatosensory system, Springer, Berlin, pp 253-270
Selective activation of C-fibers. Pfltigers Arch 301:32%333 Received October 6
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Zimmermann M (1968) Selective activation of C-fibers. Pfltigers Arch 301:32%333 Received October 6, 1986 / Accepted January 12, 1987
Effects of spinal cord between afferent inputs Signals and noise in evoked brain potentials
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Martin HF, Katz S, Blackburn JG (1980) Effects of spinal cord between afferent inputs. Electroenceph Clin Ncurophysio150: 186-195 McGillem CD, Aunon JI, Yu KB (1985) Signals and noise in evoked brain potentials. IEEE Trans Biomed Eng 32: 1012-1016
Cognitive component in cerebral event-related potentials and selective attention Primary afferent and spinal sensory neurons that respond to brief pulses of intense infrared radiation: a preliminary survey in rats
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Desmedt JE (1979) Cognitive component in cerebral event-related potentials and selective attention. Progress in Clinical Neurophysiology, Vol 6, Karger, Basel Devor M, Carmon A, Frostig R (1982) Primary afferent and spinal sensory neurons that respond to brief pulses of intense infrared radiation: a preliminary survey in rats. Exp Neurol 76:483-494
Cognitive component in cerebral event-related potentials and selective attention
- J E Desmedt
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Are cerebral evoked potentials reliable indices of first or second pain?
- S W Harkins
- D D Price
- M A Katz
- SW Harkins