Valéry Legrain

A neurocognitive model of attention to pain: Behavioral and neuroimaging evidence

READ – Unite de Readaptation et de Medecine physique, Universite catholique de Louvain, Louvain-la-Neuve & Brussels, 1200 Brussels, Belgium Department of Experimental-Clinical and Health Psychology, Universiteit Gent, Ghent, Belgium Centre for Pain Research, University of Bath, UK Division of Brain, Imaging and Behaviour, Toronto Western Research Institute, University Health Network & Department of Surgery and Institute of Medical Science, University of Toronto, Canada Alan Edwards Centre for Research on Pain, Faculty of Dentistry, McGill University, Montreal, Canada

Attentional modulation of the nociceptive processing into the human brain: selective spatial attention, probability of stimulus occurrence, and target detection effects on laser evoked potentials

&NA; Laser evoked potentials (LEPs) are brain responses to activation of skin nociceptors by laser heat stimuli. LEPs consist of three components: N1, N2, and P2. Previous reports have suggested that in contrast to earlier activities (N1), LEPs responses after 230–250 ms (N2–P2) are modulated by attention to painful laser stimuli. However, the experimental paradigms used were not designed to specify the attentional processes involved in these LEP modulations. We investigated the effects of selective spatial attention and oddball tasks on LEPs. CO2 laser stimuli of two different intensities were delivered on the dorsum of both hands of ten subjects. One intensity was frequently presented, and the other rarely. Subjects were asked to pay attention to stimuli delivered on one hand and to count rare stimuli, while ignoring stimuli on the other hand. Frequent and rare attended stimuli evoked enhanced N160 (N1) and N230 (N2) components in comparison to LEPs from unattended stimuli. Both components showed scalp distribution contralateral to the stimulus location. The vertex P400 (P2) was unaffected by spatial attention and stimulus location, but its amplitude increased after rare stimuli, whether attended or unattended. An additional parietal P600 component was induced by the attended rare stimuli. It is suggested that several attentional processes can modify nociceptive processing in the brain at different stages. LEP activities in the time‐range of N1 and N2 (120–270 ms) showed evidence of processes modulated by the direction of spatial attention. Conversely, processes underlying P2 (400 ms) were not affected by spatial attention, but by the probability of the stimulus. This probability effect was not due to P3b‐related processes that were observed at a later latency (600 ms). Indeed, P600 could be seen as a P3b evoked by conscious detection of rare targets.

Nociceptive processing in the human brain of infrequent task-relevant and task-irrelevant noxious stimuli. A study with event-related potentials evoked by CO2 laser radiant heat stimuli.

&NA; Laser evoked potentials (LEPs) are nociceptive‐related brain responses to activation of cutaneous nociceptors by laser radiant heat stimuli. We previously showed that LEP amplitude during the P2 period (∼400 ms) was increased by rare noxious stimuli, inside and outside the focus of spatial attention. It was postulated that this effect reflected a P3a response indexing an involuntary shift of attention. In the present study, LEPs were recorded in a three‐stimulus oddball paradigm, commonly used to evoke P3a (or novelty‐P3). CO2 laser‐induced noxious stimuli were delivered on one hand (80%, frequent). Two series of rare stronger‐intensity deviant stimuli were randomly intermixed: target stimuli (10%) were delivered on the same hand while distractor stimuli (10%) were delivered on the other hand. Subjects were instructed to count targets. During an additional session, strong stimuli were delivered alone on one hand without instruction (100%, no‐task stimuli). All stimulus types evoked a first positivity around 360 ms (P360). Targets and distractors elicited a late positive complex (LPC) around 465–500 ms. Topography of LPC to distractors was central and significantly more anterior than that of LPC to targets. Distractor LPC corresponds to P3a (or novelty‐P3) indexing an involuntary orientation of attention toward an unexpected new/deviant event. It suggests that at least an early part of the LEP positivity (P360) is independent of P3‐activities.Abbreviations: ISI, interstimulus interval; LEP, laser evoked potential; LPC, late positive complex; SW, subtraction wave

INVOLUNTARY ORIENTING OF ATTENTION TO NOCICEPTIVE EVENTS. NEURAL AND BEHAVIORAL SIGNATURES.

Pain can involuntarily capture attention and disrupt pain-unrelated cognitive activities. The brain mechanisms of these effects were explored by laser- and visual-evoked potentials. Consecutive nociceptive laser stimuli and visual stimuli were delivered in pairs. Subjects were instructed to ignore nociceptive stimuli while performing a task on visual targets. Because involuntary attention is particularly sensitive to novelty, in some trials (17%), unexpected laser stimuli were delivered on a different hand area (location-deviant) relative to the more frequent standard laser stimuli. Compared with frequent standard laser stimuli, deviant stimuli enhanced all nociceptive-evoked brain potentials (laser N1, N2, P2a, P2b). Deviant laser stimuli also decreased the amplitude of late latency-evoked responses (visual N2-P3) to the subsequent visual targets and delayed reaction times to them. The data confirm that nociceptive processing competes with pain-unrelated cognitive activities for attentional resources and that concomitant nociceptive events affect behavior by depressing attention allocation to ongoing cognitive processing. The laser-evoked potential magnitude reflected the engagement of attention to the novel nociceptive stimuli. We conclude that the laser-evoked potentials index the activity of a neural system involved in the detection of novel salient stimuli in order to focus attention and prioritize action to potentially damaging dangers.

Cognitive aspects of nociception and pain: bridging neurophysiology with cognitive psychology

The event-related brain potentials (ERPs) elicited by nociceptive stimuli are largely influenced by vigilance, emotion, alertness, and attention. Studies that specifically investigated the effects of cognition on nociceptive ERPs support the idea that most of these ERP components can be regarded as the neurophysiological indexes of the processes underlying detection and orientation of attention toward the eliciting stimulus. Such detection is determined both by the salience of the stimulus that makes it pop out from the environmental context (bottom-up capture of attention) and by its relevance according to the subjects goals and motivation (top-down attentional control). The fact that nociceptive ERPs are largely influenced by information from other sensory modalities such as vision and proprioception, as well as from motor preparation, suggests that these ERPs reflect a cortical system involved in the detection of potentially meaningful stimuli for the body, with the purpose to respond adequately to potential threats. In such a theoretical framework, pain is seen as an epiphenomenon of warning processes, encoded in multimodal and multiframe representations of the body, well suited to guide defensive actions. The findings here reviewed highlight that the ERPs elicited by selective activation of nociceptors may reflect an attentional gain apt to bridge a coherent perception of salient sensory events with action selection processes.

Electrophysiological correlates of attentional orientation in humans to strong intensity deviant nociceptive stimuli, inside and outside the focus of spatial attention.

Laser evoked potentials (LEPs) are electrical brain responses to nociceptive heat stimuli. In a recent study [Legrain, V., Guérit, J.M., Bruyer, R. and Plaghki, L., Pain, 99 (2002) 21-39.], we found that amplitude at approximately 400 ms was increased by rare intensity deviant nociceptive stimuli (P400 effect). In that study, laser stimuli were randomly delivered on both hands, and subjects were focusing attention on one hand in order to detect rare stimuli. As the P400 effect was found for rare stimuli when spatial attention was directed both towards and away from the stimulated hand, it was postulated to represent a P3a component reflecting an involuntary orientation of attention to unexpected deviant stimuli. However LEPs to strong and weak intensity stimuli were averaged together and some effects could have been underestimated. So, we present a new interpretation of the P400 effect based on separate analyses of strong and weak intensity deviant stimuli. Indeed, the P400 effect was only observed for strong stimuli, and again on both attended and unattended hands. Thus, if the P400 effect reflects P3a, only strong deviant stimuli provided enough signals to induce attentional switching even when they were delivered outside the focus of spatial attention. It is suggested that attentional switching could have been triggered by neural systems having detected sharp increase of intensity. Weak deviant stimuli were not salient enough to induce attentional switching.

Laser evoked responses to painful stimulation persist during sleep and predict subsequent arousals

&NA; We studied behavioural responses and 32‐channel brain potentials to nociceptive stimuli during all‐night sleep in 12 healthy subjects, using sequences of thermal laser pulses delivered over the dorsum of the hand. Laser stimuli less than 20 dB over perception threshold had clear awakening properties, in accordance with the intrinsic threatening value of nociceptive signals. Even in cases where nociceptive stimulation did not interrupt sleep, it triggered motor responses in 11% of trials. Only four subjects reported dreams, and on morning questionnaires there was no evidence of incorporation to dreams of nociceptive stimuli. Contrary to previous reports suggesting the absence of cortical nociceptive responses during sleep, we were able to record brain‐evoked potentials to laser (LEPs) during all sleep stages. Sleep LEPs were in general attenuated, but their morphology was sleep‐stage‐dependent: in stage 2, the weakened initial response was often followed by a high‐amplitude negative wave with typical features of a K‐complex. During paradoxical sleep (PS) LEP morphology was similar to that of waking, but frontal components showed strong attenuation, consistent with the reported frontal metabolic deactivation. A late positive component (450–650 ms) was recorded in both stage 2 and PS, the amplitude of which was significantly enhanced in trials that were followed by an arousal. This response appeared functionally related to the P3 wave, which in waking subjects has been associated to conscious perception and memory encoding.

Thermal detection thresholds of Aδ- and C-fibre afferents activated by brief CO2 laser pulses applied onto the human hairy skin.

Brief high-power laser pulses applied onto the hairy skin of the distal end of a limb generate a double sensation related to the activation of Aδ- and C-fibres, referred to as first and second pain. However, neurophysiological and behavioural responses related to the activation of C-fibres can be studied reliably only if the concomitant activation of Aδ-fibres is avoided. Here, using a novel CO2 laser stimulator able to deliver constant-temperature heat pulses through a feedback regulation of laser power by an online measurement of skin temperature at target site, combined with an adaptive staircase algorithm using reaction-time to distinguish between responses triggered by Aδ- and C-fibre input, we show that it is possible to estimate robustly and independently the thermal detection thresholds of Aδ-fibres (46.9±1.7°C) and C-fibres (39.8±1.7°C). Furthermore, we show that both thresholds are dependent on the skin temperature preceding and/or surrounding the test stimulus, indicating that the Aδ- and C-fibre afferents triggering the behavioural responses to brief laser pulses behave, at least partially, as detectors of a change in skin temperature rather than as pure level detectors. Most importantly, our results show that the difference in threshold between Aδ- and C-fibre afferents activated by brief laser pulses can be exploited to activate C-fibres selectively and reliably, provided that the rise in skin temperature generated by the laser stimulator is well-controlled. Our approach could constitute a tool to explore, in humans, the physiological and pathophysiological mechanisms involved in processing C- and Aδ-fibre input, respectively.

Evoked potentials to nociceptive stimuli delivered by CO2 or Nd:YAP lasers

OBJECTIVE This study compares the amplitude, latency, morphology, scalp topography and intracranial generators of laser-evoked potentials (LEPs) to CO(2) and Nd:YAP laser stimuli. METHODS LEPs were assessed in 11 healthy subjects (6 men, mean age 39+/-10 years) using a 32-channel acquisition system. Laser stimuli were delivered on the dorsum of both hands (intensity slightly above pain threshold), and permitted to obtain lateralised (N1) and vertex components (N2-P2) with similar scalp distribution for both types of lasers. RESULTS The N1-YAP had similar latencies but significantly higher amplitudes relative to N1-CO(2). The N2-P2 complex showed earlier latencies, higher amplitudes (N2) and more synchronised responses when using Nd:YAP stimulation. The distribution of intracranial generators assessed with source localization analyses (sLORETA) was similar for Nd:YAP and CO(2) lasers. The insular, opercular, and primary sensorimotor cortices were active during the N1 time-window, whereas the anterior midcingulate, supplementary motor areas and mid-anterior insulae were active concomitant to the N2-P2 complex. CONCLUSIONS Earlier latencies and larger amplitudes recorded when using Nd:YAP pulses suggest a more synchronized nociceptive afferent volley with this type of laser. SIGNIFICANCE This, together with its handy utilization due to optic fibre transmission, may favour the use of Nd:YAP lasers in clinical settings.

Nociceptive steady-state evoked potentials elicited by rapid periodic thermal stimulation of cutaneous nociceptors

The periodic presentation of a sensory stimulus induces, at certain frequencies of stimulation, a sustained electroencephalographic response known as steady-state evoked potential (SS-EP). In the somatosensory, visual, and auditory modalities, SS-EPs are considered to constitute an electrophysiological correlate of cortical sensory networks resonating at the frequency of stimulation. In the present study, we describe and characterize, for the first time, SS-EPs elicited by the selective activation of skin nociceptors in humans. The stimulation consisted of 2.3-s-long trains of 16 identical infrared laser pulses (frequency, 7 Hz), applied to the dorsum of the left and right hand and foot. Two different stimulation energies were used. The low energy activated only C-nociceptors, whereas the high energy activated both Aδ- and C-nociceptors. Innocuous electrical stimulation of large-diameter Aβ-fibers involved in the perception of touch and vibration was used as control. The high-energy nociceptive stimulus elicited a consistent SS-EP, related to the activation of Aδ-nociceptors. Regardless of stimulus location, the scalp topography of this response was maximal at the vertex. This was noticeably different from the scalp topography of the SS-EPs elicited by innocuous vibrotactile stimulation, which displayed a clear maximum over the parietal region contralateral to the stimulated side. Therefore, we hypothesize that the SS-EPs elicited by the rapid periodic thermal activation of nociceptors may reflect the activation of a network that is preferentially involved in processing nociceptive input and may thus provide some important insight into the cortical processes generating painful percepts.