Quickly responding C-fibre nociceptors contribute to heat hypersensitivity in the area of secondary hyperalgesia.

KEY POINTS: A recent animal study showed that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation at the spinal cord that is hypothesized to mediate secondary hyperalgesia in humans. Here this hypothesis was tested by predominantly activating C-fibre nociceptors in the area of secondary mechanical hyperalgesia induced by HFS in humans. It is shown that heat perception elicited by stimuli predominantly activating C-fibre nociceptors is greater, as compared to the control site, after HFS in the area of secondary mechanical hyperalgesia. This is the first study that confirms in humans the involvement of C-fibre nociceptors in the changes in heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. ABSTRACT: It has recently been shown that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation (LTP) at the spinal cord in animals, which has been hypothesized to be the underlying mechanism of secondary hyperalgesia in humans. Here we tested this hypothesis using a method to predominantly activate quickly responding C-fibre nociceptors in the area of secondary hyperalgesia induced by HFS in humans. HFS was delivered to one of the two volar forearms in 18 healthy volunteers. Before, 20 min and 45 min after HFS, short-lasting (10 ms) high-intensity CO2 laser heat stimuli delivered to a very small area of the skin (0.15 mm2 ) were applied to the area of increased mechanical pinprick sensitivity at the HFS-treated arm and the homologous area of the contralateral control arm. During heat stimulation the electroencephalogram, reaction times and intensity of perception (numerical rating scale 0-100) were measured. After HFS, we observed a greater heat sensitivity, an enhancement in the number of detected trials, faster reaction times and an enhancement of the N2 wave of C-fibre laser-evoked potentials at the HFS-treated arm compared to the control arm. This is the first study that confirms in humans the involvement of C-fibre nociceptors in enhanced heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS.

The effect of heterotopic noxious conditioning stimulation on Aδ-, C- and Aß-fibre brain responses in humans.

Human studies have shown that heterotopic nociceptive conditioning stimulation (HNCS) applied to a given body location reduces the percept and brain responses elicited by noxious test stimuli delivered at a remote body location. It remains unclear to what extent this effect of HNCS relies on the spinal-bulbar-spinal loop mediating the effect of diffuse noxious inhibitory controls (DNICs) described in animals, and/or on top-down cortical mechanisms modulating nociception. Importantly, some studies have examined the effects of HNCS on the brain responses to nociceptive input conveyed by Aδ-fibres. In contrast, no studies have explored the effects of HNCS on the responses to selective nociceptive C-fibre input and non-nociceptive Aß-fibre input. In this study, we measured the intensity of perception and event-related potentials (ERPs) to stimuli activating Aδ-, C- and Aß-fibres, before, during and after HNCS, obtained by immersing one foot in painful cold water. We observed that (i) the perceived intensity of nociceptive Aδ- and C-stimuli was reduced during HNCS, and (ii) the ERPs elicited by Aδ- and Aß- and C-stimuli were also reduced during HNCS. Importantly, because Aß-ERPs are related to primary afferents that ascend directly through the dorsal columns without being relayed at spinal level, the modulation of these responses may not be explained by an influence of descending projections modulating the transmission of nociceptive input at spinal level. Therefore, our results indicate that, in humans, HNCS should be used with caution as a direct measure of DNIC-related mechanisms.

Biological inflammatory markers mediate the effect of preoperative pain-related behaviours on postoperative analgesics requirements.

BACKGROUND: The predictive value of an individual's attitude towards painful situations and the status of his immune system for postoperative analgesic requirements are not well understood. These may help the clinician to anticipate individual patient's needs. METHODS: Sixty patients, who underwent a laparoscopic cholecystectomy under standardised general anaesthesia, were included. The total analgesic requirements during the first 48 h were the primary endpoint (unitary dosage, UD). The individual's attitude towards imaginary painful situations was measured with the Situational Pain Scale (SPS). The emotional status was assessed by the Hospital Anxiety and Depression Scale (HADS) and the inflammatory status by the neutrophil-to-lymphocyte ratio (NLR). RESULTS: Univariate analyses revealed a significant association between UD and SPS, HADS and NLR. A negative relationship between SPS and NLR (NLR = 0.820-0.180*SPS;R(2) = 0.211;P < 0.001) and a positive relationship between SPS and HADS (HADS = 14.8 + 1.63*SPS; R(2) = 0.159;P = 0.002) were observed. A multiple linear regression analysis showed that the contribution of NLR to the UD was the most effective. A mediation analysis showed a complete mediation of the effect of SPS on UD (R(2) = 0.103;P = 0.012), by the NLR (SPS on NLR: R(2) = 0.211;P = <0.001), the HADS (SPS on HADS: R(2) = 0.159;P = 0.002). The variance in UD explained by the SPS was indirect and amounts to 46% through NLR and to 34% through HADS. CONCLUSIONS: In this series, preoperative pain-related attitudes (SPS) were associated with the postoperative analgesic requirements (UD) after a cholecystectomy. Eighty per cent of this effect was mediated by the HADS and the NLR.

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 Aß-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.

Clinical, functional and structural determinants of central pain in syringomyelia.

The present study aimed to investigate the relationship between neuropathic symptoms (i.e. pain and paraesthesia/dysaesthesia) and structural damage and functional alterations of spinal sensory tracts in patients with syringomyelia. Three-dimensional fibre tracking of the cervical spinal cord (at level C3-C4), electrophysiological assessments of nociceptive (laser-evoked potentials) and non-nociceptive (somatosensory-evoked potentials) pathways and quantitative sensory testing were carried out in 37 patients with syringomyelia, 27 with neuropathic pain and 21 controls. Four regions of the body (both hands and shoulders) were systematically examined with laser-evoked potentials and quantitative sensory testing, and somatosensory-evoked potentials were induced from both hands. The diffusion tensor imaging variables investigated included the mean fractional anisotropy, the mean apparent diffusion coefficient and the number of reconstructed nerve fibres of the tracts located within three volumes of interest (full spinal section, anterior cord and posterior cord). Consistent with the results of previous studies, patients with or without neuropathic pain were indistinguishable on the basis of quantitative sensory testing, laser-evoked and somatosensory-evoked potentials and three-dimensional fibre tracking analyses. However, in patients with neuropathic pain, higher average daily pain intensity was correlated with greater structural damage to the spinal cord, as assessed by fractional anisotropy (Spearman's ρ = -0.64, P = 0.020) and the number of reconstructed nerve fibres (r = -0.75; P = 0.020) of the full spinal cord. The number of reconstructed nerve fibres was negatively correlated with two neuropathic dimensions, i.e. 'deep spontaneous pain' (r = -0.59, P = 0.040) and 'paraesthesia/dysaesthesia' (i.e. pins and needles/tingling) (r = -0.67, P = 0.020), suggesting that various pain descriptors have distinct underlying mechanisms. Patients with both spontaneous and evoked pain clearly differed from patients with spontaneous pain only. Patients with spontaneous pain only had more severe spinal cord damage, and the correlation between average daily pain intensity and fractional anisotropy of the full spinal cord was particularly strong in this subgroup of patients (Spearman's ρ = -0.93, P = 0.008). By contrast, patients with both spontaneous and evoked pain had not only less structural spinal cord damage, but also better preserved spinothalamic and lemniscal tracts on quantitative sensory testing and electrophysiological testing. These data showed, for the first time, a direct relationship between central neuropathic pain and objective markers of spinal cord damage, and confirmed the clinical relevance of 3D fibre tracking for the sensory assessment of patients with a spinal cord lesion.

An adaptive procedure for routine measurement of light-touch sensitivity threshold.

Quantitative sensory testing with Semmes-Weinstein monofilaments suffers from several pitfalls. Our aims were to assess the reliability of these filaments for touch-pressure threshold detection, develop and validate a rapid and accurate procedure for measurements at the bedside, and establish normative data. After calibration of the monofilaments, an adaptive staircase algorithm was validated and used to establish normative data in healthy subjects. Calibration showed significant differences between manufacturer- and investigator-produced data. The relative humidity significantly affected the force exerted by the filaments. The adaptive procedure showed good accuracy and substantial time-saving. Touch-pressure thresholds showed significant gender differences (mean +/- 2 SD for females/males: 2.82-12.3/3.09-17.78 g/mm(2)). The influence of body site and age is small. Accurate use of Semmes-Weinstein monofilaments requires prior calibration, correction for humidity, and use of a validated procedure. In this study we provide normative data that can be used with our algorithm.

Fibromyalgia syndrome-A laser-evoked potentials study unsupportive of small nerve fibre involvement.

BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic pain syndrome characterized by widespread pain and a variety of non-pain symptoms. Central sensitivity phenomena are found consistently in FMS. Additionally, several researchers proclaimed that a subgroup of FMS patients may present with unrecognized peripheral small fibre neuropathy (SFN). Laser-evoked brain potentials (LEP) are considered as a reliable method for the functional assessment of the thermo-nociceptive system, including the evaluation of SFN. OBJECTIVES: The aim of this retrospective study was to estimate the prevalence of thermo-nociceptive system dysfunction based on LEPs in FMS. METHODS: LEP recordings of 92 FMS patients and 39 age and gender-matched healthy controls were selected from a database collected between 2003 and 2012 with standardized settings for laser stimulation and EEG recording. The N1, N2 and P2 LEP components were identified and characterized by peak latency and amplitude. RESULTS: None of the FMS patients showed signs of loss of function of the nociceptive responses evoked by A δ-nociceptor activation, compared to healthy controls. 6.5% of the FMS patients had N2-P2 peak-to-peak amplitudes above the upper limit of the 99%-confidence interval. N2-P2 peak-to-peak amplitudes were negatively correlated with age, without age-related differences between groups. CONCLUSIONS: The characteristic signs of a damaged thermo-nociceptive system as revealed by LEPs were absent in this large cohort of FMS patients. SIGNIFICANCE: The present research does not support the hypothesis that small fibre neuropathy is a significant contributor to the pathophysiology of FMS.

Assessing thermal sensitivity using transient heat and cold stimuli combined with a Bayesian adaptive method in a clinical setting: A proof of concept study.

BACKGROUND: Quantitative sensory testing of thermal detection abilities is used as a clinical tool to assess the function of pain pathways. The most common procedure to assess thermal sensitivity, the 'method of limits', provides a quick but rough estimate of detection thresholds. Here, we investigate the potential of evaluating not only the threshold but also the slope of the psychometric functions for cold and warm detection. METHOD: A convenience sample of 15 patients with diabetes mellitus (DM) and 15 age-matched healthy controls (HC) was tested. Thirty brief (100 ms) stimuli of each modality were applied to the volar wrist and foot dorsum. Cold and warm stimuli were delivered with a Peltier thermode and a temperature-controlled CO2 laser, respectively. Stimulus intensities were dynamically selected using an adaptive Bayesian algorithm (psi method) maximizing information gain for threshold and slope estimation. ROC analyses were used to assess the ability of slopes, thresholds and the combination of both to discriminate between groups. RESULTS: Assessment of the slope and threshold of the psychometric function for thermal detection took about 10 min. The ability to detect warmth was not reduced in DM patients as compared to HC. Cold detection performance assessed using slope or threshold parameters separated DM from HC with good discriminative power. Discrimination was further increased when both parameters were used together (93% sensitivity and 87% specificity), indicating that they provide complementary information on patient status. CONCLUSION: The psi method may be an interesting alternative to the classical method of limits for thermal QST. SIGNIFICANCE: Current QST protocols provide an incomplete and potentially biased estimate of sensory detection performance. We propose a method that estimates the slope and the threshold of the psychometric function, defining heat and cold sensory detection performance, in only a few minutes. Furthermore, we provide preliminary evidence that combining slope and threshold parameters of cold detection performance leads to a better discriminative ability than relying solely on the threshold.

Aδ and not C fibers mediate thermal hyperalgesia to short laser stimuli after burn injury in man.

It remains unclear which nerve fibers are responsible for mediating hyperalgesia after skin injury. Here, we examined the role of Aδ and C fibers in inflammatory hyperalgesia after a first-degree burn injury. A CO2 laser delivered ultrafast short constant-temperature heat pulses to the upper part of the lower leg to stimulate selectively the relatively fast-conducting thinly myelinated Aδ and the slowly conducting unmyelinated C fibers. Participants were asked to respond as fast as possible whenever they detected a thermal stimulus. Thresholds and reaction times to selective Aδ and C fiber activations were measured in the conditioned and the surrounding intact skin, at pre-injury, and 1 hour and 24 hours after injury. First-degree burn injury caused a significant decrease in Aδ fiber detection thresholds and a significant increase in the proportion of Aδ-fiber-mediated responses in the inflamed area 24 hours, but not 1 hour, after burn injury. No changes in heat perception were observed in the intact skin surrounding the injury. No group differences in C-fiber-mediated sensations were observed. Our findings indicate that quickly adapting Aδ fibers but not quickly adapting C fibers are sensitized when activated by short and ultrafast heat stimuli after skin burn injury. Our results further show that this change occurs between 1 hour and 24 hours after injury and that it does not extend to the skin surrounding the injury.

Measure of experimental pain using Rasch analysis.

Most common instruments used to assess the painfulness of nociceptive stimuli and the perception of such stimuli are ordinal. This property limits arithmetical operations and statistical procedures that can be applied on their numbers. The Rasch methodology provides mathematical procedures for transforming scores on an ordinal scale into measures on an interval scale. The present paper aims at presenting the basics of this methodology by applying it to the measurement of experimentally induced pain. Six blocks of seven CO(2) laser heat stimuli varying in intensity were delivered on the hand of 100 healthy subjects. They rated their pain perception on a three-level verbal rating scale (not painful, slightly painful, painful). One member of the family of Rasch models, the many-facet model, was applied to the analysis of these ratings. The analysis provided linear measures of the painfulness for each intensity of stimulation, of the pain perception of each subject and of the painfulness of each successive block. All these measures are located on a single pain perception continuum. Advantages and disadvantages of this methodology will be discussed in terms of subsequent possible mathematical analyses, statistical tests and implications for experimental and clinical investigations.

Laser-evoked potentials correlate with clinical evolution in a case of spontaneous and recurrent complex regional pain syndrome type I.

We describe a case of spontaneous complex regional pain syndrome developing first in the left arm and 2 years later in the right foot of a 14-year-old girl. Physical examination showed abnormalities in tactile and thermal sensitivity. Laser-evoked potentials (LEPs) after stimulation of the affected right foot were absent in the acute phase and then progressively recovered over a period of 5 months, in correlation with clinical changes. To our knowledge, no systematic analysis of LEPs in complex regional pain syndrome has been published. We suggest that the observed electrophysiologic alterations could result from a temporary dysfunction of attentional systems, which are assumed to contribute greatly to the LEPs vertex complex. Further studies are needed to test this hypothesis.

Respiratory hypoalgesia? Breath-holding, but not respiratory phase modulates nociceptive flexion reflex and pain intensity.

Several observations suggest that respiratory phase (inhalation vs. exhalation) and post-inspiratory breath-holds could modulate pain and the nociceptive reflex. This experiment aimed to investigate the role of both mechanisms. Thirty-two healthy participants received supra-threshold electrocutaneous stimulations to elicit both the Nociceptive Flexion Reflex (NFR) and pain, either during spontaneous inhalations or exhalations, or during three types of instructed breath-holds: following exhalation, at mid-inhalation and at full-capacity inhalation. Whether the electrocutaneous stimulus was applied during inhalation or exhalation did not affect the NFR or pain. Self-reported pain was reduced and the NFR was increased during breath-holding compared to spontaneous breathing. Whereas the type of breath-hold did not impact on self-reported pain, breath-holds at full-capacity inhalation and following exhalation were associated with a lower NFR amplitude compared to breath-holds at mid-inhalation. The present findings confirm that breath-holding can modulate pain (sensitivity) and suggest that both attentional distraction and changes in vagal activity may underlie the observed effects.

NRP-1 Receptor Expression Mismatch in Skin of Subjects with Experimental and Diabetic Small Fiber Neuropathy.

The in vivo cutaneous nerve regeneration model using capsaicin is applied extensively to study the regenerative mechanisms and therapeutic efficacy of disease modifying molecules for small fiber neuropathy (SFN). Since mismatches between functional and morphological nerve fiber recovery are described for this model, we aimed at determining the capability of the capsaicin model to truly mimic the morphological manifestations of SFN in diabetes. As nerve and blood vessel growth and regenerative capacities are defective in diabetes, we focused on studying the key regulator of these processes, the neuropilin-1 (NRP-1)/semaphorin pathway. This led us to the evaluation of NRP-1 receptor expression in epidermis and dermis of subjects presenting experimentally induced small fiber neuropathy, diabetic polyneuropathy and of diabetic subjects without clinical signs of small fiber neuropathy. The NRP-1 receptor was co-stained with CD31 vessel-marker using immunofluorescence and analyzed with Definiens® technology. This study indicates that capsaicin application results in significant loss of epidermal NRP-1 receptor expression, whereas diabetic subjects presenting small fiber neuropathy show full epidermal NRP-1 expression in contrast to the basal expression pattern seen in healthy controls. Capsaicin induced a decrease in dermal non-vascular NRP-1 receptor expression which did not appear in diabetic polyneuropathy. We can conclude that the capsaicin model does not mimic diabetic neuropathy related changes for cutaneous NRP-1 receptor expression. In addition, our data suggest that NRP-1 might play an important role in epidermal nerve fiber loss and/or defective regeneration and that NRP-1 receptor could change the epidermal environment to a nerve fiber repellant bed possibly through Sem3A in diabetes.

Automated PGP9.5 immunofluorescence staining: a valuable tool in the assessment of small fiber neuropathy?

BACKGROUND: In this study we explored the possibility of automating the PGP9.5 immunofluorescence staining assay for the diagnosis of small fiber neuropathy using skin punch biopsies. The laboratory developed test (LDT) was subjected to a validation strategy as required by good laboratory practice guidelines and compared to the well-established gold standard method approved by the European Federation of Neurological Societies (EFNS). To facilitate automation, the use of thinner sections. (16 µm) was evaluated. Biopsies from previously published studies were used. The aim was to evaluate the diagnostic performance of the LDT compared to the gold standard. We focused on technical aspects to reach high-quality standardization of the PGP9.5 assay and finally evaluate its potential for use in large scale batch testing. RESULTS: We first studied linear nerve fiber densities in skin of healthy volunteers to establish reference ranges, and compared our LDT using the modifications to the EFNS counting rule to the gold standard in visualizing and quantifying the epidermal nerve fiber network. As the LDT requires the use of 16 µm tissue sections, a higher incidence of intra-epidermal nerve fiber fragments and a lower incidence of secondary branches were detected. Nevertheless, the LDT showed excellent concordance with the gold standard method. Next, the diagnostic performance and yield of the LDT were explored and challenged to the gold standard using skin punch biopsies of capsaicin treated subjects, and patients with diabetic polyneuropathy. The LDT reached good agreement with the gold standard in identifying small fiber neuropathy. The reduction of section thickness from 50 to 16 µm resulted in a significantly lower visualization of the three-dimensional epidermal nerve fiber network, as expected. However, the diagnostic performance of the LDT was adequate as characterized by a sensitivity and specificity of 80 and 64 %, respectively. CONCLUSIONS: This study, designed as a proof of principle, indicated that the LDT is an accurate, robust and automated assay, which adequately and reliably identifies patients presenting with small fiber neuropathy, and therefore has potential for use in large scale clinical studies.

EEG and laser stimulation as tools for pain research.

Laser heat stimulators selectively activate Adelta and C-nociceptors in the superficial layers of the skin. Their high power output produces steep heating ramps, which improve synchronization of afferent volleys and therefore allow the recording of time-locked events, such as laser-evoked brain potentials. Study of the electrical brain activity evoked by Adelta- and C-nociceptor afferent volleys revealed the existence of an extensive, sequentially activated, cortical network. These electrophysiological responses are modulated by stimulus-driven and, even more extensively, top-down processes. The specificity and validity of these components for pain research are currently under intense scrutiny.

Innocuous skin cooling modulates perception and neurophysiological correlates of brief CO2 laser stimuli in humans.

The present study examined the influence of innocuous skin cooling on the perception and neurophysiological correlates of brief noxious CO2 laser stimuli. In nine normal subjects, brief CO2 laser pulses of four different intensities (duration 50 ms; diameter 5 mm; intensity range 5.8-10.6 mJ/mm2) were delivered at random every 5-10 s on the dorsum of the hand. Innocuous skin cooling was performed by a thermode (20 degrees C; 3x3 cm) with a central hole for the laser test stimuli. Quality and intensity (VAS) of perceptions, reaction times and laser evoked potentials (LEPs) were examined. Signal detection theory analysis was performed to evaluate discrimination performance and decision criterion. During innocuous skin cooling, detection threshold increased from 4.8+/-1.81 to 8.2+/-1.05 mJ/mm2 and pain threshold from 8.7+/-1.53 to 13.5+/-1.57 mJ/mm2. proportion of detected stimuli decreased from 87% to 48% and pain reports from 42% to 10%. The well localized 'pricking' sensation mediated by Adelta-nociceptors almost vanished. The intensity of sensations (VAS scores) was considerably reduced. Sensory discriminative performance was significantly depressed but decision criterion remained unchanged. Reaction times were delayed. The late-LEPs, correlates of Adelta-nociceptor activations, were also significantly depressed while the ultra-late LEPs, correlates of C-nociceptors, were not affected. Taken together, these results strongly suggest that innocuous skin cooling interfered with the sensory processing of laser heat stimuli and more prominently with those related to Adelta-nociceptive input.

Involuntary orientation of attention to unattended deviant nociceptive stimuli is modulated by concomitant visual task difficulty. Evidence from laser evoked potentials.

OBJECTIVE: Recent laser evoked potential (LEP) studies showed that unattended rare intensity-deviant nociceptive stimuli enhance the LEP vertex positivity P2 ('P400 effect'). It was hypothesized to reflect an involuntary switch of attention to nociceptive events. If true the P400 effect (1) should be produced when attention is focused on a task in another sensory modality (primary task), and (2) should be modulated by the primary task difficulty. METHODS: Subjects had to count the number of visual symbols presented on a screen. In a difficult condition, symbols were digits 1-4 (interference between amount and meaning). In an easy condition, symbols were letters X (no interference). Nociceptive CO2 laser stimuli were simultaneously delivered on the left hand. Occasional stronger deviant stimuli (16%) were presented at random. In additional sessions, the strong stimuli were presented alone in homogenous series (100%). RESULTS: LEP amplitude at about 400 ms was larger for rare deviant than for homogenous stimuli. Visual task difficulty decreased LEP amplitude at this latency. Deviant stimuli seemed also to interfere with performance in the visual task. CONCLUSIONS: The results give evidence for considering the P400 effect as reflecting an involuntary attentional shift to nociceptive events. SIGNIFICANCE: The study provides electrophysiological evidences for an intrusive capacity of pain to attract attention and to decrease behavioural performance in concurrent processes. In turn, such an attentional shift is tampered if attention is very engaged in a concomitant task.

Affective associative learning modifies the sensory perception of nociceptive stimuli without participant's awareness.

The present experiment examined the possibility to change the sensory and/or the affective perception of thermal stimuli by an emotional associative learning procedure known to operate without participants' awareness (evaluative conditioning). In a mixed design, an aversive conditioning procedure was compared between subjects to an appetitive conditioning procedure. Both groups were also compared within-subject to a control condition (neutral conditioning). The aversive conditioning was induced by associating non-painful and painful thermal stimuli - delivered on the right forearm - with unpleasant slides. The appetitive conditioning consisted in an association between thermal stimuli - also delivered on the right forearm - and pleasant slides. The control condition consisted in an association between thermal stimuli - delivered for all participants on the left forearm - and neutral slides. The effects of the conditioning procedures on the sensory and affective dimensions were evaluated with visual analogue scale (VAS)-intensity and VAS-unpleasantness. Startle reflex was used as a physiological index of emotional valence disposition. Results confirmed that no participants were aware of the conditioning procedure. After unpleasant slides (aversive conditioning), non-painful and painful thermal stimuli were judged more intense and more unpleasant than when preceded by neutral slides (control condition) or pleasant slides (appetitive conditioning). Despite a strong correlation between the intensity and the unpleasantness scales, effects were weaker for the affective scale and, became statistically non-significant when VAS-intensity was used as covariate. This experiment shows that it is possible to modify the perception of intensity of thermal stimuli by a non-conscious learning procedure based on the transfer of the valence of the unconditioned stimuli (pleasant or unpleasant slides) towards the conditioned stimuli (non-painful and painful thermal stimuli). These results plead for a conception of pain as a conscious output of complex informational processes all of which are not accessible to participants' awareness. Mechanisms by which affective input may influence sensory experience and clinical implications of the present study are discussed.

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.

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 (approximately 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). CO(2) 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.

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.

Laser evoked potentials (LEPs) are brain responses to activation of skin nociceptors by laser heat stimuli. LEPs consist of three components: N1, N2, and P2. Previous reports have suggested that in contrast to earlier activities (N1), LEPs responses after 230-250 ms (N2-P2) are modulated by attention to painful laser stimuli. However, the experimental paradigms used were not designed to specify the attentional processes involved in these LEP modulations. We investigated the effects of selective spatial attention and oddball tasks on LEPs. CO(2) laser stimuli of two different intensities were delivered on the dorsum of both hands of ten subjects. One intensity was frequently presented, and the other rarely. Subjects were asked to pay attention to stimuli delivered on one hand and to count rare stimuli, while ignoring stimuli on the other hand. Frequent and rare attended stimuli evoked enhanced N160 (N1) and N230 (N2) components in comparison to LEPs from unattended stimuli. Both components showed scalp distribution contralateral to the stimulus location. The vertex P400 (P2) was unaffected by spatial attention and stimulus location, but its amplitude increased after rare stimuli, whether attended or unattended. An additional parietal P600 component was induced by the attended rare stimuli. It is suggested that several attentional processes can modify nociceptive processing in the brain at different stages. LEP activities in the time-range of N1 and N2 (120-270 ms) showed evidence of processes modulated by the direction of spatial attention. Conversely, processes underlying P2 (400 ms) were not affected by spatial attention, but by the probability of the stimulus. This probability effect was not due to P3b-related processes that were observed at a later latency (600 ms). Indeed, P600 could be seen as a P3b evoked by conscious detection of rare targets.