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Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation
Abstract
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)
... For this purpose, BioPain has designed four placebocontrolled RCTs in healthy subjects with the objective of profiling four sets of pain biomarkers derived from noninvasive measures of peripheral nerve excitability (IMI2-PainCare-BioPain-RCT1), 1 , electrophysiological measures of spinal cord and brainstem reflex activity (IMI2-PainCare-BioPain-RCT2), 2 electroencephalographic (EEG) measures of brain activity (IMI2-PainCare-Bio-Pain-RCT3), 3 and functional magnetic resonance imaging measures of brain activity (IMI2-PainCare-BioPain-RCT4), 4 using three drugs registered as analgesics or known to act on the nociceptive system, given as a single dose in four separate study periods: lacosamide acting preferentially on nociception at peripheral level, pregabalin acting preferentially on nociception at the spinal level, and tapentadol acting preferentially on nociception at the supraspinal level. ...
... 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]. ...
... After each stimulation block, the subject will be requested to rate the unpleasantness of the elicited sensation, as detailed in the next section. This EEG data will allow measuring the average amplitude of the negativepositive (N2-P2) vertex potential elicited by laser stimulation [3], required to generate the primary endpoint "LEP N2-P2_amp," also used for the key secondary analyses. The processing steps to obtain this measurement are detailed in a separate operational manual. ...
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 ).
... In human studies, brief infrared laser pulses are widely used as nociceptive stimuli, and laser-evoked potentials are regularly recorded in pain studies using methods like EEG or ECoG (Bromm and Treede, 1984;Cruccu and Garcia-Larrea, 2004;Ohara et al., 2004;Rosenberger et al., 2020). Several experiments on animals have also used laser-evoked potentials, including ECoG recordings from unrestraint rats (Ljungquist et al., 2016;Peng et al., 2018). ...
... Therefore, the alignment and averaging of evoked potentials on the basis of behavioral responses can be noisy. One approach is to use devices with noxious stimulation inducing very prompt behavioral reflexes (Bromm and Treede, 1984). Here we describe another approach, aligning electrographic responses with precisely measurable cue times and using behavioral data only for the assessment of pain. ...
... Laser evoked potentials were broadly adopted for thermal pain studies in humans (Treede et al., 2003). For example, brief painful infrared lasers were established and validated as a nociceptive stimulus in humans (Bromm and Treede, 1984;Plaghki and Mouraux, 2003). Laser evoked potentials can be easily recorded by human EEG or ECoG for pain study (Bromm and Treede, 1991;Cruccu and Garcia-Larrea, 2004;Ohara et al., 2004). ...
Experiments on pain processing in animals face several methodological challenges including the reproducible application of painful stimuli. Ideally, behavioral and physiological correlates of pain should be assessed in freely behaving mice, avoiding stress, fear or behavioral restriction as confounding factors. Moreover, the time of pain-evoked brain activity should be precisely related to the time of stimulation, such that pain-specific neuronal activity can be unambiguously identified. This can be achieved with laser-evoked heat stimuli which are also well established for human pain research. However, laser-evoked neuronal potentials are rarely investigated in awake unrestrained rodents, partially due to the practical difficulties in precisely and reliably targeting and triggering stimulation. In order to facilitate such studies we have developed a versatile stimulation and recording system for freely moving mice. The custom-made apparatus can provide both laser- and mechanical stimuli with simultaneous recording of evoked potentials and behavioral responses. Evoked potentials can be recorded from superficial and deep brain areas showing graded pain responses which correlate with pain-specific behavioral reactions. Non-painful mechanical stimuli can be applied as a control, yielding clearly different electrophysiological and behavioral responses. The apparatus is suited for simultaneous acquisition of precisely timed electrophysiological and behavioral evoked responses in freely moving mice. Besides its application in pain research it may be also useful in other fields of sensory physiology.
... Applications of the laser radiation for therapeutic purposes is based on photochemical reactions. Short heat bursts generated by infrared laser stimulators are used to selectively excite free nerve endings located in the upper layers of the skin [6,7,8]. Such stimuli trigger series of electrical brain reactions, some of which can be detected on the electroencephalogram (EEG) [9,10]. ...
... In stark contrast to the behavior of all other brain reactions, the reaction initiated by the laser and to eventrelated desynchronization (ERD) starting about 500 ms after the stimulus triggered and centered alpha rhythm zone (8)(9)(10)(11)(12), was not correlated with the perception intensity, not affected by the stimulus repetition [6]. It was shown that the magnitude of fluctuations in alpha rhythms varies depending on sensory, motor and cognitive operations [11]. ...
... The laser stimulus activates the nociceptive system by a completely selective way [7,8], these responses most effectively reflect the nervous processes, but are triggered by any significant stimulus that occurs in the sensory environment, regardless of its sensory modality. ...
... Ultra-short laser stimulation with a carbon dioxide (CO 2 ) laser meets these criteria and has been used to induce selective activation of C-fibres in humans [3][4][5], mainly based on different thermal thresholds of Aδ-and C-fibre nociceptors. It has also been used to evoke separate pain responses mediated by Aδ-and C-fibres [3,[5][6][7][8][9], based on differences in nociceptive response latency and neuronal conduction velocity, and assessed by visual analogue scale (VAS) scoring [8,10], in humans. ...
... Our approximately one-second difference in time latency between the first and second pain responses strengthens their likelihood of reflecting Aδ-and C-fibre mediated transmission of pain [3,7,16], respectively, corresponding to levels of neuronal conduction velocity estimated at 11-19 [3,[15][16][17] versus 0.7-1.5 [3, 6, 13, 15, 16] m/s. Hence, the short-lasting pulses of laser stimulation used in the present and previous [3, [5][6][7][8][9] studies allow both pain components to be independently evaluated, provided that the temperature thresholds of Aδ-and C-fibre nociceptors are both exceeded. Higher separation in time between the first and second pain responses is achieved by inducing pain in the foot, as done in the present and previous [3,7,16] studies, instead of in the hand [1, 4-6, 8-10, 14, 15, 18, 19], considering the up to 35% more delayed transmission of second (C-fibre mediated) pain along the estimated 80-100 cm axonal distance between the plantar arc and the lumbosacral spinal cord [3,7,16]. ...
... Results reported here were obtained in more study participants compared with most previous studies based on laser-induced pain [1,[3][4][5][6][7][8][9][10]14], except for two previous [16,18] and one recent [19] studies in similar numbers of subjects. The risk for carry-over effects was reduced by allowing minute-long time intervals between stimulations to avoid overlapping of subsequent pain responses. ...
Background
This preclinical study in humans was designed to selectively induce delayed nociceptive pain responses to individually titrated laser stimulation, enabling separate bedside intensity scoring of both immediate and delayed pain.
Methods
Forty-four (fourteen female) healthy volunteers were subjected to repeated nociceptive dermal stimulation in the plantar arc, based on ultra-short carbon dioxide laser with individually titrated energy levels associated with mild pain.
Results
Data was analysed in 42 (12 female) subjects, and 29 of them (11 females) consistently reported immediate and delayed pain responses at second-long intervals to each nociceptive stimulus. All single pain responses were delayed and associated with lower levels (p = 0.003) of laser energy density (median 61; IQR 54–71 mJ/mm²), compared with double pain responses (88; 64–110 mJ/mm²). Pain intensity levels associated with either kind of response were readily assessable at bedside.
Conclusions
This study is the first one to show in humans that individually titrated ultra-short pulses of laser stimulation, enabling separate pain intensity scoring of immediate and delayed responses at bedside, can be used to selectively induce and evaluate delayed nociceptive pain, most likely reflecting C-fibre-mediated transmission. These findings might facilitate future research on perception and management of C-fibre-mediated pain in humans.
... Since a wide range of laser stimulators have been developed so far (most common ones described above: 1.4 Laser stimulation as a method to activate heat-gated ion channels), the results obtained from them have shown different aspects of the nociceptive pathway. Studies using laser stimulation to investigate single neuron properties in primary afferents have been performed extensively during recent decades 10,50,56,94,95,113,114,118,[127][128][129][130] . Bromm and colleagues measured microneurographic recordings of primary afferents in the radial nerve in response to laser-heat stimulation on the receptive fields of identified units and observed that the largest receptor class which was activated by CO 2 laser stimuli were polymodal Cnociceptors 114 . ...
... Studies using laser stimulation to investigate single neuron properties in primary afferents have been performed extensively during recent decades 10,50,56,94,95,113,114,118,[127][128][129][130] . Bromm and colleagues measured microneurographic recordings of primary afferents in the radial nerve in response to laser-heat stimulation on the receptive fields of identified units and observed that the largest receptor class which was activated by CO 2 laser stimuli were polymodal Cnociceptors 114 . Then, Treede and coworkers found that the sizes of mechanosensitive and heat-sensitive receptive fields of polymodal C-nociceptors in monkeys are virtually equal 10 . ...
... Studies using laser-heat as a model to investigate the nociceptive system at the dorsal horn of the spinal cord [133][134][135] , and at the brain 91,99,110,114,115,127,[136][137][138][139][140][141][142][143] , used laser with beam diameters down to 1 mm. While Devor and coworkers observed mainly that dorsal horn neurons responding to laser-heat stimuli were located in superficial and deep zones from the dorsal horn, and were able to evoke potentials through signals mediated by C-polymodal nociceptors 133 ; Sikandar and collaborators extended those observations by recordings in dorsal horn neurons in the spinal segment L4-L5 in rodents and detected response latencies to different laser intensities mediated by both C-(in all power intensities) and Aδ-fiber afferents (only at higher power intensities) 134 . ...
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.
... Evoked potentials elicited by hot nociceptive and cold stimulations were obtained by averaging epochs that did not contain ocular artifacts or eye blinks. N2 and P2 peak detection analyses were performed semiautomatically on electrode Cz, which is where the amplitude of these components reach their maximum [30,44,45]. According to previous studies [30,44,45], the N2 wave was defined as the most negative deflection between 200 and 400 ms, and the P2 wave was defined as the most positive deflection between 300 and 600 ms. ...
... N2 and P2 peak detection analyses were performed semiautomatically on electrode Cz, which is where the amplitude of these components reach their maximum [30,44,45]. According to previous studies [30,44,45], the N2 wave was defined as the most negative deflection between 200 and 400 ms, and the P2 wave was defined as the most positive deflection between 300 and 600 ms. The N2 and P2 amplitudes were summed to determine the peak-to-peak amplitudes of the N2P2 components. ...
Objective
In this study, we compared two working memory conditions to study the analgesic effect of a distraction in elderly versus young people and the effect of pain on performance on the distracting task.
Methods
Twenty-seven young and 34 old subjects performed 1- and 2-Back working memory tasks, representing low and high cognitive loads, respectively. Infrequent, brief hot nociceptive and cold non-nociceptive stimulations were delivered 100 ms prior to visual N-Back stimuli. Contact heat and cold evoked potentials were analyzed in the absence of cognitive tasks and during the N-Back tasks. We compared the pain and cold intensity ratings and reaction times in trials preceded by nociceptive and cold stimulations and in trials not preceded by thermal stimulations between groups and between N-Back conditions.
Results
In both groups, performing the 1- and 2-Back working memory tasks reduced the perceived intensity of nociceptive and cold stimuli. In elderly subjects performing 2-Back memory tasks, response times to trials following nociceptive stimulation were longer than to trials following cold or non-stimulation. By contrast, thermal stimulations had no effect on reaction times in young subjects. The amplitude of the N2P2 component was lower in the old compared to the young group in the absence of cognitive task. In the old group, N-Back tasks had no effect on the N2P2 amplitude, whereas it reduced N2P2 amplitude in the young.
Conclusion
Distraction analgesia is preserved in elderly subjects. However, this successful pain modulation seems to be accompanied by performance costs in the distracting tasks.
... The techniques used in present and previous studies regarding visuo-nociceptive interactions mostly targeted activation of the quickly responding cutaneous thermo-nociceptors that preferentially respond to phasic stimulation. Slow-adapting thinly myelinated and unmyelinated fibers were also described to respond preferentially to more tonic stimulation profiles (Bromm and Treede 1984;Meyer and Campbell 1981;Schepers and Ringkamp 2010;Treede et al. 1995Treede et al. , 1998. It might be relevant to use other stimulation techniques and procedures that preferentially activate those receptors to investigate whether multisensory interactions with thermo-nociceptive stimuli applied distantly could be facilitated by the activity of nociceptors more sensitive to sustained stimulation. ...
To protect our body against physical threats, it is important to integrate the somatic and extra-somatic inputs generated by these stimuli. Temporal synchrony is an important parameter determining multisensory interaction, and the time taken by a given sensory input to reach the brain depends on the length and conduction velocity of the specific pathways through which it is transmitted. Nociceptive inputs are transmitted through very slow conducting unmyelinated C and thinly myelinated Aδ nociceptive fibers. It was previously shown that to perceive a visual stimulus and a thermo-nociceptive stimulus applied on the hand as coinciding in time, the nociceptive stimulus must precede the visual one by 76 ms for nociceptive inputs conveyed by Aδ fibers and 577 ms for inputs conveyed by C fibers. Since spatial proximity is also hypothesized to contribute to multisensory interaction, the present study investigated the effect of spatial congruence between visual and nociceptive stimuli. Participants judged the temporal order of visual and nociceptive stimuli, with the visual stimuli flashed either next to the stimulated hand or next to the opposite unstimulated hand, and with nociceptive stimuli evoking responses mediated by either Aδ or C fibers. The amount of time by which the nociceptive stimulus had to precede the visual stimulus for them to be perceived as appearing concomitantly was smaller when the visual stimulus occurred near the hand receiving the nociceptive stimulus as compared to when it occurred near the contralateral hand. This illustrates the challenge for the brain to process the synchrony between nociceptive and non-nociceptive stimuli to enable their efficient interaction to optimize defensive reaction against physical dangers.
... 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]. ...
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.
... [138,[230][231][232][233][234]. ...
Focal vibration therapy seeks to restore the physiological function of tissues and the nervous system. Recommendations for vibration settings, e.g., that could improve residual limb health and prosthesis acceptance in people with amputation, are pending. To establish a physiological connection between focal vibration settings, clinical outcomes, and molecular and neuronal mechanisms, we combined the literature on focal vibration therapy, vibrotactile feedback, mechanosensitive Piezo ion channels, touch, proprioception, neuromodulation, and the recovery of blood vessels and nerves. In summary, intermittent focal vibration increases endothelial shear stress when applied superficially to blood vessels and tissues and triggers Piezo1 signaling, supporting the repair and formation of blood vessels and nerves. Conversely, stimulating Piezo1 in peripheral axon growth cones could reduce the growth of painful neuromas. Vibrotactile feedback also creates sensory inputs to the motor cortex, predominantly through Piezo2-related channels, and modulates sensory signals in the dorsal horn and ascending arousal system. Thus, sensory feedback supports physiological recovery from maladaptations and can alleviate phantom pain and promote body awareness and physical activity. We recommend focal vibration of phantom limb maps with frequencies from ~60–120 Hz and amplitudes up to 1 mm to positively affect motor control, locomotion, pain, nerves, and blood vessels while avoiding adverse effects.
... Briefly, noxious stimuli applied in the periphery results in activation in nociceptors and the recruitment of small and thinly myelinated afferents, which synapse in the dorsal horn of the spinal cord before ascending via the spinothalamic tract to supraspinal structures (3,4). Assessed in the time domain, nociceptive-evoked potentials consist of three main components: an early negative response (N1), maximal over the contralateral central-temporal region (5), and a biphasic negative-positive wave form (N2P2) detected maximally at the scalp vertex (6). Although the amplitude of evoked potentials elicited by nociceptive stimuli are correlated with subjective pain reports, these responses are now widely regarded as reflecting nonpain-specific aspects of somatosensory processing (e.g., stimulus saliency) (7,8). ...
Painful contact heat and laser stimulation offer an avenue to characterize nociceptive pathways involved in acute pain processing, by way of evoked potentials. Direct comparisons of radiant laser and contact heat are limited, particularly in context of examining time-frequency responses to stimulation. This is important in light of recent evidence to suggest that gamma band oscillations (GBOs) represent a functionally heterogeneous measure of pain. The purpose of the current study was to investigate differences in GBOs generated in response to laser and contact heat stimulation of the non-dominant forearm. Following intensity matching to pain ratings, evoked electroencephalography (EEG) responses to laser and contact heat stimulation were examined in the time-frequency domain in the same participants (19 healthy adults) across two sessions. At approximately 200ms, both contact heat and laser stimulation resulted in significant, group-level event related synchronization (ERS) in the low gamma band (i.e., 30 to 60Hz) in central electrode locations (Cc, Cz, Ci). Laser stimulation also generated ERS in the 60 to 100Hz range (i.e., high gamma), at approximately 200ms, while contact heat led to a significant period of desynchronization in the high gamma range between 400 and 600ms. Both contact heat and laser GBOs were stronger on the central electrodes contralateral to the stimulated forearm, indicative of primary somatosensory cortex involvement. Based on our findings, and taken in conjunction with previous studies, laser and contact heat stimulation generate characteristically different responses in the brain, with only the former leading to high frequency GBOs characteristic of painful stimuli.
... The laser beam was set at a diameter of $7 mm by focusing lenses connected to the optic fiber, with a fixed stimulus intensity of 3.5 J to elicit a painful pinprick sensation (Bromm & Treede, 1984). To prevent nociceptor fatigue or sensitization, the laser beam target was manually shifted by about 1 cm in a random direction after each stimulus (Jin et al., 2018). ...
Studies on functional and structural changes in the primary somatosensory cortex (S1) have provided important insights into neural mechanisms underlying several chronic pain conditions. However, the role of S1 plasticity in postherpetic neuralgia (PHN) remains elusive. Combining psychophysics and magnetic resonance imaging (MRI), we investigated whether pain in PHN patients is linked to S1 reorganization as compared with healthy controls. Results from voxel-based morphometry showed no structural differences between groups. To characterize functional plasticity, we compared S1 responses to noxious laser stimuli of a fixed intensity between both groups and assessed the relationship between S1 activation and spontaneous pain in PHN patients. Although the intensity of evoked pain was comparable in both groups, PHN patients exhibited greater activation in S1 ipsilateral to the stimulated hand. Pain-related activity was identified in contralateral superior S1 (SS1) in controls as expected, but in bilateral inferior S1 (IS1) in PHN patients with no overlap between SS1 and IS1. Contralateral SS1 engaged during evoked pain in controls encoded spontaneous pain in patients, suggesting functional S1 reorganization in PHN. Resting-state fMRI data showed decreased functional connectivity between left and right SS1 in PHN patients, which scaled with the intensity of spontaneous pain. Finally, multivariate pattern analyses (MVPA) demonstrated that BOLD activity and resting-state functional connectivity of S1 predicted within-subject variations of evoked and spontaneous pain intensities across groups. In summary, functional reorganization in S1 might play a key role in chronic pain related to PHN and could be a potential treatment target in this patient group.
... The CO 2 laser activates the A-delta and C-fibres at conduction velocities of~10 m/s and~1.0 m/s, respectively, producing a localized 'sharp pricking' sensation and 'diffuse' and 'burning' after-sensation [88,89]. The acute and fast activation of the A-delta fibres allowed for a precise anticipation period. ...
Striatal dopamine dysfunction is associated with the altered top-down modulation of pain processing. The dopamine D2-like receptor family is a potential substrate for such effects due to its primary expression in the striatum, but evidence for this is currently lacking. Here, we investigated the effect of pharmacologically manipulating striatal dopamine D2 receptor activity on the anticipation and perception of acute pain stimuli in humans. Participants received visual cues that induced either certain or uncertain anticipation of two pain intensity levels delivered via a CO2 laser. Rating of the pain intensity and unpleasantness was recorded. Brain activity was recorded with EEG and analysed via source localisation to investigate neural activity during the anticipation and receipt of pain. Participants completed the experiment under three conditions, control (Sodium Chloride), D2 receptor agonist (Cabergoline), and D2 receptor antagonist (Amisulpride), in a repeated-measures, triple-crossover, double-blind study. The antagonist reduced an individuals’ ability to distinguish between low and high pain following uncertain anticipation. The EEG source localisation showed that the agonist and antagonist reduced neural activations in specific brain regions associated with the sensory integration of salient stimuli during the anticipation and receipt of pain. During anticipation, the agonist reduced activity in the right mid-temporal region and the right angular gyrus, whilst the antagonist reduced activity within the right postcentral, right mid-temporal, and right inferior parietal regions. In comparison to control, the antagonist reduced activity within the insula during the receipt of pain, a key structure involved in the integration of the sensory and affective aspects of pain. Pain sensitivity and unpleasantness were not changed by D2R modulation. Our results support the notion that D2 receptor neurotransmission has a role in the top-down modulation of pain.
... The 775 exogenous source of these distal drives is currently unknown and is likely different from the ventrobasal 776 lemniscal thalamic drive inducing the initial feedforward MN response. Not only does the LE response 777begin at a greater latency from stimulation onset (~170 ms), reflecting in part that it is transmitted through 778 slow Aδ fibers from the periphery to the spinal cord(Bromm and Treede, 1984;Treede et al., 1995Treede et al., , 1988, 779 but early LE supragranular drive likely hales from non-sensory-specific ventromedial thalamus (VM) 780(Borszcz, 2006; Desbois and Villanueva, 2001; Glenn et al., 1982; Monconduit et al., 2003, 1999) or from 781 the secondary somatosensory cortex (SII) (Baumgärtner et al., 2006; Iannetti et al., 2005; Ploner et al., 782 1999; Qiu et al., 2006; Treede et al., 2003; Vierck et al., 2013). As such, the source of this initial drive may 783 ...
Magneto- and/or electro-encephalography (M/EEG) are non-invasive clinically-relevant tools that have long been used to measure electromagnetic fields in somatosensory cortex evoked by non-painful and painful somatosensory stimuli. Two commonly applied stimulation paradigms that produce distinct responses in primary somatosensory cortex (SI) linked to non-painful and painful sensations are electrical median nerve (MN) stimulation and cutaneous laser-evoked (LE) stimulation to the dorsum of the hand, respectively. Despite their prevalence, the physiological mechanisms that produce stereotypic macroscale MN and LE responses have yet to be fully articulated, limiting their utility in understanding brain dynamics associated with non-painful or painful somatosensation. We examined the neocortical circuit mechanisms contributing to MN and LE responses in SI using the Human Neocortical Neurosolver (HNN) neural modeling software tool. HNN was specifically designed for biophysically principled interpretation of the cell and circuit origin of M/EEG signals (Neymotin et al., 2020). Detailed analysis of the timing and orientation of peaks in source localized SI current dipole responses from MN and laser-evoked (LE) stimulation showed that these features were robust and conserved across prior studies. The first peak in the MN response at ∼20 ms corresponds to outward-directed deep-to-superficial electrical current flow through the cortical laminae, while the initial LE response occurs later at ∼170 ms and is oriented in the opposite direction. Historically, these peaks have both been labeled N20 and N1, despite their opposite current orientations. Simulating the cellular and circuit-level mechanisms accounting for these and later peaks with HNN’s detailed laminar neocortical column model revealed that the MN response can be simulated with a sequence of layer-specific exogenous excitatory feedforward and feedback synaptic drive. This sequence was similar to that previously reported for tactile evoked responses (Jones et al., 2007; Neymotin et al., 2020), with the novel discovery of an early excitatory feedback input to superficial layers at ∼30 ms post-stimulus that facilitated generation of the MN response’s first prominent inward-oriented deflection, known historically as the P30. Simulations of the LE response revealed that the initial ∼170 ms inward-deflection required a burst of repetitive gamma-frequency (∼40 Hz) excitatory supragranular feedback drives, consistent with prior reports of LE gamma-frequency activity. These results make novel and detailed multiscale predictions about the dynamic laminar circuit mechanisms underlying temporal and spectral features of MN and LE responses in SI, and can guide further investigations in follow-up studies. Ultimately, these findings may help with the development of targeted therapeutics for pathological somatosensation, such as chronic and neuropathic pain.
... Nociceptive heat stimulation of the skin was made with a CO 2 laser pulse (wavelength, 10.6 m; MedArt VariMed Diode Laser System, Denmark); pulse duration 20 to 32 ms, beam diameter 3.0 mm, and 5-W output power (75,76). Tactile stimulation was delivered through a handheld magnetic tactile stimulator (with onset time <2 ms from initiation). ...
The lack of satisfactory treatment for persistent pain profoundly impairs the quality of life for many patients. Stimulation of brainstem pain control systems can trigger powerful analgesia, but their complex network organi-zation frequently prevents separation of analgesia from side effects. To overcome this long-standing challenge, we developed a biocompatible gelatin-embedded cluster of ultrathin microelectrodes that enables fine-tuned, high-definition three-dimensional stimulation in periaqueductal gray/dorsal raphe nucleus in awake rats. Analgesia was assessed from both motor reactions and intracortical signals, corresponding to pain-related signals in humans. We could select an individual-specific subset of microelectrodes in each animal that reliably provided strong pain inhibition during normal and hyperalgesia conditions, without noticeable behavioral side effects. Gait, spontaneous cortical activity at rest, and cortical tactile responses were minimally affected, indicating a highly selective action. In conclusion, our developed biocompatible microelectrode cluster and stimulation paradigm reliably enabled powerful, fine-tuned, and selective analgesia without noticeable side effects.
... Research has shown that the modulation of the P2 and P3 waves reaches the maximum amplitude at the Cz site and amplitude changes in these two components are valid indicators of placeboinduced phasic pain [47,53] and empathy pain reductions [38,54]. Moreover, these studies have suggested that the ERPs' P2, N2, and P3 components reflect the activation of Aδ fibers that generate a consecutive activation of C fibers associated with the engenders of an ultralate P4 wave (400-600 ms) [55,56]. In this vein, empathy-related studies [43,[57][58][59] have suggested that the P3 component is associated with empathy pain processing. ...
This study evaluates the modulation of phasic pain and empathy for pain induced by placebo analgesia during pain and empathy for pain tasks. Because pain can be conceptualized as a dangerous stimulus that generates avoidance, we evaluated how approach and avoidance personality traits modulate pain and empathy for pain responses. We induced placebo analgesia to test whether this also reduces self-pain and other pain. Amplitude measures of the N1, P2, and P3 ERPs components, elicited by electric stimulations, were obtained during a painful control, as well as during a placebo treatment expected to induce placebo analgesia. The placebo treatment produced a reduction in pain and unpleasantness perceived, whereas we observed a decrease in the empathy unpleasantness alone during the empathy pain condition. The moderator effects of the fight-flight-freeze system (FFFS) in the relationships linking P2 and P3 amplitude changes with pain reduction were both significant among low to moderate FFFS values. These observations are consistent with the idea that lower FFFS (active avoidance) scores can predict placebo-induced pain reduction. Finally, in line with the revised Reinforcement Sensitivity Theory (r-RST), we can assume that phasic pain is an aversive stimulus activating the active-avoidance behavior to bring the system back to homeostasis.
... The R2 onset latency of these studies was approximately 70 ms. Considering the heat conduction time for laser beams to activate nociceptors (Bromm and Treede, 1984), the value appears comparable with ours. Therefore, we consider that cutaneous A-delta fibers were successfully stimulated in the present study. ...
Although conditioned pain modulation (CPM) is considered to represent descending pain inhibitory mechanisms triggered by noxious stimuli applied to a remote area, there have been no previous studies comparing CPM between pain and tactile systems. In this study, we compared CPM between the two systems objectively using blink reflexes. Intra-epidermal electrical stimulation (IES) and transcutaneous electrical stimulation (TS) were applied to the right skin area over the supraorbital foramen to evoke a nociceptive or a non-nociceptive blink reflex, respectively, in 15 healthy males. In the test session, IES or TS were applied six times and subjects reported the intensity of each stimulus on a numerical rating scale (NRS). Blink reflexes were measured using electromyography (R2). The first and second sessions were control sessions, while in the third session, the left hand was immersed in cold water at 10°C as a conditioning stimulus. The magnitude of the R2 blink and NRS scores were compared among the sessions by 2-way ANOVA. Both the NRS score and nociceptive R2 were significantly decreased in the third session for IES, with a significant correlation between the two variables; whereas, TS-induced non-nociceptive R2 did not change among the sessions. Although the conditioning stimulus decreased the NRS score for TS, the CPM effect was significantly smaller than that for IES (p = 0.002). The present findings suggest the presence of a pain-specific CPM effect to a heterotopic noxious stimulus.
... Neural correlates of pain may be studied by brief painful stimulation of the skin activating nociceptive Aδ -and/or C-fiber free nerve endings (Bromm and Treede, 1984). Cortical responses to these stimuli can be detected in the human electroencephalogram (EEG) (Inui et al., 2002;Mouraux et al., 2003) as event related potentials (ERPs). ...
Objective
Previous studies have shown increased pain scores to painful stimulation after experimental sleep restriction, but reduced or unchanged magnitude of the event related potentials (ERPs) when averaged in the time-domain. However, some studies found increased response magnitude when averaging in the time-frequency domain. The aim of this study was to determine whether ERP-latency jitter may contribute to this discrepancy.
Methods
Ninety painful electrical stimuli were given to 21 volunteers after two nights of 50% sleep restriction and after two nights of habitual sleep. ERPs were analyzed in the time-domain (N2-and P2-peaks) and time-frequency domain (power spectral density). We quantified latency jitter by the mean consecutive difference (MCD) between single-trial peak latencies and by phase locking value (PLV) across trials.
Results
P2-MCD increased from 20.4 ± 2.1 ms after habitual sleep to 24.3 ± 2.2 ms after sleep restriction (19%, p = 0.038) and PLV decreased from 0.582 ± 0.015 after habitual sleep to 0.536 ± 0.015 after sleep restriction (7.9%, p = 0.009). We found no difference for N2-MCD.
Conclusions
Our results indicate that partial sleep restriction increase latency jitter in cortical responses to experimental pain.
Significance
Latency jitter may contribute to the discrepancies between ERP-responses in the time-frequency domain and time-domain. Latency jitter should be considered when ERPs are analyzed.
... It is important to note that, even in the same condition, pain experience is not static over time within one individual, and pain perception can fluctuate from time to time 14 . Brief painful heat pulses, as generated by infrared laser stimulator, have been adopted as a selective way to activate nociceptive Aδ-and C-fiber afferents and have been widely used to assess the function of the nociceptive system in humans 15,16 . It is well known that radiant-heat laser stimuli could induce pure pain (without tactile sensation) and robust BOLD activation and deactivation in multiple brain structures, which are responsible for the processing of the sensory, cognitive, and affective components of pain 17 . ...
Pain perception is a subjective experience and highly variable across time. Brain responses evoked by nociceptive stimuli are highly associated with pain perception and also showed considerable variability. To date, the test–retest reliability of laser-evoked pain perception and its associated brain responses across sessions remain unclear. Here, an experiment with a within-subject repeated-measures design was performed in 22 healthy volunteers. Radiant-heat laser stimuli were delivered on subjects’ left-hand dorsum in two sessions separated by 1–5 days. We observed that laser-evoked pain perception was significantly declined across sessions, coupled with decreased brain responses in the bilateral primary somatosensory cortex (S1), right primary motor cortex, supplementary motor area, and middle cingulate cortex. Intraclass correlation coefficients between the two sessions showed “fair” to “moderate” test–retest reliability for pain perception and brain responses. Additionally, we observed lower resting-state brain activity in the right S1 and lower resting-state functional connectivity between right S1 and dorsolateral prefrontal cortex in the second session than the first session. Altogether, being possibly influenced by changes of baseline mental state, laser-evoked pain perception and brain responses showed considerable across-session variability. This phenomenon should be considered when designing experiments for laboratory studies and evaluating pain abnormalities in clinical practice.
... The power output of the laser was adjusted to raise the target skin temperature to 62.5 °C in 10 ms and to maintain this temperature for 40 ms. This target temperature was chosen as it was previously shown to be always perceived as clearly painful and pricking 3,4 , and detected with reaction times compatible with the conduction velocity of A-delta fiber nociceptors 38 . To prevent nociceptor fatigue or sensitization, the laser beam was manually displaced after each stimulus 39 . ...
Brief thermo-nociceptive stimuli elicit low-frequency phase-locked local field potentials (LFPs) and high-frequency gamma-band oscillations (GBOs) in the human insula. Although neither of these responses constitute a direct correlate of pain perception, previous findings suggest that insular GBOs may be strongly related to the activation of the spinothalamic system and/or to the processing of thermal information. To disentangle these different features of the stimulation, we compared the insular responses to brief painful thermonociceptive stimuli, non-painful cool stimuli, mechano-nociceptive stimuli, and innocuous vibrotactile stimuli, recorded using intracerebral electroencephalograpic activity in 7 epileptic patients (9 depth electrodes, 58 insular contacts). All four types of stimuli elicited consistent low-frequency phase-locked LFPs throughout the insula, possibly reflecting supramodal activity. The latencies of thermo-nociceptive and cool low-frequency phase-locked LFPs were shorter in the posterior insula compared to the anterior insula, suggesting a similar processing of thermal input initiating in the posterior insula, regardless of whether the input produces pain and regardless of thermal modality. In contrast, only thermo-nociceptive stimuli elicited an enhancement of insular GBOs, suggesting that these activities are not simply related to the activation of the spinothalamic system or to the conveyance of thermal information.
... Therefore, it is an ideal method to investigate somatosensory processing during experimental nociceptive stimulation paradigms. So-called event-related potential (ERP) recordings, where EEG signals are recorded in response to specific stimuli and characterized by a latency and amplitude, are typically used for these evaluations, as these are accepted as a gold standard in the assessment of the global integrity of the nociceptive system [30][31][32][33][34]. The assessment of the global integrity of the nociceptive system is especially valuable in case of neuropathic pain mechanisms, whereas in nociplastic pain mechanisms, ERP analyses are used to elucidate the functionality of the nociceptive pathways and central nervous system. ...
Background
With its high temporal resolution, electroencephalography (EEG), a technique that records electrical activity of cortical neuronal cells, is a potentially suitable technique to investigate human somatosensory processing. By using EEG, the processing of (nociceptive) stimuli can be investigated, along with the functionality of the nociceptive pathway. Therefore, it can be applied in chronic pain patients to objectify whether changes have occurred in nociceptive processing. Typically, so-called event-related potential (ERP) recordings are used, where EEG signals are recorded in response to specific stimuli and characterized by latency and amplitude.
Objective
To summarize whether differences in somatosensory processing occur between chronic pain patients and healthy controls, measured with ERPs, and determine whether this response is related to the subjective pain intensity.
Design
Systematic review.
Setting and Methods
PubMed, Web of Science, and Embase were consulted, and 18 case–control studies were finally included.
Subjects
The chronic pain patients suffered from tension-type headache, back pain, migraine, fibromyalgia, carpal tunnel syndrome, prostatitis, or complex regional pain syndrome.
Results
Chronic neuropathic pain patients showed increased latencies of the N2 and P2 components, along with a decreased amplitude of the N2-P2 complex, which was also obtained in FM patients with small fiber dysfunction. The latter also showed a decreased amplitude of the N2-P3 and N1-P1 complex. For the other chronic pain patients, the latencies and the amplitudes of the ERP components did not seem to differ from healthy controls. One paper indicated that the N2-P3 peak-to-peak amplitude correlates with the subjective experience of the stimulus.
Conclusions
Differences in ERPs with healthy controls can mostly be found in chronic pain populations that suffer from neuropathic pain or where fiber dysfunction is present. In chronic pain populations with other etiological mechanisms, limited differences were found or agreed upon across studies.
... Critical roles for peripheral nociceptors in driving conscious pain have been demonstrated conclusively in humans. Nociceptor activity evoked in human volunteers by noxious cutaneous stimuli is correlated with pain (e.g., Bromm and Treede, 1984;Van Hees and Gybels, 1972;Wiesenfeld-Hallin et al., 1984). Moreover, selective electrical stimulation of nociceptor fibers is sufficient to produce pain in humans (Ochoa and Torebjörk, 1989). ...
Synopsis
Functional and mechanistic studies of nociception and pain are reviewed, focusing on the few species in which the same type of neuron – the primary nociceptor – has been investigated in two or more phyla. Findings from selected species in five different phyla show that nociceptors transduce noxious stimuli using highly conserved ion channels, eliciting similar immediate nocifensive behavior and sometimes long-lasting sensitization. Nociceptive sensitization is known to be evolutionarily adaptive, and some of the underlying cell signaling mechanisms are shared across phyla. Far more is known about sensory aspects of nociception than the motivational-affective aspects, especially in non-mammalian species.
... Since this simultaneous activation raises inhibitory mechanisms at both cortical [210] and spinal [211,212] level, galvanic stimuli are not suitable to evoke brain responses specifically related to the nociceptive input. As demonstrated by an early microneurographic study, laser pulses applied on the hairy skin stimulate the thin myelinated (Aδ) and the unmyelinated (C) fibers selectively, without a concurrent activation of the non-nociceptive Aβ fibers [213]. The main LEP component is represented by a negative/positive complex (N2/P2), widely distributed over the scalp and reaching its maximal amplitude at the vertex. ...
Event-related potentials (ERPs) are obtained from the electroencephalogram (EEG) or the magnetoencephalogram (MEG, event-related fields (ERF)), extracting the activity that is time-locked to an event. Despite the potential utility of ERP/ERF in cognitive domain, the clinical standardization of their use is presently undefined for most of procedures. The aim of the present review is to establish limits and reliability of ERP medical application, summarize main methodological issues, and present evidence of clinical application and future improvement. The present section of the review focuses on well-standardized ERP methods, including P300, Contingent Negative Variation (CNV), Mismatch Negativity (MMN), and N400, with a chapter dedicated to laser-evoked potentials (LEPs). One section is dedicated to proactive preparatory brain activity as the Bereitschaftspotential and the prefrontal negativity (BP and pN). The P300 and the MMN potentials have a limited but recognized role in the diagnosis of cognitive impairment and consciousness disorders. LEPs have a well-documented usefulness in the diagnosis of neuropathic pain, with low application in clinical assessment of psychophysiological basis of pain. The other ERP components mentioned here, though largely applied in normal and pathological cases and well standardized, are still confined to the research field. CNV, BP, and pN deserve to be largely tested in movement disorders, just to explain possible functional changes in motor preparation circuits subtending different clinical pictures and responses to treatments.
... A He-Ne laser pointed to the area to be stimulated. The laser beam was set at a diameter of~7 mm by focusing lenses connected to the optic fiber, with a fixed stimulus intensity of 3.5 J to elicit a painful pinprick sensation (Bromm & Treede, 1984). To prevent fatigue or sensitization of the nociceptors, the laser beam target was manually shifted by at least 1 cm in a random direction after each stimulus. ...
Clinical observations showed that schizophrenia (SCZ) patients reported little or no pain under various conditions that are commonly associated with intense painful sensations, leading to a higher risk of morbidity and mortality. However, this phenomenon has received little attention and its underlying neural mechanisms remain unclear. Here, we conducted two experiments combining psychophysics, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI) techniques to investigate neural mechanisms of pain insensitivity in SCZ patients. Specifically, we adopted a stimulus-response paradigm with brief stimuli of different sensory modalities (i.e., nociceptive, non-nociceptive somatosensory, and auditory) to test whether pain insensitivity in SCZ patients is supra-modal or modality-specific, and used EEG and fMRI techniques to clarify its neural mechanisms. We observed that perceived intensities to nociceptive stimuli were significantly smaller in SCZ patients than healthy controls, whereas perceived intensities to non-nociceptive somatosensory and auditory stimuli were not significantly different. The behavioral results were confirmed by stimulus-evoked brain responses sampled by EEG and fMRI techniques, thus verifying the modality-specific nature of the modulation of nociceptive information processing in SCZ patients. Additionally, significant group differences were observed in the spectral power of alpha oscillations in prestimulus EEG and the seed-based functional connectivity in resting-state fMRI (seeds: the thalamus and periaqueductal gray that are key nodes in ascending and descending pain pathways respectively), suggesting a possible contribution of cortical-subcortical dysfunction to the phenomenon. Overall, our study provides insight into the neural mechanisms of pain insensitivity in SCZ and highlights a need for systematic assessments of their pain-related diseases.
... At this wavelength, the laser pulses activate directly nociceptive terminals in the most superficial skin layers. 26,27 The laser beam was transmitted via an optic fiber and its diameter was set at approximately 7 mm (~38 mm 2 ) by focusing lenses. Laser pulses were delivered to a circular area (diameter = 4 cm) on the dorsum of participants' left hands. ...
Background
Music is sometimes used as an adjunct to pain management. However, there is limited understanding of by what means music modulates pain perception and how the brain responds to nociceptive inputs while listening to music, because clinical practice typically involves the coexistence of multiple therapeutic interventions. To address this challenge, laboratory studies with experimental and control conditions are needed.
Methods
In the present investigation, we delivered nociceptive laser stimuli on 30 participants under three conditions – participants were sitting in silence, listening to their preferred music, or listening to white noise. Differences among conditions were quantified by self-reports of pain intensity and unpleasantness, and brain activity sampled by electroencephalography (EEG).
Results
Compared with the noise and silence conditions, participants in the music condition reported lower ratings on pain unpleasantness, as reflected by reduced brain oscillations immediately prior to the nociceptive laser stimulus at frequencies of 4–15 Hz in EEG. In addition, participants showed smaller P2 amplitudes in laser-evoked potentials (LEPs) when they were listening to music or white noise in comparison to sitting in silence. These findings suggest that a general modulation effect of sounds on pain, with a specific reduction of pain unpleasantness induced by the positive emotional impact.
Conclusion
Music may serve as a real-time regulator to modulate pain unpleasantness. Results are discussed in view of current understandings of music-induced analgesia.
... A reliable laboratory tool for assessing human nociceptive pathways is laser evoked potential (LEP) recording (Cruccu et al., 2010). Laser stimulation excites the free nerve endings (A-δ and C fibres) in the superficial skin layers, without any involvement of Aβ fibres (Bromm & Treede, 1984), and generates the LEPs by Aδ-fibre input (Valeriani, Pazzaglia, Cruccu, & Truini, 2012). LEP recording represents the most reliable neurophysiological method to assess the nociceptive pathways . ...
Background:
Non-coding RNAs (lncRNAs) are a group of non-coding RNAs that act as regulators of gene expression; they are implicated in various human diseases and have been reported to be involved in the modulation of pain. We aimed to study whether: (a) lncRNAs modifications could be found in an experimental model of pain; (b) there was a correlation between lncRNA changes and laser evoked potential (LEP) amplitude/laser-pain rating.
Methods:
Laser evoked potentials were recorded from 11 healthy subjects to both left hand and perioral region stimulation. Three consecutive averages were calculated for each stimulation site in order to investigate the LEP amplitude habituation. Blood samples were obtained immediately before LEP recording (pre-pain) and 30-min after the recording of the last LEP average (post-pain). Eighty-four lncRNAs, involved in autoimmunity and human inflammatory response, were screened. The criteria used for lncRNAs analysis were fold change >2 and p < .05. By Real-Time PCR, we identified two lncRNAs up-regulated at the post-pain time, as compared to the pre-pain time: RP11-819C21.1 (fold change = 8.2; p = .038) and ZNRD1 antisense RNA 1 non-protein coding (ZNRD1-AS; fold change = 6.3; p = .037).
Results:
The ZNRD1-AS up-regulation was directly correlated with the N1 amplitude, while the RP11-819C21.1 increase after pain showed a correlation with the reduced N2/P2 amplitude and laser-pain habituation.
Conclusion:
IncRNA changes in a human experimental phasic pain model. The correlation between lncRNA changes and LEP amplitude and habituation suggests that RP11-819C21.1 and ZNRD1-AS could be involved in the pathophysiology of painful diseases characterized by abnormal excitability of the cerebral cortex.
Significance:
Long non-coding RNAs are upregulated after experimental pain. RP11-819C21.1 and ZNRD1 could be involved in the pathophysiology of diseases characterized by reduced habituation to pain.
... Laser-evoked potential (LEP) recording represents the most reliable neurophysiological technique to assess the human nociceptive system function (evidence level A) [10]. CO 2 laser pulses delivered on the skin activate the nociceptive Aδ and C fibers, without any stimulation of the nonnociceptive Aβ afferents [11]. ...
Restless legs syndrome (RLS) is characterized by unpleasant sensations generally localized to legs, associated with an urge to move. A likely pathogenetic mechanism is a central dopaminergic dysfunction. .e exact role of pain system is unclear. .e purpose of the study was to investigate the nociceptive pathways in idiopathic RLS patients. We enrolled 11 patients (mean age 53.2 ± 19.7 years; 7 men) suffering from severe, primary RLS. We recorded scalp laser-evoked potentials (LEPs) to stimulation of different sites (hands and feet) and during two different time conditions (daytime and nighttime). Finally, we compared the results with a matched control group of healthy subjects. .e Aδ responses obtained from patients did not differ from those recorded from control subjects. However, the N1 and the N2-P2 amplitudes' night/day ratios after foot stimulation were increased in patients, as compared to controls (N1: patients: 133.91 ± 50.42%; controls: 83.74 ± 34.45%; p � 0.016; Aδ-N2-P2: patients: 119.15 ± 15.56%; controls: 88.42 ± 23.41%; p � 0.003). .ese results suggest that RLS patients present circadian modifications in the pain system, which are not present in healthy controls. Both sensory-discriminative and affective-emotional components of pain experience show parallel changes. .is study confirms the structural integrity of Aδ nociceptive system in idiopathic RLS, but it also suggests that RLS patients present circadian modifications in the pain system. .ese findings could potentially help clinicians and contribute to identify new therapeutic approaches.
... Rapidly conducting, thickly myelinated cutaneous afferents constitute the A group, whereas slowly conducting, thinly myelinated or unmyelinated afferents belong to the A and C groups, respectively (2,3). In humans, all cutaneous A afferents are considered to exclusively signal the discriminative aspects of touch, whereas A and C afferents signal pain ("fast" and "slow" pain, respectively) in addition to temperature and affective touch sensations (4)(5)(6)(7)(8). Consistently, the consensus protocol for somatosensory testing in neuropathic pain (9) recommends that the assessment of vibration and punctate touch reflects the functions of A afferents, whereas the assessment of mechanical pain and temperature reflects the functions of A and C afferents. ...
The canonical view is that touch is signaled by fast-conducting, thickly myelinated afferents, whereas pain is signaled by slow-conducting, thinly myelinated ("fast" pain) or unmyelinated ("slow" pain) afferents. While other mammals have thickly myelinated afferents signaling pain (ultrafast nociceptors), these have not been demonstrated in humans. Here, we performed single-unit axonal recordings (microneurography) from cutaneous mechanoreceptive afferents in healthy participants. We identified A-fiber high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and displayed conduction velocities similar to A-fiber low-threshold mechanoreceptors. Intraneural electrical stimulation of single ultrafast A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed impaired pain judgments to graded mechanical stimuli only when thickly myelinated fibers were absent. This function was preserved in patients with a loss-of-function mutation in mechanotransduction channel PIEZO2. These findings demonstrate that human mechanical pain does not require PIEZO2 and can be signaled by fast-conducting, thickly myelinated afferents.
... CHEPs represent pain-related brain activity associated with synchronized activation of A-delta fibers to intense heat stimuli, although C-nociceptive fibers are also activated during heat stimulation (Kramer et al. 2012). A preferential A-fiber block is required to isolate EEG activity related to C-fiber responses (Bromm and Treede 1984). Cognitive mechanisms can also modulate the early components of LEP (Legrain et al. 2002). ...
Background and objectives
Pain is a complex experience involving both nociceptive and affective–cognitive mechanisms. The present study evaluated whether modulation of pain perception, employing a conditioned pain modulation (CPM) paradigm, is paralleled by changes in contact heat-evoked potentials (CHEPs), a brain response to nociceptive stimuli.
Methods
Participants were 25 healthy, pain-free, college students (12 males, 13 females, mean age 19.24 ± 0.97 years). Twenty computer-controlled heat stimuli were delivered to the non-dominant forearm and CHEPs were recorded at Cz using a 32-channel EEG system. After each stimulus, participants rated the intensity of the heat pain using the 0–100 numerical rating scale. The latency and amplitude of N2, P2 components as well as single-sweep spectral analysis of individual CHEPs were measured offline. For CPM, participants had to submerge their dominant foot into a neutral (32 °C) or noxious (0 °C) water bath. CHEPs and heat pain ratings were recorded in 3 different conditions: without CPM, after neutral CPM (32 °C) and after noxious CPM (0 °C).
Results
The noxious CPM induced a facilitatory pain response (p = 0.001) with an increase in heat pain following noxious CPM compared to neutral CPM (p = 0.001) and no CPM (p = 0.001). Changes in CHEPs did not differ between conditions when measured as N2–P2 peak-to-peak amplitude (p = 0.33) but the CPM significantly suppressed the CHEPs-related delta power (p = 0.03). Changes in heat pain in the noxious CPM were predicted by trait catastrophizing variables (p = 0.04).
Conclusion
The current study revealed that pain facilitatory CPM is related to suppression of CHEPs delta power which could be related to dissociation between brain responses to noxious heat and pain perception.
... A reliable laboratory tool for assessing human nociceptive pathways is laser evoked potential (LEP) recording (Cruccu et al., 2010). Laser stimulation excites the free nerve endings (A-δ and C fibres) in the superficial skin layers, without any involvement of Aβ fibres (Bromm & Treede, 1984), and generates the LEPs by Aδ-fibre input (Valeriani, Pazzaglia, Cruccu, & Truini, 2012). LEP recording represents the most reliable neurophysiological method to assess the nociceptive pathways . ...
Long non-coding RNAs (lncRNAs) are a group of 200 nucleotides acting as regulators of gene expression implicated in various diseases such as cancer, cardiovascular diseases, autoimmune and neurodegenerative disorders. Moreover, lncRNAs are involved in pain modulation. We recorded LEPs in order to study: (1) lncRNAs modifications in experimental pain model; (2) correlation between the lncRNA changes and objective measure of pain perception. LEPs were recorded in 12 healthy subjects after hand and perioral region stimulation. Three consecutive series were recorded for each stimulation site in order to investigate the habituation. Blood samples were obtained immediately before LEP recording (baseline) and after 30-min (post-pain). We screened 84 lncRNAs, involved in autoimmunity and inflammatory response.
Two lncRNAs were up-regulated after pain: RP11-819C21.1 (fold change = 8.2; p = 0.038) and ZNRD1 antisense-RNA1 non-protein coding (ZNRD1-AS) (fold change = 6.3; p = 0.037). lncRNAs up-regulated showed a significant positive correlation with perioral LEP habituation (p = 0.04 and p = 0.01, respectively). This is the first study showing lncRNA changes in a pain experimental model. RP11-819C21.1 and ZNRD1-AS shows as direct target miR-19a andmiR19b, a class of microRNAs involved in modulation of multiple potassium channel α-subunits. lncRNAs could be involved in the pathophysiology of painful diseases characterized by reduced habituation to pain.
... Los láseres de CO 2 fueron los primeros láseres utilizados para estos fines, 2 aunque otros tipos de láseres pueden ser utilizados para provocar sensaciones de dolor y temperatura. 3 Si el haz de un láser de CO 2 de apropiada energía y duración de pulso ilumina la piel de un sujeto sano, él sentirá un "pinchazo" seguido de una sensación de quemadura, lo que corresponde a la excitación de las fibras nerviosas δ A y C, cuyas terminaciones se encuentran en la epidermis basal. El potencial eléctrico de acción resultante puede ser recogido mediante microelectrodos, pero es más fácil la recogida de potenciales eléctricos cerebrales sobre el cuero cabelludo. ...
Los dolorímetros láser son un tipo de estimulador que se emplea para investigar clínicamente desórdenes de las fibras nerviosas Aδ y C. Ellos no se producen comercialmente. En el trabajo se analizan las principales insuficiencias de los dolorímetros láser reportados en la literatura. Se describe el dolorímetro láser Estimulas 2, con énfasis en su bloque de control. Se analizan los criterios técnicos aplicados al diseño de este dolorímetro, que permiten que esté libre de las deficiencias de dolorímetros anteriores. Se muestran los potenciales evocados láser por dolor obtenidos con este dolorímetro.
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.
Magneto- and/or electro-encephalography (M/EEG) are non-invasive clinically relevant tools that have long been used to measure electromagnetic fields in the somatosensory cortex evoked by innocuous and noxious somatosensory stimuli. Two commonly applied stimulation paradigms that produce distinct responses in the primary somatosensory cortex (SI) linked to innocuous and noxious sensations are electrical median nerve (MN) stimulation and cutaneous laser-evoked (LE) stimulation to the dorsum of the hand, respectively. Despite their prevalence, the physiological mechanisms that produce stereotypic macroscale MN and LE responses have yet to be fully articulated, limiting their utility in understanding brain dynamics associated with non-painful and/or painful somatosensation. Through a literature review, we detailed features of MN and LE responses source-localized to SI that are robust and reproducible across studies. We showed that the first peak in the MN response at ~20 ms post-stimulus (i.e., MN N1) corresponds to upward-directed deep-to-superficial electrical current flow through the cortical laminae, which is followed by downward-directed current at ~30 ms (i.e., MN P1). In contrast, the initial LE response occurs later at ~170 ms (i.e., LE N1) and is directed downward and opposite the direction of the MN N1. We then examined the neocortical circuit mechanisms contributing to the robust features of each response using the Human Neocortical Neurosolver (HNN) neural modeling software tool (Neymotin et al., 2020). Using HNN as a hypothesis development and testing tool, model results predicted the MN response can be simulated with a sequence of layer-specific thalamocortical and cortico-cortical synaptic drive similar to that previously reported for tactile evoked responses (S. R. Jones et al., 2007; Neymotin et al., 2020), with the novel discovery that an early excitatory input to supragranular layers at ~30 ms is an essential mechanism contributing to the downward current flow of the MN P1. Model results further predicted that the initial ~170 ms downward current flow of the LE N1 was generated by a burst of repetitive gamma-frequency (~40 Hz) excitatory synaptic drive to supragranular layers, consistent with prior reports of LE gamma-frequency activity. These results make novel and detailed multiscale predictions about the dynamic laminar circuit mechanisms underlying temporal and spectral features of MN and LE responses in SI and can guide further investigations in follow-up studies. Ultimately, these findings may help with the development of targeted therapeutics for pathological somatosensation, such as somatic sensitivity and acute neuropathic pain.
Introduction
Pain is frequently accompanied by enhanced arousal and hypervigilance to painful sensations. Here, we describe our findings in an experimental vigilance task requiring healthy participants to indicate when randomly timed moderately painful stimuli occur in a long train of mildly painful stimuli.
Methods
During a continuous performance task with painful laser stimuli (CPTpain), 18 participants rated pain intensity, unpleasantness, and salience. We tested for a vigilance decrement over time using classical metrics including correct targets (hits), incorrectly identified non-targets (false alarms), hit reaction time, and false alarm reaction time. We measured state anxiety and tense arousal before and after the task.
Results
We found a vigilance decrement across four 12.5-minute blocks of painful laser stimuli in hits [F3,51=2.91; p=0.043; time block 1>block 4 (t=2.77; p=0.035)]. Both self-report state anxiety (tpaired,17=3.34; p=0.0039) and tense arousal (tpaired,17=3.20; p=0.0053) increased after the task. We found a vigilance decrement during our laser pain vigilance task consistent with vigilance decrements found in other stimulus modalities. Furthermore, state anxiety positively correlated with tense arousal.
Discussion
CPTpain acutely increased tense arousal and state anxiety, consistent with previous results implicating the reciprocal interaction of state anxiety and acute painful sensations and the role of pain in augmenting tense arousal. These results may indicate a psychological process which predisposes the hypervigilant to developing greater acute pain, resulting in positive feedback, greater pain and anxiety.
Laser-evoked brain potentials (LEPs) are brain responses elicited by the brief activation of heat-sensitive skin nociceptors and their spinothalamic projections. LEPs are currently the best-available clinical tool to assess spinothalamic function. An additional clinical tool for the assessment of small sensory nerve fiber function is offered by the contact heat evoked potential stimulator (CHEPS); it provides a clinically practical, noninvasive, and objective measure and can be a useful additional tool for the assessment of sensory small-fiber neuropathy. Another objective method for the evaluation of the nociceptive system is represented by the recording of pain-related evoked potentials (PREPs). The skin afferents are transcutaneously excited by a concentric electrode that produces a high current density at low current intensities. Therefore, the depolarization of nociceptive fibers is limited to the superficial layer of the dermis and does not reach the deeper layers that predominantly excite Aβ fibers.
All these neurophysiological techniques cause nociceptive stimulations which are registered by the scalp in the form of EEG. It is possible to improve the study of the nociceptive system by looking at other EEG features induced by noxious stimuli. Actually, most EEG studies examining pain processing using laser stimuli have examined the components of laser-evoked potential (LEP). Knowledge of pain processing mechanisms can be improved with new methods that can detect subtle changes in EEG rhythms through painful stimulation. Brain network analysis may give an aid in understanding subtle changes of pain processing under laser stimuli in patients with neuropathic pain. The study of the dynamical relationships between signals recorded at different scalp locations can help to confirm and formulate hypotheses on the physiological mechanisms related to stimuli processing.
Previous studies on the potential effects of unpredictability on pain perception and its neural correlates yielded divergent results. This study examined whether this may be explained by differences in acquired expectations. We presented 41 healthy volunteers with laser heat stimuli of different intensities. The stimuli were preceded either by predictable low, medium, or high cues or by unpredictable low–medium, medium–high, or low–high cues. We recorded self-reports of pain intensity and unpleasantness and laser-evoked potentials (LEPs). Furthermore, we investigated whether dynamic expectations that evolved throughout the experiment based on past trials were better predictors of pain ratings than fixed (nonevolving) expectations. Our results replicate previous findings that unpredictable pain is higher than predictable pain for low-intensity stimuli but lower for high-intensity stimuli. Moreover, we observed higher ratings for the medium–high unpredictable condition than the medium–low unpredictable condition, in line with an effect of expectation. We found significant interactions (N1, N2) for the LEP components between intensity and unpredictability. However, the few significant differences in LEP peak amplitudes between cue conditions did not survive correction for multiple testing. In line with predictive coding perspectives, pain ratings were best predicted by dynamic expectations. Surprisingly, expectations of reduced precision (increased variance) were associated with lower pain ratings. Our findings provide strong evidence that (dynamic) expectations contribute to the opposing effects of unpredictability on pain perception; therefore, we highlight the importance of controlling for them in pain unpredictability manipulations. We also suggest to conceptualize pain expectations more often as dynamic constructs incorporating previous experiences.
The clinical investigation of the skin sensory function is well codified. For long, a cotton pad, a needle, a diapason (100 or 128 Hz), hot or cold water have been the main tools used by clinicians. Pieces of different fabrics or other various objects in metal, wood, or plastic which can be calibrated can also be used. It is then possible to investigate the perception of shapes, weights and textures. However these tools are not standardised and their main drawback is their selection by the investigator. Quantitative exploration, more adapted to clinical research and psychophysiology, requires several standardised and reproducible techniques which necessitate a more costly and complicated equipment.
Spinal cord stimulation (SCS) and external low-frequency peripheral nerve stimulation (LFS) are palliative neurostimulation interventions for intractable neuropathic pain. However, understanding of the neural mechanisms underlying SCS and LFS is limited. Neurostimulation parameters such as waveform type and intensity modulate peripheral and central nociceptive pathways, which influence their therapeutic effects. The current thesis aimed to investigate the effects of varying intensities of burst and tonic SCS on resting cortical oscillations and somatosensory processing, and the temporal dynamics of LFS on somatosensory processing. Effects of SCS on oscillatory dynamics were assessed in patients using burst and tonic SCS for neuropathic leg pain. Spontaneous resting oscillations and event-related desynchronisation during brushing of a pain-free leg were examined at four SCS intensities. Temporal effects of LFS applied to the radial nerve were examined using source dipole modelling in healthy volunteers at varying intensities. Change in resting EEG and nociceptive processing were investigated after LFS. Results of four empirical studies pointed towards intensity-related changes in cortical activation during both SCS and LFS. Greater intensities of SCS and LFS were associated with decreased cortical excitability primarily in central and parietal scalp regions. Facilitatory effects of stimulation intensity were also identified in sensorimotor sources. Cortical activation changes during processing of somatosensory input were found between burst and tonic SCS. Intensity-related changes in cortical excitability during SCS and LFS may be partially explained by the Gate Control Theory and long-term depression, respectively. Coexistence of attenuated cortical excitability and sensorimotor facilitation suggests that these neurostimulation interventions do not have simple gating effects. Results support different underlying mechanisms between burst and tonic SCS which are engaged during somatosensory input. Findings have important clinical implications for the palliative treatment of neuropathic pain syndromes.
Objective
Nociceptive stimuli have been studied either by dipolar modelling using electroencephalography (EEG) or magnetoencephalography (MEG), but rarely using both techniques simultaneously. This study aims to investigate the spatiotemporal representation of cortical activity in response to non-nociceptive (tactile) and nociceptive (laser) stimuli using parallel EEG-MEG recordings.
Methods
We performed simultaneous EEG and MEG recordings in 12 healthy subjects by applying pneumatic tactile and nociceptive laser stimuli on the right- and left-hand dorsum. We analyzed brain responses for both modalities and methods by means of global field power (GFP), and dipole source locations, strengths and orientations calculated in the depth to identify similarities and differences.
Results
Prominent GFP peaks were similar in EEG and MEG for tactile responses but different for nociceptive responses.
Conclusions
Methodically, MEG was superior to EEG in detecting the earliest nociceptive laser-evoked components with earlier latency in primary- and secondary somatosensory cortices, whereas EEG was superior to MEG in detecting late nociceptive components due to radially oriented deeper cortical activity.
Significance
EEG and MEG revealed in part differential nociceptive waveform patterns, peak latencies, and source orientations, making combined recordings favorable to examine pain-related activity as a whole in high temporal-spatial resolution.
Objective
Dorsal root ganglion stimulation (DRGS) is able to relieve chronic neuropathic pain. There seems evidence that DRGS might achieve this by gradually influencing pain pathways. We used laser evoked potentials (LEP) to verify our hypothesis that the recovery of the LEP may reflect DRGS induced changes within the nociceptive system.
Methods
Nine patients (mean age 56.8 years, range 36 to 77 years, 2 females) diagnosed with chronic neuropathic pain in the knee or groin were enrolled in the study. We measured each patient’s LEP at the painful limb and contralateral control limb on the first, fourth, and seventh day after implantation of the DRGS system. We used the numeric rating scale (NRS) for the simultaneous pain assessment.
Results
The LEP amplitude of the N2-P2 complex showed a significant increase on day 7 when compared to day 1 (Z = -2.666, p = 0.008) and to day 4 (Z = -2.547, p = 0.011), respectively. There was no significant difference in the N2-P2 complex amplitude between ON and OFF states during DRGS. The patients’ NRS significantly decreased after 1 day (p = 0.007), 4 days (p = 0.007), and 7 days (p = 0.007) when compared to the baseline.
Conclusions
The results show that with DRGS, the LEP recovered gradually within 7 days in neuropathic pain patients. Therefore, reduction of the NRS in patients with chronic neuropathic pain might be due to DRGS induced processes within the nociceptive system. These processes might indicate neuroplasticity mediated recovery of the LEP.
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.
Objective
Many studies have examined the effectiveness of transcranial direct current stimulation (tDCS) on human pain perception in both healthy populations and pain patients. Nevertheless, studies have yielded conflicting results, likely due to differences in stimulation parameters, experimental paradigms, and outcome measures. Human experimental pain models that utilize indices of pain in response to well-controlled noxious stimuli can avoid many confounds present in clinical data. This study aimed to assess the robustness of tDCS effects on experimental pain perception among healthy populations.
Methods
We conducted three meta-analyses that analyzed tDCS effects on ratings of perceived pain intensity to suprathreshold noxious stimuli, pain threshold and tolerance.
Results
The meta-analyses showed a statically significant tDCS effect on attenuating pain-intensity ratings to suprathreshold noxious stimuli. In contrast, tDCS effects on pain threshold and pain tolerance were statistically non-significant. Moderator analysis further suggested that stimulation parameters (active electrode size and current density) and experimental pain modality moderated the effectiveness of tDCS in attenuating pain-intensity ratings.
Conclusion
The effectiveness of tDCS on attenuating experimental pain perception depends on both stimulation parameters of tDCS and the modality of experimental pain.
Significance
This study provides some theoretical basis for the application of tDCS in pain management.
Objective
Nociceptive activity in some brain areas has concordantly been reported in EEG source models, such as the anterior/mid-cingulate cortex and the parasylvian area. Whereas the posterior insula has been constantly reported to be active in intracortical and fMRI studies, non-invasive EEG and MEG recordings mostly failed to detect activity in this region. This study aimed to determine an appropriate inverse modeling approach in EEG recordings to model posterior insular activity, assuming the late LEP (laser evoked potential) time window to yield a better separation from other ongoing cortical activity.
Methods
In 12 healthy volunteers, nociceptive stimuli of three intensities were applied. LEP were recorded using 32-channel EEG recordings. Source analysis was performed in specific time windows defined in the grand-average dataset. Two distinct dipole-pairs located close to the operculo-insular area were compared.
Results
Our results show that posterior insular activity yields a substantial contribution to the latest part (positive component) of the LEP.
Conclusions
Even though the initial insular activity onset is in the early LEP time window, modeling the insular activity in the late LEP time window might result in better separation from other ongoing cortical activity.
Significance
Modeling the late LEP activity might enable to distinguish posterior insular activity.
Laser-evoked potentials (LEPs) are a reliable tool to explore the cortical response to nociceptive afferents. They are highly selective and extensively used in neuropathic pain and primary headaches. Their employment in primary headaches gave a contribution to the knowledge of physiopathology and effects of pharmacological and non-pharmacological treatments. Other pain-related evoked potentials (PREPs) were obtained by electrical stimuli delivered via electrodes with specificity for thin myelinated and unmyelinated fibers. Their application in trigeminal neuralgia and primary headaches showed basal mechanism of pain and complex phenomena such as central sensitization and altered pain modulation. The use of reliable, safe, and cheap stimulators could better clarify the mechanisms of pain processing in primary headaches, thus supporting the mode of treatment action and disease improving.
Notre objectif était d’optimiser la prise en charge de la douleur aiguë sévère en médecine d’urgence. La titration morphinique intraveineuse qui fait actuellement référence doit se moderniser pour répondre aux nouveaux enjeux de la pratique en même temps que l’on doit garantir une balance bénéfice risque inchangée dans la lutte contre l’oligoanalgésie. Le travail décrit dans cette thèse, constitue une première étape d’évaluation d’une alternative nébulisée à la titration morphinique, à travers 3 études cliniques (AEROMORPH1, CLIN-AEROMORPH, EPIMORPH) et l’étude de son contexte dans la littérature. Des travaux chez le volontaire sain ont permis d’établir un mode opératoire avec une technique aérosol simple et accessible, de courte durée (5 min), que l’on peut répéter en titration (toutes les 10 min). Sa faisabilité est en voie d’être confirmée à grande échelle dans une étude multicentrique clinique et sa non-infériorité en termes d’efficacité est en cours d’évaluation. Des données pharmacologiques chez le volontaire sain et chez les patients confirment une concentration sanguine en morphine proche des concentrations efficaces observées en intraveineux (1 à 120 ng/ml dans CLIN-AEROMORPH), ce qui est déjà un résultat positif démontré par nos travaux. Par ailleurs, sur le plan de son éligibilité, nos données observationnelles et de simulation de décision, associées aux données médico-économiques que nous avons analysées dans la littérature, suggèrent la nécessité de baser son indication autrement que sur la simple évaluation par EVA/EN à l’accueil. Dans ce travail nous montrons que la pratique des praticiens témoigne aujourd’hui de leur manque d’adhésion au déclenchement systématique de la prescription d’opiacés Iv titrés par l’autoévaluation de la douleur sévère (de 6 à 20% de respect des critères SFMU, 61% de réinterprétation des scores EVA/EN). Si la titration aérosol est uniquement proposée en starter de la titration morphinique sans moderniser les algorithmes de décision de prescription opiacée dans les protocoles d’urgences, il est probable que cette nouvelle proposition thérapeutique ne résoudra qu’une partie de la problématique actuellement posée. Une prise en charge pharmacologique la plus individualisée possible est plus que jamais pertinente, avec une prescription ciblée de la titration morphinique selon la typologie du patient, en plus d’une priorisation par typologie douloureuse. En développant un « modèle douleur » original chez le volontaire sain, nous avons d’ailleurs mis en lumière des profils de patients « hyperesthésiques » et « endurants », sur le plan neurophysiologique et biochimique, qui sont sûrement retrouvés en pratique clinique quotidienne. L’ensemble de ces éléments doivent donc être pris en compte pour améliorer la prise en charge de la douleur en médecine d’urgence, avec une vision plus systémique, et davantage d’études dédiées, utilisant des méthodes d’évaluation innovantes mêlant critères quantitatifs robustes et qualitatifs exhaustifs.
This article reviews the literature on neurophysiological techniques for the diagnosis of small fiber neuropathy. The review is focused on clinical approach to suspected small fiber neuropathy, letting aside techniques whose clinical applicability is doubtful. We include, however, the special techniques required to examine C and Aδ fibers, which cannot be evaluated directly with conventional neurophysiological methods. The most relevant publications are summarized and recommendations for the clinical assessment of small fiber neuropathy are provided.
Neural signals from the skin, joints, and muscles inform us about the state of our limbs and convey information about the objects with which we interact. Without these sensory signals, we become severely impaired in our ability to move our bodies and interact with objects. In this chapter, we discuss the receptors in our skin and muscles that mediate the senses of touch and proprioception. First, we describe the mechanisms that underlie the transduction of mechanical deformations into neuronal responses. Then, we examine how sensory information is encoded in the responses of the nerve fibers that carry signals from these receptors. Finally, we consider how these streams of afferent information are integrated to enable perception and action.
Neural signals from the skin, joints, and muscles inform us about the state of our limbs and convey information about the objects with which we interact. Without these sensory signals, we become severely impaired in our ability to move our bodies and interact with objects. In this chapter, we discuss the receptors in our skin and muscles that mediate the senses of touch and proprioception. First, we describe the mechanisms that underlie the transduction of mechanical deformations into neuronal responses. Then, we examine how sensory information is encoded in the responses of the nerve fibers that carry signals from these receptors. Finally, we consider how these streams of afferent information are integrated to enable perception and action.
This chapter aims to provide background knowledge necessary to understand electroencephalography (EEG) technique and its applications. First, the information about how EEG, evoked potentials (EPs), and event-related potentials (ERPs) are generated and obtained are summarized. Next, a brief overview of EPs and ERPs is provided, and classical EP and ERP components that are applied in clinical and neuroscience studies are also described, with an emphasis on different sensory modalities through which the stimuli are presented. Finally, the pitfalls and promise in EP and ERP studies are discussed.
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