Pain-related gamma band activity is dependent on the features of nociceptive stimuli: a comparison of laser and contact heat.

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 nondominant 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 ∼200 ms, both contact heat and laser stimulation resulted in significant, group-level event-related synchronization (ERS) in the low gamma band (i.e., 30-60 Hz) in central electrode locations (Cc, Cz, Ci). Laser stimulation also generated ERS in the 60-100 Hz range (i.e., high gamma), at ∼200 ms, while contact heat led to a significant period of desynchronization in the high gamma range between 400 and 600 ms. 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.NEW & NOTEWORTHY Despite matching pain perception between noxious laser and contact heat stimuli, we report notable differences in gamma band oscillations (GBO), measured via electroencephalography. GBOs produced following contact heat more closely resembled that of nonnoxious stimuli, while GBOs following laser stimuli were in line with previous reports. Taken together, 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.

Defect of the Endogenous Inhibitory Pain System in Idiopathic Restless Legs Syndrome: A Laser Evoked Potentials Study.

BACKGROUND: Restless legs syndrome (RLS) is a complex sensorimotor disorder. Symptoms worsen toward evening and at rest and are temporarily relieved by movement. Symptoms are perceived as painful in up to 45% of cases, and nociception system may be involved. OBJECTIVES: To assess the descending diffuse noxious inhibitory control in RLS patients. METHODS: Twenty-one RLS patients and twenty age and sex-matched healthy controls (HC) underwent a conditioned pain modulation protocol. Cutaneous heat stimuli were delivered via laser evoked potentials (LEPs) on the dorsum of the right hand (UL) and foot (LL). N2 and P2 latencies, N2/P2 amplitude and pain ratings (NRS) were recorded before (baseline), during, and after a heterotopic noxious conditioning stimulation (HNCS) application. The baseline/HNCS ratio was calculated for both UL and LL. RESULTS: N2 and P2 latencies did not vary between groups at each condition and limbs. Both groups showed a physiological N2/P2 amplitude and NRS reduction during the HNCS condition in UL and LL in comparison to baseline and post conditions (all, P < 0.003). Between-groups comparisons revealed a significant lower amplitude reduction in RLS at the N2/P2 amplitude during the HNCS condition only for LL (RLS, 13.6 µV; HC, 10.1 µV; P = 0.004). Such result was confirmed by the significant difference at the ratio (RLS, 69%, HC, 52.5%; P = 0.038). CONCLUSIONS: The lower physiological reduction during the HNCS condition at LL in RLS patients suggests a defect in the endogenous inhibitory pain system. Further studies should clarify the causal link of this finding, also investigating the circadian modulation of this paradigm. © 2023 International Parkinson and Movement Disorder Society.

Clinical criteria and diagnostic assessment of fibromyalgia: position statement of the Italian Society of Neurology-Neuropathic Pain Study Group.

BACKGROUND: The role of central and/or peripheral nervous system dysfunction is basically fundamental in fibromyalgia. AIM: The aim of this position statement on behalf of the Neuropathic Pain Study Group of the Italian Society of Neurology is to give practical guidelines for the clinical and instrumental assessment of fibromyalgia (FM) in the neurological clinical practice, taking into consideration recent studies. METHODS: Criteria for study selection and consideration were original studies, case-controls design, use of standardized methodologies for clinical practice, and FM diagnosis with ACR criteria (2010, 2011, 2016). RESULTS: ACR criteria were revised. For diagnostic procedure of small-fiber pathology, 47 studies were totally considered. Recent diagnostic criteria should be applied (ACR, 2016). A rheumatologic visit seems mandatory. The involvement of small fibers should request at least 2 among HRV + SSR and/or laser-evoked responses and/or skin biopsy and/or corneal confocal microscopy, eventually followed by monitoring of metabolic and/or immunological/ and or/paraneoplastic basis, to be repeated at 1-year follow-up. CONCLUSIONS: The correct diagnostic approach to FM could promote the exclusion of the known causes of small-fiber impairment. The research toward common genetic factors would be useful to promote a more specific therapeutic approach.

Laser-evoked potentials recover gradually when using dorsal root ganglion stimulation, and this influences nociceptive pathways in neuropathic pain patients.

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 36-77 years, two 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.

Processing of Laser-Evoked Potentials in Patients with Chronic Whiplash-Associated Disorders, Chronic Fatigue Syndrome, and Healthy Controls: A Case-Control Study.

OBJECTIVE: Laser-evoked potentials (LEPs) are among the reliable neurophysiological tools to investigate patients with neuropathic pain, as they can provide an objective account of the functional status of thermo-nociceptive pathways. The goal of this study was to explore the functioning of the nociceptive afferent pathways by examining LEPs in patients with chronic whiplash-associated disorders (cWAD), patients with chronic fatigue syndrome (CFS), and healthy controls (HCs). DESIGN: Case-control study. SETTING: A single medical center in Belgium. SUBJECTS: The LEPs of 21 patients with cWAD, 19 patients with CFS, and 18 HCs were analyzed in this study. METHODS: All participants received brief nociceptive CO2 laser stimuli applied to the dorsum of the left hand and left foot while brain activity was recorded with a 32-channel electroencephalogram (EEG). LEP signals and transient power modulations were compared between patient groups and HCs. RESULTS: No between-group differences were found for stimulus intensity, which was supraliminal for Aδ fibers. The amplitudes and latencies of LEP wave components N1, N2, and P2 in patients with cWAD and CFS were statistically similar to those of HCs. There were no significant differences between the time-frequency maps of EEG oscillation amplitude between HCs and both patient populations. CONCLUSIONS: EEG responses of heat-sensitive Aδ fibers in patients with cWAD and CFS revealed no significant differences from the responses of HCs. These findings thus do not support a state of generalized central nervous system hyperexcitability in those patients.

Pearls and pitfalls in brain functional analysis by event-related potentials: a narrative review by the Italian Psychophysiology and Cognitive Neuroscience Society on methodological limits and clinical reliability-part I.

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.

Thermonociceptive interaction: interchannel pain modulation occurs before intrachannel convergence of warmth.

Nonnoxious warmth reduces both perceived pain intensity and the amplitude of EEG markers of pain. However, the spatial properties of thermonociceptive interaction, and the level of sensory processing at which it occurs, remain unclear. We investigated whether interchannel warmth-pain interactions occur before or after intrachannel spatial summation of warmth. Warm stimuli were applied to the fingers of the right hand. Their number and location were manipulated in different conditions. A concomitant noxious test pulse was delivered to the middle finger using a CO2 laser. We replicated the classical suppressive effect of warmth on both perceived pain intensity and EEG markers. Importantly, inhibition of pain was not affected by the location and the number of thermal stimuli, even though they increased the perceived intensity of warmth. Our results therefore suggest that the inhibitory effect of warmth on pain is not somatotopically organized. The results also rule out the possibility that warmth affects nociceptive processing after intrachannel warmth summation. NEW & NOTEWORTHY We used spatial summation of warmth as a model to investigate thermonociceptive interactions. Painful CO2 laser pulses were delivered during different thermal conditions. We found that warmth inhibited pain regardless of its location. Crucially, spatial summation of multiple warm stimuli did not further inhibit pain. These findings suggest that warmth-pain interaction occurs independently of or after spatial summation of warmth.

Neurophysiological Effects of Dorsal Root Ganglion Stimulation (DRGS) in Pain Processing at the Cortical Level.

OBJECTIVES: Dorsal root ganglion stimulation (DRGS) has been used successfully against localized neuropathic pain. Nevertheless, the effects of DRGS on pain processing, particularly at the cortical level, remain largely unknown. In this study, we investigated whether positive responses to DRGS treatment would alter patients' laser-evoked potentials (LEP). METHODS: We prospectively enrolled 12 adult patients with unilateral localized neuropathic pain in the lower limbs or inguinal region and followed them up for six months. LEPs were assessed at baseline, after one month of DRGS, and after six months of DRGS. Clinical assessment included the Numerical Rating Scale (NRS), Brief Pain Inventory (BPI), SF-36, and Beck Depression Inventory (BDI). For each patient, LEP amplitudes and latencies of the N2 and P2 components on the deafferented side were measured and compared to those of the healthy side and correlated with pain intensity, as measured with the NRS. RESULTS: At the one- and six-month follow-ups, N2-P2 amplitudes were significantly greater and NRS scores were significantly lower compared with baseline (all p's < 0.01). There was a negative correlation between LEP amplitudes and NRS scores (rs = -0.31, p < 0.10). CONCLUSIONS: DRGS is able to restore LEPs to normal values in patients with localized neuropathic pain, and LEP alterations are correlated with clinical response in terms of pain intensity.

Electrophysiology in diagnosis and management of neuropathic pain.

Electrophysiological techniques demonstrate abnormalities in somatosensory transmission, hence providing objective evidence of 'somatosensory lesion or disease' which is crucial to the diagnosis of neuropathic pain (NP). Since most instances of NP result from damage to thermo-nociceptive pathways (thin fibres and spino-thalamo-cortical systems), specific activation of these is critical to ensure diagnostic accuracy. This is currently achieved using laser pulses or contact heat stimuli, and in a near future probably also with contact cold and intra-epidermal low-intensity currents. Standard electrical stimuli, although of lesser diagnostic yield, are useful when large and small fibres are affected together. Nociceptive evoked potentials to laser (LEPs) and contact heat (CHEPs) have shown adequate sensitivity and specificity to be of clinical use in the differential diagnosis of NP, in conditions involving Aδ of C-fibres and spino-thalamo-cortical pathways. LEPs have also a role in the detection of patients at risk of developing central post-stroke pain after brainstem, thalamic or cortical injury. Cognitive cortical responses and autonomic reactions (sympathetic skin responses) reflect pain-related arousal and can document objectively positive symptoms such as allodynia and hyperalgesia. They are of help in the differential diagnosis of somatisation disorders, by discriminating conscious simulation (malingering) from conversive sensory loss. The electrophysiological approach to patients suspected, or at risk, of NP is a cost-effective procedure that should never be absent in the diagnostic armamentarium of pain clinics.

Effects of external trigeminal nerve stimulation (eTNS) on laser evoked cortical potentials (LEP): A pilot study in migraine patients and controls.

Background Transcutaneous external supraorbital nerve stimulation has emerged as a treatment option for primary headache disorders, though its action mechanism is still unclear. Study aim In this randomized, sham-controlled pilot study we aimed to test the effects of a single external transcutaneous nerve stimulation session on pain perception and cortical responses induced by painful laser stimuli delivered to the right forehead and the right hand in a cohort of migraine without aura patients and healthy controls. Methods Seventeen migraine without aura patients and 21 age- and sex-matched controls were selected and randomly assigned to a real or sham external transcutaneous nerve stimulation single stimulation session. The external transcutaneous nerve stimulation was delivered with a self-adhesive electrode placed on the forehead and generating a 60 Hz pulse at 16 mA intensity for 20 minutes. For sham stimulation, we used 2 mA intensity. Laser evoked responses were recorded from 21 scalp electrodes in basal condition (T0), during external transcutaneous nerve stimulation and sham stimulation (T1), and immediately after these (T2). The laser evoked responses were analyzed by LORETA software. Results The real external transcutaneous nerve stimulation reduced the trigeminal N2P2 amplitude in migraine and control groups significantly in respect to placebo. The real stimulation was associated with lower activity in the anterior cingulate cortex under trigeminal laser stimuli. The pattern of LEP-reduced habituation was reverted by real and sham transcutaneous stimulation in migraine patients. Conclusions The present results could suggest that the external transcutaneous nerve stimulation may interfere with the threshold and the extent of trigeminal system activation, with a mechanism of potential utility in the resolution and prevention of migraine attacks.

Functional MRI and laser-evoked potentials evaluation in Charcot-Marie-Tooth syndrome.

Charcot-Marie-Tooth (CMT) disease is a genetically heterogeneous group of disorders. Pain is a less common symptom complained by CMT patients. We described a case of a 39-year-old male patient affect by Charcot-Marie-Tooth (CMT) disease compared to five healthy controls (HC), to assess the sensory and the nociceptive pathways by using LEPs recording associated to fMRI examination, to find an "objective" marker which could be used in the management of CMT patient. The nociceptive system was evaluated by laser-evoked potentials (LEPs). Moreover, fMRI (functional magnetic resonance imaging) examination, by using laser stimuli, was performed. LEPs' examination showed an increase of latency and an amplitude reduction respect to HC. The laser stimulation during fMRI showed a decreased cortical activations if compared to HC. The originality of this paper, although limited to a single case, resides in a detailed evaluation of CMT1 patient performed by using neurophysiologic and neuroimaging methods to investigate extensively the sensory nociceptive pathways.

Neurophysiological Comparison Among Tonic, High Frequency, and Burst Spinal Cord Stimulation: Novel Insights Into Spinal and Brain Mechanisms of Action.

RATIONALE: Spinal cord stimulation (SCS) is an effective option for neuropathic pain treatment. New technological developments, as high-frequency (HF) and theta burst stimulation (TBS), have shown promising results, although putative mechanisms of action still remain debated. METHODS: thirty patients with lower back pain were enrolled and underwent LF, HF, and TBS. Laser evoked potentials (LEPs) were recorded by using a Nd:YAG laser. Amplitudes and latencies of the main two components (N1, N2/P2) were compared among different experimental sessions. Changes in resting motor threshold (RMT), cortical silent period (cSP), short intracortical inhibition (SICI), and intracortical facilitation (ICF) were also evaluated. RESULTS: TBS dampened LEP amplitudes compared with LF (N1: p = 0.032; N2/P2: p < 0.0001) and HF stimulation (N1: p = 0.029; N2/P2: p < 0.0001, Holm-Sidak post-hoc test). Concurrently, TBS increased N1 latency, when compared with baseline and LF stimulation (p = 0.009 and 0.0033). Whereas RMT and SICI did not change among experimental conditions, TBS significantly prolonged cSP duration compared with baseline (p = 0.002), LF (p = 0.048), and HF-SCS (p = 0.016); finally, both HF (p = 0.004) and TBS (p = 0.0039) increased ICF. CONCLUSION: TBS modulates medial and lateral pain pathways through distinct mechanisms, possibly involving both GABA(a)ergic and Glutamatergic networks at an intracortical level. These results may have implications for therapy and for the choice of best stimulation protocol.

Evidence-based source modeling of nociceptive cortical responses: A direct comparison of scalp and intracranial activity in humans.

BACKGROUND: Source modeling of EEG traditionally relies on interplay between physiological hypotheses and mathematical estimates. We propose to optimize the process by using evidence gathered from brain imaging and intracortical recordings. METHODS: We recorded laser-evoked potentials in 18 healthy participants, using high-density EEG. Brain sources were modeled during the first second poststimulus, constraining their initial position to regions where nociceptive-related activity has been ascertained by intracranial EEG. These comprised the two posterior operculo-insular regions, primary sensorimotor, posterior parietal, anterior cingulate/supplementary motor (ACC/SMA), bilateral frontal/anterior insular, and posterior cingulate (PCC) cortices. RESULTS: The model yielded an average goodness of fit of 91% for individual and 95.8% for grand-average data. When compared with intracranial recordings from 27 human subjects, no significant difference in peak latencies was observed between modeled and intracranial data for 5 of the 6 assessable regions. Morphological match was excellent for operculo-insular, frontal, ACC/SMA and PCC regions (cross-correlation > 0.7) and fair for sensori-motor and posterior parietal cortex (c-c ∼ 0.5). CONCLUSIONS: Multiple overlapping activities evoked by nociceptive input can be disentangled from high-density scalp EEG guided by intracranial data. Modeled sources accurately described the timing and morphology of most activities recorded with intracranial electrodes, including those coinciding with the emergence of stimulus awareness. Hum Brain Mapp 38:6083-6095, 2017. © 2017 Wiley Periodicals, Inc.

High Hypnotizability Impairs the Cerebellar Control of Pain.

In the general population, transcranial anodal direct current stimulation of the cerebellum (ctDCS) reduces pain intensity and the amplitude of nociceptive laser evoked potentials (LEPs), whereas cathodal ctDCS elicits opposite effects. Since behavioral findings suggest that the cerebellar activity of highly hypnotizable individuals (highs) differs from the general population, we investigated whether hypnotizability-related differences occur in the modulation of pain by ctDCS. Sixteen healthy highs (according to the Stanford Hypnotic Susceptibility Scale, form A) and 16 participants not selected according to hypnotizability (controls) volunteered to undergo laser nociceptive stimulation of the dorsum of the left hand before and after anodal or cathodal ctDCS. LEPs amplitudes and latencies and the subjective pain experience (Numerical Rating Scale) were analyzed. Smaller LEP amplitudes and longer latencies were observed in highs with respect to controls independently of stimulation. After anodal and cathodal cerebellar stimulation, controls reported lower and higher pain than before it, respectively. In contrast, highs did not report significant changes in the perceived pain after both stimulations. They increased significantly their N2/P2 amplitude after anodal ctDCS and did not exhibit any significant change after cathodal tDCS, whereas controls decreased the N1 and N2P2 amplitude and increased their latency after anodal cerebellar stimulation and did the opposite after cathodal ctDCS. In conclusion, the study showed impaired cerebellar pain modulation and suggested altered cerebral cortical representation of pain in subjects with high hypnotizability scores.

Investigation of the predictive validity of laser-EPs in normal, UVB-inflamed and capsaicin-irritated skin with four analgesic compounds in healthy volunteers.

AIMS: The aim of the present study was to assess the predictivity of laser-(radiant-heat)-evoked potentials (LEPs) from the vertex electroencephalogram, using an algesimetric procedure, testing the anti-nociceptive/anti-hyperalgesic effects of single oral doses of four marketed analgesics (of different compound classes) vs. placebo, in healthy volunteers with three skin types. METHODS: This was a randomized, placebo-controlled, single-blind, five-way-crossover trial. Twenty-five healthy male/female Caucasians were included (receiving celecoxib 200 mg, pregabalin 150 mg, duloxetine 60 mg, lacosamide 100 mg or placebo) in a Williams design, with CO2 laser-induced painful stimuli to normal, ultraviolet (UV) B-inflamed and capsaicin-irritated skin. LEPs and visual analogue scale ratings were taken at baseline and hourly for 6 h postdose from all three skin types. RESULTS: In normal skin, the averaged postdose LEP peak-to-peak-(PtP)-amplitudes were reduced by pregabalin (-2.68 µV; 95% confidence interval (CI) -4.16, 1.19) and duloxetine (-1.73 µV; 95% CI -3.21, -0.26) but not by lacosamide and celecoxib vs. placebo. On UVB-irradiated skin, reflecting inflammatory pain, celecoxib induced a pronounced reduction in LEP PtP amplitudes vs. placebo (-6.2 µV; 95% CI -7.88, -4.51), with a smaller reduction by duloxetine (-4.54 µV; 95% CI -6.21, -2.87) and pregabalin (-3.72 µV; 95% CI -5.40, -2.04), whereas lacosamide was inactive. LEP PtP amplitudes on capsaicin-irritated skin, reflecting peripheral/spinal sensitization, as in neuropathic pain, were reduced by pregabalin (-3.78 µV; 95% CI -5.31, -2.25) and duloxetine (-2.32 µV; 95% CI -3.82, -0.82) but not by celecoxib or lacosamide vs. placebo, which was in agreement with known clinical profiles. Overall, PtP amplitude reductions were in agreement with subjective ratings. CONCLUSIONS: LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development.

Thalamic pain: anatomical and physiological indices of prediction.

Thalamic pain is a severe and treatment-resistant type of central pain that may develop after thalamic stroke. Lesions within the ventrocaudal regions of the thalamus carry the highest risk to develop pain, but its emergence in individual patients remains impossible to predict. Because damage to the spino-thalamo-cortical system is a crucial factor in the development of central pain, in this study we combined detailed anatomical atlas-based mapping of thalamic lesions and assessment of spinothalamic integrity using quantitative sensory analysis and laser-evoked potentials in 42 thalamic stroke patients, of whom 31 had developed thalamic pain. More than 97% of lesions involved an area between 2 and 7 mm above the anterior-posterior commissural plane. Although most thalamic lesions affected several nuclei, patients with central pain showed maximal lesion convergence on the anterior pulvinar nucleus (a major spinothalamic target) while the convergence area lay within the ventral posterior lateral nucleus in pain-free patients. Both involvement of the anterior pulvinar nucleus and spinothalamic dysfunction (nociceptive thresholds, laser-evoked potentials) were significantly associated with the development of thalamic pain, whereas involvement of ventral posterior lateral nucleus and lemniscal dysfunction (position sense, graphaesthesia, pallaesthesia, stereognosis, standard somatosensory potentials) were similarly distributed in patients with or without pain. A logistic regression model combining spinothalamic dysfunction and anterior pulvinar nucleus involvement as regressors had 93% sensitivity and 87% positive predictive value for thalamic pain. Lesion of spinothalamic afferents to the posterior thalamus appears therefore determinant to the development of central pain after thalamic stroke. Sorting out of patients at different risks of developing thalamic pain may be achievable at the individual level by combining lesion localization and functional investigation of the spinothalamic system. As the methods proposed here do not need complex manipulations, they can be added to routine patients' work up, and the results replicated by other investigators in the field.

Differences in Pain Perception Between Men and Women of Reproductive Age: A Laser-Evoked Potentials Study.

Objective: We investigated differences in pain perception between men and women of reproductive age by using Laser-Evoked Potentials (LEPs). Design, Setting, Subjects: Forty-four right-handed healthy volunteers (19 males/25 females), aged 30­40 years were studied. A CO2 laser generated three series of 10 thermal pulses (4.5 W) on the radial aspect of the dorsum of the left hand. A recording montage for late LEPs was used, and the potentials of each series of stimuli were averaged to calculate mean latency and amplitude for each subject. Volunteers scored verbally pain intensity (Numerical rating scale [NRS]; 0­10). Three series of 10 numbers were averaged for calculation of mean NRS score. Methods: LEP peak-to-peak amplitude, latency, and NRS scoring were compared between genders, and correlations between LEP amplitude/latency and NRS scores were assessed. Results: Data from 44 subjects were analyzed. LEP amplitudes differed significantly (P < 0.001) between men (24.2 ± 6.0 µV) and women (38.9 ± 15.28 µV), while no difference was found for latency (156.5 ± 8.6 versus 160.4 ± 19.8 ms, P = 0.42) or NRS score (2.6 ± 1.5 versus 2.4 ± 1.4, P = 0.63), respectively. Menstrual cycle phase did not influence LEP parameters (P = 0.59 for amplitude and P = 0.69 for latency) or NRS score (P = 0.95). No significant correlation was found between latency or amplitude and NRS score (P = 0.43 and P = 0.90, respectively). Conclusions: Our results demonstrate a significant gender-related difference in LEP amplitudes with lower mean values in men, while no difference was found in LEP latencies or in subjective pain ratings. Further research is required to clarify the clinical significance of the above experimental findings.

Focal Mechanical Vibration Does not Change Laser-Pain Perception and Laser-Evoked Potentials: A Pilot Study.

BACKGROUND: Nonpainful tactile and electrical stimulation of the large myelinated fibers reduces spontaneous pain and the amplitude of laser-evoked potentials (LEPs), which represent the most reliable technique to assess the nociceptive pathway function. Focal mechanical vibration stimulates the Aß afferents selectively; thus, it is conceivable its action on nociceptive pathways. AIM: The aim of this study was to investigate the effect of vibratory stimuli, activating either both muscle and skin receptors or cutaneous afferents only on the LEPs and subjective laser-pain rating. METHODS: Ten healthy volunteers were studied. The subjects were evaluated in two different sessions to test muscle and skin receptors or cutaneous afferents only. In each session, LEPs were recorded to stimulation of the dorsal hand skin in radial and ulnar territory bilaterally, while the vibratory stimulus was delivered on the radial territory of the right forearm. RESULTS: The results showed a substantial stability of the potential N1 and N2/P2 after the two protocols, with a declining trend from the initial to the last test of the same session, probably due to habituation. Accordingly, the laser-pain perception did not change during the experimental setting. CONCLUSIONS: We conclude that a vibratory stimulus is ineffective in reducing the laser-evoked potentials and laser-pain perception.

Laser-evoked cortical responses in freely-moving rats reflect the activation of C-fibre afferent pathways.

The limited success of translating basic animal findings into effective clinical treatments of pain can be partly ascribed to the use of sub-optimal models. Murine models of pain often consist in recording (1) threshold responses (like the tail-flick reflex) elicited by (2) non-nociceptive specific inputs in (3) anaesthetized animals. The direct cortical recording of laser-evoked potentials (LEPs) elicited by stimuli of graded energies in freely-moving rodents avoids these three important pitfalls, and has thus the potential of improving such translation. Murine LEPs are classically reported to consist of two distinct components, reflecting the activity of Aδ- and C-fibre afferent pathways. However, we have recently demonstrated that the so-called "Aδ-LEPs" in fact reflect the activation of the auditory system by laser-generated ultrasounds. Here we used ongoing white noise to avoid the confound represented by the early auditory response, and thereby comprehensively characterized the physiological properties of C-fibre LEPs recorded directly from the exposed surface of the rat brain. Stimulus-response functions indicated that response amplitude is positively related to the stimulus energy, as well as to nocifensive behavioral score. When displayed using average reference, murine LEPs consist of three distinct deflections, whose polarity, order, and topography are surprisingly similar to human LEPs. The scalp topography of the early N1 wave is somatotopically-organized, likely reflecting the activity of the primary somatosensory cortex, while topographies of the later N2 and P2 waves are more centrally distributed. These results indicate that recording LEPs in freely-moving rats is a valid model to improve the translation of animal results to human physiology and pathophysiology.

Mapping multidimensional pain experience onto electrophysiological responses to noxious laser heat stimuli.

The origin of the conscious experience of pain in the brain is a continuing enigma in neuroscience. To shed light on the brain representation of a multifaceted pain experience in humans, we combined multivariate analysis of subjective aspects of pain sensations with detailed, single-trial analysis of electrophysiological brain responses. Participants were asked to fully focus on any painful or non-painful sensations occurring in their left hand during an interval surrounding the onset of noxious laser heat stimuli, and to rate their sensations using a set of visual analogue scales. Statistical parametric mapping was used to compute a multivariate regression analysis of subjective responses and single-trial laser evoked potentials (LEPs) at subject and group levels. Standardized Low Resolution Electromagnetic Tomography method was used to reconstruct sources of LEPs. Factor analysis of subjective responses yielded five factors. Factor 1, representing pain, mapped firstly as a negative potential at the vertex and a positive potential at the fronto-temporal region during the 208-260ms interval, and secondly as a strong negative potential in the right lateral frontal and prefrontal scalp regions during the 1292-1340ms interval. Three other factors, labelled "anticipated pain", "stimulus onset time", and "body sensations", represented non-specific aspects of the pain experience, and explained portions of LEPs in the latency range from 200ms to 700ms. The subjective space of pain during noxious laser stimulation is represented by one large factor featuring pain intensity, and by other factors accounting for non-specific parts of the sensory experience. Pain is encoded in two separate latency components with different scalp and brain representations.