Cortical Responsiveness to Nociceptive Stimuli in Patients with Chronic Disorders of Consciousness: Do C-Fiber Laser Evoked Potentials Have a Role?

It has been shown that the presence of Aδ-fiber laser evoked potentials (Aδ-LEP) in patients suffering from chronic disorders of consciousness (DOC), such as vegetative state (VS) and minimally conscious state (MCS), may be the expression of a residual cortical pain arousal. Interestingly, the study of C-fiber LEP (C-LEP) could be useful in the assessment of cortical pain arousal in the DOC individuals who lack of Aδ-LEP. To this end, we enrolled 38 DOC patients following post-anoxic or post-traumatic brain injury, who met the international criteria for VS and MCS diagnosis. Each subject was clinically evaluated, through the coma recovery scale-revised (CRS-R) and the nociceptive coma scale-revised (NCS-R), and electrophysiologically tested by means of a solid-state laser for Aδ-LEP and C-LEP. VS individuals showed increased latencies and reduced amplitudes of both the Aδ-LEP and C-LEP components in comparison to MCS patients. Although nearly all of the patients had both the LEP components, some VS individuals showed only the C-LEP ones. Notably, such patients had a similar NCS-R score to those having both the LEP components. Hence, we could hypothesize that C-LEP generators may be rearranged or partially spared in order to still guarantee cortical pain arousal when Aδ-LEP generators are damaged. Therefore, the residual presence of C-LEP should be assessed when Aδ-LEP are missing, since a potential pain experience should be still present in some patients, so to properly initiate, or adapt, the most appropriate pain treatment.

Related papers:

title: Pain-related middle-latency somatosensory evoked potentials in the prognosis of post anoxic coma: a preliminary report.
abstract: Regarding hypoxic-ischemic encephalopathy, while the bilateral absence of N20/P25 somatosensory evoked potentials (SEPs) is considered to be the best indicator of adverse outcomes, the presence of middle latency evoked potentials (MLCEPs) is associated with a favourable neurological prognosis. The main aim of the present study was to investigate whether painful electrical stimulation might be considered a provocative test in producing MLCEPs and predictor of patient's outcomes after cardiac arrest.



Retrospective pilot study. SEPs with and without pain-related electrical stimulation in both median nerves were recorded in 17 patients with post anoxic coma after cardiac arrest. Glasgow Coma Scale, electroencephalograms, heart rate and blood pressure changes were also recorded at the same time. Three months after cardiac arrest the same measures with inclusion of Glasgow Outcome Scale Extended were also performed only in the remaining patients with severe neurological outcome. No one intervention was made.



Patients who showed MLCEPs had a good outcome, while patients without N20/P25 SEPs but with increases in blood pressure remained in a vegetative state. Patients who did not show N20/P25 SEPs and increase in blood pressure died within one week. Only one patient who showed N20/P25 SEPs was minimally conscious.



These preliminary data suggest that MLCEPs elicited by painful electrical stimulation seem to be a sensitive method to predict the neurological outcome of patients in the acute phase of coma. Blood pressure response might be a prognostic physiological measure of survival in the vegetative state in patients without N20/P25 SEPs.

title: Cerebral processing of auditory and noxious stimuli in severely brain injured patients: Differences between VS and MCS
abstract: We review cerebral processing of auditory and noxious stimuli in minimally conscious state (MCS) and vegetative state (VS) patients. In contrast with limited brain activation found in VS patients, MCS patients show activation similar to controls in response to auditory, emotional and noxious stimuli. Despite an apparent clinical similarity between MCS and VS patients, functional imaging data show striking differences in cortical segregation and integration between these two conditions. However, in the absence of a generally accepted neural correlate of consciousness as measured by functional neuroimaging, clinical assessment remains the gold standard for the evaluation and management of severely brain damaged patients. This research was supported by the Fonds National de la Recherche Scientifique, (FNRS), by the Reine Elisabeth Medical Foundation, by funds of the University of Liège and the Centre Hospitalier Universitaire Sart Tilman, Liège, Belgium, and by a Tom Slick Research Award on Consciousness of the Mind Science Foundation, TX. S. Laureys and P. Maquet are Research Associate and Research Director at the FNRS.

title: Cortical Processing of Noxious Somatosensory Stimuli in the Persistent Vegetative State
abstract: The persistent vegetative state (PVS) is a devastating medical condition characterized by preserved wakefulness contrasting with absent voluntary interaction with the environment. We used positron emission tomography to assess the central processing of noxious somatosensory stimuli in the PVS. Changes in regional cerebral blood flow were measured during high-intensity electrical stimulation of the median nerve compared with rest in 15 nonsedated patients and in 15 healthy controls. Evoked potentials were recorded simultaneously. The stimuli were experienced as highly unpleasant to painful in controls. Brain glucose metabolism was also studied with [(18)F]fluorodeoxyglucose in resting conditions. In PVS patients, overall cerebral metabolism was 40% of normal values. Nevertheless, noxious somatosensory stimulation-activated midbrain, contralateral thalamus, and primary somatosensory cortex in each and every PVS patient, even in the absence of detectable cortical evoked potentials. Secondary somatosensory, bilateral insular, posterior parietal, and anterior cingulate cortices did not show activation in any patient. Moreover, in PVS patients, the activated primary somatosensory cortex was functionally disconnected from secondary somatosensory, bilateral posterior parietal, premotor, polysensory superior temporal, and prefrontal cortices. In conclusion, somatosensory stimulation of PVS patients, at intensities that elicited pain in controls, resulted in increased neuronal activity in primary somatosensory cortex, even if resting brain metabolism was severely impaired. However, this activation of primary cortex seems to be isolated and dissociated from higher-order associative cortices.

title: Nociceptive laser-evoked brain potentials do not reflect nociceptive-specific neural activity.
abstract: Brief radiant laser pulses can be used to activate cutaneous Adelta and C nociceptors selectively and elicit a number of transient brain responses [laser-evoked potentials (LEPs)] in the ongoing EEG. LEPs have been used extensively in the past 30 years to gain knowledge about the cortical mechanisms underlying nociception and pain in humans, by assuming that they reflect at least neural activities uniquely or preferentially involved in processing nociceptive input. Here, by applying a novel blind source separation algorithm (probabilistic independent component analysis) to 124-channel event-related potentials elicited by a random sequence of nociceptive and non-nociceptive somatosensory, auditory, and visual stimuli, we provide compelling evidence that this assumption is incorrect: LEPs do not reflect nociceptive-specific neural activity. Indeed, our results indicate that LEPs can be entirely explained by a combination of multimodal neural activities (i.e., activities also elicited by stimuli of other sensory modalities) and somatosensory-specific, but not nociceptive-specific, neural activities (i.e., activities elicited by both nociceptive and non-nociceptive somatosensory stimuli). Regardless of the sensory modality of the eliciting stimulus, the magnitude of multimodal activities correlated with the subjective rating of saliency, suggesting that these multimodal activities are involved in stimulus-triggered mechanisms of arousal or attentional reorientation.

title: Brain generators of laser-evoked potentials: from dipoles to functional significance
abstract: In this work we review data on cortical generators of laser-evoked potentials (LEPs) in humans, as inferred from dipolar modelling of scalp EEG/MEG results, as well as from intracranial data recorded with subdural grids or intracortical electrodes. The cortical regions most consistently tagged as sources of scalp LERs are the suprasylvian region (parietal operculum, SII) and the anterior cingulate cortex (ACC). Variability in opercular sources across studies appear mainly in the anterior-posterior direction, where sources tend to follow the axis of the Sylvian fissure. As compared with parasylvian activation described in functional pain imaging studies, LEP opercular sources tended to cluster at more superior sites and not to involve the insula. The existence of suprasylvian opercular LEPs has been confirmed by both epicortical (subdural) and intracortical recordings. In dipole-modelling studies, these sources appear to become active less than 150 ms post-stimulus, and remain in action for longer than opercular responses recorded intracortically, thus suggesting that modelled opercular dipoles reflect a "lumped" activation of several sources in the suprasylvian region, including both the operculum and the insula. Participation of SI sources to explain LEP scalp distribution remains controversial, but evidence is emerging that both SI and opercular sources may be concomitantly activated by laser pulses, with very similar time courses. Should these data be confirmed, it would suggest that a parallel processing in SI and SII has remained functional in humans for noxious inputs, whereas hierarchical processing from SI toward SII has emerged for other somatosensory sub-modalities. The ACC has been described as a source of LEPs by virtually all EEG studies so far, with activation times roughly corresponding to scalp P2. Activation is generally confined to area 24 in the caudal ACC, and has been confirmed by subdural and intracortical recordings. The inability of most MEG studies to disclose such ACC activity may be due to the radial orientation of ACC currents relative to scalp. ACC dipole sources have been consistently located between the VAC and VPC lines of Talairach's space, near to the cingulate subsections activated by motor tasks involving control of the hand. Together with the fact that scalp activities at this latency are very sensitive to arousal and attention, this supports the hypothesis that laser-evoked ACC activity may underlie orienting reactions tightly coupled with limb withdrawal (or control of withdrawal). With much less consistency than the above-mentioned areas, posterior parietal, medial temporal and anterior insular regions have been occasionally tagged as possible contributors to LEPs. Dipoles ascribed to medial temporal lobe may be in some cases re-interpreted as being located at or near the insular cortex. This would make sense as the insular region has been shown to respond to thermal pain stimuli in both functional imaging and intracranial EEG studies.

title: Pain in prolonged disorders of consciousness: Laser evoked potentials findings in patients with vegetative and minimally conscious states
abstract: Pain perception is currently an open question in patients suffering from prolonged disorders of consciousness. The aim of the present study was to examine nociceptive specific laser evoked responses (LEPs) in view of long-latency evoked potentials by non-painful electrical stimuli (SEPs) and auditory mismatch negativity (MM).  Three vegetative state (VS), four minimal Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, stimulating the dorsum of the right hand by noxious laser and innocuous electrical stimulus, according to normal controls subjective rating. An auditory paradigm for MM was also employed.  The MM was present in all patients. The LEP vertex complex was recognizable in all cases, with a significant latency increase of both N2 and P2 which displayed changes of topographic representation. Late SEPs were absent in all patients except in one MCS case, who showed a significant N2 and P2 latency increase.  The results may suggest that high relevant stimuli may be processed even in patients with severe brain damage. Larger series and multimodal approaches may contribute to confirm that cortical arousal toward pain salience may be a primary function for life persistence.

title: Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state
abstract: Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient visual, acoustic, somatosensory electric non-nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation.  Five Vegetative State (VS), 4 Minimally Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 s. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2) vertex complex in the 500 ms post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R) and Coma Recovery Scale (CRS-R) for clinical evaluation of pain perception and consciousness impairment.  The laser evoked potentials (LEPs) were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery.  pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the degree of cognitive and motor behavior recovery. This underlines the importance of considering the potential experience of pain also in patients in vegetative state and to appropriately assess a possible treatment also in those patients.

title: Determinants of laser-evoked EEG responses: pain perception or stimulus saliency?
abstract: Although laser-evoked electroencephalographic (EEG) responses are increasingly used to investigate nociceptive pathways, their functional significance remains unclear. The reproducible observation of a robust correlation between the intensity of pain perception and the magnitude of the laser-evoked N1, N2, and P2 responses has led some investigators to consider these responses a direct correlate of the neural activity responsible for pain intensity coding in the human cortex. Here, we provide compelling evidence to the contrary. By delivering trains of three identical laser pulses at four different energies, we explored the modulation exerted by the temporal expectancy of the stimulus on the relationship between intensity of pain perception and magnitude of the following laser-evoked brain responses: the phase-locked N1, N2, and P2 waves, and the non-phase-locked laser-induced synchronization (ERS) and desynchronization (ERD). We showed that increasing the temporal expectancy of the stimulus through stimulus repetition at a constant interstimulus interval 1) significantly reduces the magnitudes of the laser-evoked N1, N2, P2, and ERS; and 2) disrupts the relationship between the intensity of pain perception and the magnitude of these responses. Taken together, our results indicate that laser-evoked EEG responses are not determined by the perception of pain per se, but are mainly determined by the saliency of the eliciting nociceptive stimulus (i.e., its ability to capture attention). Therefore laser-evoked EEG responses represent an indirect readout of the function of the nociceptive system.

title: Evidence of a specific spinal pathway for the sense of warmth in humans.
abstract: While research on human sensory processing shows that warm input is conveyed from the periphery by specific, unmyelinated primary sensory neurons, its pathways in the central nervous system (CNS) remain unclear. To gain physiological information on the spinal pathways that convey warmth or nociceptive sensations, in 15 healthy subjects, we studied the cerebral evoked responses and reaction times in response to laser stimuli selectively exciting Adelta nociceptors or C warmth receptors at different levels along the spine. To minimize the conduction distance along the primary sensory neuron, we directed CO(2)-laser pulses to the skin overlying the vertebral spinous processes. Using brain source analysis of the evoked responses with high-resolution electroencephalography and a realistic model of the head based on individual magnetic resonance imaging scans, we also studied the cortical areas involved in the cerebral processing of warm and nociceptive inputs. The activation of C warmth receptors evoked cerebral potentials with a main positive component peaking at 470-540 ms, i.e., a latency clearly longer than that of the corresponding wave yielded by Adelta nociceptive input (290-320 ms). Spinal neurons activated by the warm input had a slower conduction velocity (2.5 m/s) than the nociceptive spinal neurons (11.9 m/s). Brain source analysis of the cerebral responses evoked by the Adelta input yielded a very strong fit for one single generator in the mid portion of the cingulate gyrus; the warmth-related responses were best explained by three generators, one within the cingulate and two in the right and left opercular-insular cortices. Our results support the existence of slow-conducting second-order neurons specific for the sense of warmth.

title: Are the processes reflected by late and ultra-late laser evoked potentials specific of nociception?
abstract: Publisher Summary This chapter reviews different hypotheses and their consequences regarding the functional significance of both late and ultra-late laser-evoked brain potentials (LEPs). An alternate hypothesis is presented, challenging the nociceptive specificity that is often ascribed to LEPs. Activation of Aδ- and C-fiber nociceptors produces a sensation of first pain and second pain without necessarily evoking late and ultra-late LEP responses. This observation indicates that the processes underlying LEPs may not be directly related to the perception of nociceptive input. Occurrence and amplitude of LEPs seem strongly conditioned by the salience of the evoking afferent input, suggesting that LEPs reflect processes related to mechanisms of involuntary attentional capture. The morphological, topographical, and behavioral similarities between N2 and P2 LEP components and the late endogenous vertex potentials that can be evoked by any kind of sensory stimulation suggests that these “vertex” components reflect nonspecific processes common to all sensory modalities.

title: Novelty is not enough: laser-evoked potentials are determined by stimulus saliency, not absolute novelty.
abstract: Event-related potentials (ERPs) elicited by transient nociceptive stimuli in humans are largely sensitive to bottom-up novelty induced, for example, by changes in stimulus attributes (e.g., modality or spatial location) within a stream of repeated stimuli. Here we aimed 1) to test the contribution of a selective change of the intensity of a repeated stimulus in determining the magnitude of nociceptive ERPs, and 2) to dissect the effect of this change of intensity in terms of "novelty" and "saliency" (an increase of stimulus intensity is more salient than a decrease of stimulus intensity). Nociceptive ERPs were elicited by trains of three consecutive laser stimuli (S1-S2-S3) delivered to the hand dorsum at a constant 1-s interstimulus interval. Three, equally spaced intensities were used: low (L), medium (M), and high (H). While the intensities of S1 and S2 were always identical (L, M, or H), the intensity of S3 was either identical (e.g., HHH) or different (e.g., MMH) from the intensity of S1 and S2. Introducing a selective change in stimulus intensity elicited significantly larger N1 and N2 waves of the S3-ERP but only when the change consisted in an increase in stimulus intensity. This observation indicates that nociceptive ERPs do not simply reflect processes involved in the detection of novelty but, instead, are mainly determined by stimulus saliency.

title: Scalp topography of ultralate (C-fibres) evoked potentials following thulium YAG laser stimuli to tiny skin surface areas in humans
abstract: To investigate (1) the scalp topography of ultralate laser evoked potentials (LEPs) related to C-fibre activation, which can directly be obtained by thulium YAG (Tm YAG) laser stimulation of tiny skin surface areas (about 0.23 mm(2)) and (2) the influence of the performance of a motor task on ultralate LEPs.



Laser stimuli were applied to the dorsum of the left hand. LEPs were recorded with 58 scalp electrodes from 9 healthy subjects in two different conditions, with and without a reaction time (RT) task (press a button upon detection).



On high resolution electroenchephalogram recordings, ultralate LEPs were characterized by a broad positive component (peak latency: 1133+/-91 ms) with maximum amplitude about the vertex. Moreover, the performance of a RT task had no influence on latency, amplitude and topographical patterns of two maps chosen at the positive peak latency in ultralate LEPs. Nevertheless, a negative inflexion (latency 1300 ms) appeared after the positive component in the task condition possibly reflecting movement-related potentials.



Tm YAG laser stimulation of tiny skin surface areas allows recording the dynamic scalp topography of ultralate (C-fibres) LEPs, with or without the performance of a RT task.

title: Attention-related modifications of ultra-late CO2 laser evoked potentials to human trigeminal nerve stimulation
abstract: Our study aimed at investigating the scalp topography of ultra-late CO(2) laser evoked potentials (LEPs), which are related to C fiber activation, and at exploring the effect of attention deviation on ultra-late LEPs. Brain responses to non-painful CO(2) laser stimuli were recorded in ten healthy subjects in three different conditions: (i) neutral condition in which subjects did not have any task; (ii) distraction condition in which subjects were asked to perform a mathematical task; and (iii) attention condition in which subjects had to count the number of stimuli. In all subjects, also A fiber-related late LEPs were recorded after painful CO(2) laser stimulation. The ultra-late LEPs in attention condition included an earlier negative potential (ultra-late N1) in the contralateral temporal region and a simultaneous frontal positive response (ultra-late P1). Later, a vertex biphasic component (ultra-late N2a and ultra-late P2) was identifiable. The vertex ultra-late LEP amplitude was significantly decreased in both neutral and distraction condition. Ultra-late LEPs showed a longer latency than late LEPs, but the scalp distributions of both ultra-late and late LEPs were very similar, thus suggesting that the same cerebral areas may be involved in their generation. Since attention deviations have a strong effect on ultra-late LEP amplitude, the subject's attention should be addressed to CO(2) laser stimuli when ultra-late LEPs are used for clinical purposes.

title: Stimulus novelty, and not neural refractoriness, explains the repetition suppression of laser-evoked potentials.
abstract: Brief radiant laser pulses selectively activate skin nociceptors and elicit transient brain responses (laser-evoked potentials [LEPs]). When LEPs are elicited by pairs of stimuli (S1-S2) delivered at different interstimulus intervals (ISIs), the S2-LEP is strongly reduced at short ISIs (250 ms) and progressively recovers at longer ISIs (2,000 ms). This finding has been interpreted in terms of order of arrival of nociceptive volleys and refractoriness of neural generators of LEPs. However, an alternative explanation is the modulation of another experimental factor: the novelty of the eliciting stimulus. To test this alternative hypothesis, we recorded LEPs elicited by pairs of nociceptive stimuli delivered at four ISIs (250, 500, 1,000, 2,000 ms), using two different conditions. In the constant condition, the ISI was identical across the trials of each block, whereas in the variable condition, the ISI was varied randomly across trials and single-stimulus trials were intermixed with paired trials. Therefore the time of occurrence of S2 was both less novel and more predictable in the constant than in the variable condition. In the constant condition, we observed a significant ISI-dependent suppression of the biphasic negative-positive wave (N2-P2) complex of the S2-LEP. In contrast, in the variable condition, the S2-LEP was completely unaffected by stimulus repetition. The pain ratings elicited by S2 were not different in the two conditions. These results indicate that the repetition-suppression of the S2-LEP is not due to refractoriness in nociceptive afferent pathways, but to a modulation of novelty and/or temporal predictability of the eliciting stimulus. This provides further support to the notion that stimulus saliency constitutes a crucial determinant of LEP magnitude and that a significant fraction of the brain activity time-locked to a brief and transient sensory stimulus is not directly related to the quality and the intensity of the corresponding sensation, but to bottom-up attentional processes.

title: Recommendations for the clinical use of somatosensory-evoked potentials
abstract: The International Federation of Clinical Neurophysiology (IFCN) is in the process of updating its Recommendations for clinical practice published in 1999. These new recommendations dedicated to somatosensory-evoked potentials (SEPs) update the methodological aspects and general clinical applications of standard SEPs, and introduce new sections dedicated to the anatomical-functional organization of the somatosensory system and to special clinical applications, such as intraoperative monitoring, recordings in the intensive care unit, pain-related evoked potentials, and trigeminal and pudendal SEPs. Standard SEPs have gained an established role in the health system, and the special clinical applications we describe here are drawing increasing interest. However, to prove clinically useful each of them requires a dedicated knowledge, both technical and pathophysiological. In this article we give technical advice, report normative values, and discuss clinical applications.

title: Coma Recovery Scale-Revised: evidentiary support for hierarchical grading of level of consciousness.
abstract: To investigate the neurobehavioral pattern of recovery of consciousness as reflected by performance on the subscales of the Coma Recovery Scale-Revised (CRS-R).



Retrospective item response theory (IRT) and factor analysis.



Inpatient rehabilitation facilities.



Rehabilitation inpatients (N=180) with posttraumatic disturbance in consciousness who participated in a double-blinded, randomized, controlled drug trial.



Not applicable.



Scores on CRS-R subscales.



The CRS-R was found to fit factor analytic models adhering to the assumptions of unidimensionality and monotonicity. In addition, subscales were mutually independent based on residual correlations. Nonparametric IRT reaffirmed the finding of monotonicity. A highly constrained confirmatory factor analysis model, which imposed equal factor loadings on all items, was found to fit the data well and was used to estimate a 1-parameter IRT model.



This study provides evidence of the unidimensionality of the CRS-R and supports the hierarchical structure of the CRS-R subscales, suggesting that it is an effective tool for establishing diagnosis and monitoring recovery of consciousness after severe traumatic brain injury.

title: A sensitive scale to assess nociceptive pain in patients with disorders of consciousness
abstract: To determine the sensitivity of the Nociception Coma Scale (NCS), the first scale developed to assess nociceptive pain in vegetative state and minimally conscious state patients, in comparing behavioural changes in response to noxious versus non-noxious stimulation.  The NCS was administered to assess patients' responses in three conditions: (1) baseline (observation of spontaneous behaviours), (2) non-noxious/tactile stimulation (taps on the patient's shoulder), and (3) noxious stimulation (pressure on the nail bed).  We included 64 patients (27 vegetative state and 37 minimally conscious state; age range 20–82 years; 22 traumatic brain injury; 21 in the acute stage). The NCS total scores and subscores (motor, verbal and facial) were higher for the noxious versus the non-noxious stimulation conditions. We did not observe a difference between the non-noxious and the noxious stimulation conditions for the visual subscale. We also found a NCS cut-off value of 4 differentiating the patients receiving a noxious stimulation from patients receiving a non-noxious stimulation. The exclusion of the visual subscale increased the cut-off sensitivity (from 46% to 73%; specificity of 97% and accuracy of 85%).  We propose a new version of the NCS excluding the visual subscale, the NCS-R, which constitutes a highly sensitive tool to assess responses to nociceptive pain in severely brain injured patients.

title: The JFK coma recovery scale—revised
abstract: The JFK Coma Recovery Scale (CRS) was developed to help characterise and monitor patients functioning at Rancho Levels I–IV and has been used widely in both clinical and research settings within the US and Europe. The CRS was recently revised to address a number of concerns emanating from our own clinical experience with the scale, feedback from users and researchers as well as the results of Rasch analyses. Additionally, the CRS did not include all of the behavioural criteria necessary to diagnose the minimally conscious state (MCS), thereby limiting diagnostic utility. The revised JFK Coma Recovery Scale (CRS-R) includes addition of new items, merging of items found to be statistically similar, deletion or modification of items showing poor fit with the scale's underlying construct, renaming of items, more stringent scoring criteria, and quantification of elicited behaviours to improve accuracy of rating. Psychometric properties of the CRS-R appear to meet standards for measurement and evaluation tools for use in clinical and research settings, and diagnostic application suggests that the scale is capable of discriminating patients in the minimally conscious state from those in the vegetative state. Individuals interested in obtaining a copy of the JFK CRS-R and administration and scoring procedures are referred to the authors.

title: Direct isolation of ultra-late (C-fibre) evoked brain potentials by CO2 laser stimulation of tiny cutaneous surface areas in man
abstract: In this study, it is reported that CO2 laser heat stimulation of tiny skin surface area (0.15 mm2) provides a unique method to directly and selectively activate C-fibre as assessed by the ultra-late brain potentials (peak latencies: N810, P996) evoked consistently across a set of stimulus energy levels. On a larger surface area (15.5 mm2), low energy stimulation also resulted in minute ultra-late potential, while higher intensities induced only late potentials related to A-delta fibre activity (peak latencies: N247, P394). The selective activation of C afferent sensory terminals in the skin by stimulation of tiny surface area is explained by their relative high density and lower activation threshold.

title: Clinical usefulness of laser-evoked potentials
abstract: In contrast to the function of the visual or auditory pathways which are electrophysiologically accessible by visual or auditory evoked potentials, the somatosensory pathway cannot be investigated as a whole by conventional somatosensory evoked potentials (SEP), because these only reflect function of large fibers, dorsal columns, medial lemniscus and their thalamo-cortical projections mediating sensations like touch and vibration. The other half of the somatosensory system, signaling temperature and pain perception, uses a different set of afferents and different central pathways, the function of which is accessible by laser-evoked potentials (LEPs). LEP can document lesions of the spinothalamic tract and (lateral) brainstem and of thalamo-cortical projections conveying thermo-nociceptive signals. In the peripheral nerve, LEP can help distinguish between large and small fiber neuropathies. The rapid heating of the skin by infrared laser pulses can easily be applied to non-glabrous skin in any dermatome. In recent years, many clinical studies have demonstrated that LEP can supply evidence for establishing clinical diagnoses when deficits of the nociceptive system are present. This review outlines principles and recording techniques for LEP in patients and compiles typical LEP findings in patients with lesions due to different diseases at various levels of the nociceptive pathways. Limitations for the use of LEP are pointed out, too, like the uncertainty of lesion location along these pathways and the fact that LEP can reliably show correlates of reduced nociceptive function but only rarely of enhanced transmission (like in hyperalgesia).

title: Statistically robust measurement of evoked response onset latencies
abstract: Onset latencies of evoked responses are useful for determining delays in sensory pathways and for indicating spread of activity between brain areas, therefore inferring causality. Previous studies have applied several different methods and parameters for detecting onsets, mainly utilizing thresholds based on the mean and standard deviation (SD) of the pre-stimulus "baseline" time window, or using t-tests of group data to determine when the response first differs significantly from the baseline. However, these methods are not statistically robust, have low power when the baseline data are not normally distributed, and are heavily influenced by outliers in the baseline. Here, we examine using a modified boxplot method known as the "median rule" for determining onset latencies. This rule makes no assumptions about the baseline distribution, is resistant to outliers, and can be applied to individual level data therefore allowing intersubject and interregional comparisons. We first show with simulations that the median rule is significantly less sensitive to outliers in the baseline than the SD method. We then use simulations to demonstrate the effect of skewness on onset latencies. Finally, we use magnetoencephalography (MEG) to show that the median rule can be easily applied to real data and gives reasonable results. In most situations the different methods give similar results, which enhances comparability across studies, but in data sets with a high noise level there is a clear advantage to using a statistically robust method. In conclusion, the median rule is an excellent method for estimating onset latencies in evoked responses.

title: NeuPSIG guidelines on neuropathic pain assessment
abstract: &NA; This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes. Measurement of trigeminal reflexes mediated by A‐beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser‐evoked potentials is useful for assessing function of the A‐delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction. The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended.

title: Unmyelinated trigeminal pathways as assessed by laser stimuli in humans.
abstract: Laser pulses excite superficial free nerve endings innervated by small-myelinated (Adelta) and unmyelinated (C) fibres. Whereas laser-evoked scalp potentials (LEPs) are now reliably used to assess function of the Adelta-fibre nociceptive pathways in patients with peripheral or central lesions, the selective activation of C-fibre receptors and recording of the related brain potentials remain difficult. To investigate trigeminal C-fibre function, we directed laser pulses to the facial skin and studied sensory perception and scalp evoked potentials related to Adelta- or C-fibre activation in healthy humans and patients--one having a bilateral facial palsy, two a trigeminal neuropathy, and two a Wallenberg syndrome. We also measured afferent conduction velocity and, with source analysis, studied the brain generators. Whereas laser pulses of low intensity and small irradiated area elicited pinprick sensations and standard Adelta-LEPs, laser pulses of very-low intensity and large irradiated area elicited warmth sensations and scalp potentials with a latency compatible with C-fibre conduction (negative wave 280 ms, positive wave 380 ms); the estimated conduction velocity was 1.2 m/s. The main waves of the scalp potentials originated from the anterior cingulate gyrus; they were preceded by activity in the opercular region and followed by activity in the insular region. The patient with bilateral facial palsy, who had absent trigeminal-facial reflexes, had normal Adelta- and C-related scalp potentials; the patients with trigeminal neuropathy, characterized by loss of myelinated and sparing of unmyelinated fibres, had absent Adelta- but normal C-related potentials; and the patients with Wallenberg syndrome had absent Adelta- and C-related potentials. We conclude that laser pulses with appropriate characteristics evoke brain potentials related to the selective activation of trigeminal nociceptive Adelta or thermal C fibres. The trigeminal territory yields rewarding LEP findings owing to the high density of thermal receptors and, because the short conduction distance, minimizes the problem of signal dispersion along slow-conducting unmyelinated afferents. The opercular-insular region and the cingulate gyrus are involved in the processing of C-fibre trigeminal inputs. The method we describe may prove useful in patients with lesions affecting the trigeminal thermal pain pathways.

title: Pathophysiology of pain in postherpetic neuralgia: A clinical and neurophysiological study
abstract: Postherpetic neuralgia is an exceptionally drug‐resistant neuropathic pain. To investigate the pathophysiological mechanisms underlying postherpetic neuralgia we clinically investigated sensory disturbances, pains and itching, with an 11‐point numerical rating scale in 41 patients with ophthalmic postherpetic neuralgia. In all the patients we recorded the blink reflex, mediated by non‐nociceptive myelinated Aβ‐fibers, and trigeminal laser evoked potentials (LEPs) related to nociceptive myelinated Aδ‐ and unmyelinated C‐fiber activation. We also sought possible correlations between clinical sensory disturbances and neurophysiological data. Neurophysiological testing yielded significantly abnormal responses on the affected side compared with the normal side (P < 0.001). The blink reflex delay correlated with the intensity of paroxysmal pain, whereas the Aδ‐ and C‐LEP amplitude reduction correlated with the intensity of constant pain (P < 0.01). Allodynia correlated with none of the neurophysiological data. Our study shows that postherpetic neuralgia impairs all sensory fiber groups. The neurophysiological‐clinical correlations suggest that constant pain arises from a marked loss of nociceptive afferents, whereas paroxysmal pain is related to Aβ‐fiber demyelination. These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia.

title: CO2 laser radiant heat pulses activate C nociceptors in man
abstract: Cerebral potentials evoked by noxious CO2 laser stimuli in man have been referred to nociceptive Aδ units. This paper shows 1) that ultra short (5–50 ms) high power (≤ 50 W) CO2 laser skin stimuli are able to activate nociceptive C units in man, and 2) that these C nociceptors have to be assumed to terminate in the very superficial skin layer (≤300 μm depth).

title: Clinical evaluation criteria for the assessment of impaired pain sensitivity by thulium-laser evoked potentials
abstract: Cortical potentials evoked by carbon dioxide laser pulses have been applied in clinical practice to study nociceptive pathways for several years. In this study, we evaluate the properties of an infrared laser (thulium-YAG) with a penetration depth in the skin that matches the intracutaneous depth of nociceptors.



Temperature measurements and modelling showed that the thulium laser generates painful intracutaneous temperatures with less surface heating than the carbon dioxide laser and with no side effects (up to 600 mJ pulse energy). To develop clinical evaluation criteria, laser-evoked potentials (LEPs) were recorded from 3 midline positions (Fz, Cz, Pz) versus linked earlobes in 23 healthy subjects. Within a session, two skin areas were studied twice in a balanced sequence using randomized interstimulus intervals and two intensities in randomized order.



After hand and foot stimulation with 540 mJ pulses, all subjects showed reproducible biphasic vertex potential, consisting of a negativity (hand: 210 ms, foot: 250 ms) and a positivity (hand: 330 ms, foot: 380 ms). Mean habituation of the vertex potential amplitude across runs was 25% (hand) or 16% (foot); due to the balanced sequence it did not affect the other comparisons. Following foot stimulation, peak latencies were significantly longer (by 40-50 ms) and amplitudes were significantly smaller than following hand stimulation (22.5+/-6.7 vs. 30.3+/-10.9 microV, mean+/-SD). Using 2. 5 standard deviations from the mean as a cut-off, absolute normative values were determined for peak latencies and amplitudes. In addition, relative normative values were determined for paired comparisons (hand-hand, foot-foot, hand-foot).



The thulium-YAG laser is a useful tool for assessment of impaired pain sensitivity. Representative case reports illustrate that unlike for early SEP components, the most frequent LEP abnormalities were amplitude differences.

title: How do we selectively activate skin nociceptors with a high power infrared laser? Physiology and biophysics of laser stimulation
abstract: This review presents and discusses the leading arguments justifying the use of high power laser stimulators to explore the nociceptive system. To grasp the particularity of such stimulators, fundamentals concerning the interaction of low-energy radiation with the skin will be recalled and focused on the optimal match between the wavelength of the emitting source and the thermophysical properties of the skin. This knowledge shall allow us to discuss critical characteristics of laser stimulators. Study of the cutaneous spectrum of receptors showed that laser stimulators allow the selective activation of A(delta) and C-fiber nociceptors. We will present different methods, which increase the selectivity of the laser stimulation, restricting the activation to isolated C-fiber nociceptors. These methods open new perspectives in the study of the cerebral processing of signals ascending through A(delta) and/or C nociceptors and should contribute to a better understanding of their central interaction and integration in normal and pathological states.

title: Evoked potentials to nociceptive stimuli delivered by CO2 or Nd:YAP lasers
abstract: This study compares the amplitude, latency, morphology, scalp topography and intracranial generators of laser-evoked potentials (LEPs) to CO(2) and Nd:YAP laser stimuli.



LEPs were assessed in 11 healthy subjects (6 men, mean age 39+/-10 years) using a 32-channel acquisition system. Laser stimuli were delivered on the dorsum of both hands (intensity slightly above pain threshold), and permitted to obtain lateralised (N1) and vertex components (N2-P2) with similar scalp distribution for both types of lasers.



The N1-YAP had similar latencies but significantly higher amplitudes relative to N1-CO(2). The N2-P2 complex showed earlier latencies, higher amplitudes (N2) and more synchronised responses when using Nd:YAP stimulation. The distribution of intracranial generators assessed with source localization analyses (sLORETA) was similar for Nd:YAP and CO(2) lasers. The insular, opercular, and primary sensorimotor cortices were active during the N1 time-window, whereas the anterior midcingulate, supplementary motor areas and mid-anterior insulae were active concomitant to the N2-P2 complex.



Earlier latencies and larger amplitudes recorded when using Nd:YAP pulses suggest a more synchronized nociceptive afferent volley with this type of laser.



This, together with its handy utilization due to optic fibre transmission, may favour the use of Nd:YAP lasers in clinical settings.

title: Aδ nociceptor response to laser stimuli: selective effect of stimulus duration on skin temperature, brain potentials and pain perception
abstract: To disclose a possible effect of duration of pulsed laser heat stimuli on Adelta nociceptor responses, skin temperature profiles, brain evoked potentials and pain perception.



We used a laser stimulator which works in the millisecond range and allows us to change the duration of the pulse while keeping the total energy of the stimulus constant. In 10 healthy volunteers, we measured the intensity of perceived pain with a 0-10 scale and the latency and amplitude of the early N1 and late N2 components of the scalp potentials evoked by laser pulses of equal energy and three different stimulus durations (2, 10, and 20 ms). Using a specifically developed pyrometer with a temporal resolution lower than 1 ms we also measured stimulus-induced changes of skin temperature.



Stimulus duration significantly influenced temperature rise times, pain perception, and brain potentials. Shorter stimulus durations yielded steeper slopes in the skin temperature profiles and higher pain ratings, shortened the latency of the N1 and N2 components, and increased the amplitude of N1.



The shorter stimulus duration shortens receptor activation times and yields a more synchronous afferent volley, thus providing a stronger spatial-temporal summation at central synapses that enhances intensity of first pain and brain potentials. This may prove useful in clinical applications.

title: Human Brain Responses to Concomitant Stimulation of Aδ and C Nociceptors
abstract: Intense radiant heat pulses concomitantly activate Aδ- and C-fiber skin nociceptors, and elicit a typical double sensation: an initial Aδ-related pricking pain is followed by a C-related prolonged burning sensation. It has been repeatedly reported that C-fiber laser-evoked potentials (C-LEPs) become detectable only when the concomitant activation of Aδ-fibers is avoided or reduced. Given that the saliency of the eliciting stimulus is a major determinant of LEPs, one explanation for these observations is that the saliency of the C-input is smaller than that of the preceding Aδ-input. However, even if the saliency of the C-input is reduced because of the preceding Aδ-input, a C-LEP should still be visible even when preceded by an Aδ-LEP response. Here we tested this hypothesis by applying advanced signal processing techniques (peak alignment and time-frequency decomposition) to electroencephalographic data collected in two experiments conducted in 34 and 96 healthy participants. We show that, when using optimal stimulus parameters (delivering >80 stimuli within a small skin territory), C-LEPs can be reliably detected in most participants. Importantly, C-LEPs are observed even when preceded by Aδ-LEPs, both in average waveforms and single trials. By providing quantitative information about several response properties of C-LEPs (latency jitter, stimulus-response and perception–response functions, dependency on stimulus repetitions and stimulated area), these results define optimal parameters to record C-LEPs simply and reliably. These findings have important clinical implications for assessing small-fiber function in neuropathies and neuropathic pain.

title: Laser-evoked potential abnormalities in central pain patients: the influence of spontaneous and provoked pain.
abstract: We recorded laser-evoked cortical potentials (LEPs) in 54 consecutive patients presenting with unilateral neuropathic central pain (n = 42) or with lateralized pain of non-organic origin (n = 12). A number of cases in each group had superimposed hyperalgesia or allodynia. In patients with central pain, LEPs were significantly attenuated after stimulation over the painful territory, relative to stimulation of the homologous normal territory. LEP attenuation concerned not only patients with decreased pain/heat sensation, but also those with allodynia or hyperalgesia to laser pulses. In contrast, LEPs were never attenuated in patients with non-organic forms of pain, in whom LEPs could even be enhanced to stimulation of the painful territory. Increased responses in non-organic pain were a reminder of the cognitive modulation observed in normal subjects who direct attention to a laser stimulus. Enhanced LEPs never accompanied truly neuropathic hyperalgesia or allodynia. In central pain patients with exclusively spontaneous pain, LEP attenuation was more pronounced than that observed in those with allodynia and hyperalgesia. Patients with allodynia also presented occasionally ultra-late responses (>700 ms) to stimulation of the painful side. The hypothesis that such responses may reflect activation of a slow conducting 'medial' pain system is discussed. We conclude that, as currently recorded, LEPs essentially reflect the activity of a 'lateral' pain system subserved at the periphery by rapidly conducting A-delta fibres. They are useful to document the sensorial deficits (deafferentation) leading to neuropathic pain syndromes. Conversely, in the case of deafferentation, they fail to index adequately the affective aspects of pain sensation. On practical grounds, chronic pain coupled with reduced LEPs substantiates the diagnosis of neuropathic pain, whereas the finding of normal or enhanced LEPs to stimulation of a painful territory suggests the integrity of pain pathways, and does not support a neuropathic pathophysiology. In neuropathic cases, partial LEP preservation might increase the probability of developing provoked pain (allodynia/hyperalgesia). The possible predictive value of this phenomenon, when observed before the development of pain, remains to be demonstrated. In selected contexts (pain sine materia, non-organic anaesthesia), normal or enhanced LEPs may support a psychogenic participation in the syndrome.

title: The medial pain system, cingulate cortex, and parallel processing of nociceptive information.
abstract: Nociceptive information in the cerebral cortex is thought to be processed according to discriminative properties, including localization and intensity, and affective associations. Stimulus localization is assessed mainly in somatosensory and posterior parietal cortices, while affective responses are processed in limbic regions. It has been known for four decades that ablations of anterior cingulated cortex (ACC) and its underlying white matter, the cingulum bundle, reduce or abolish affective responses to noxious stimuli, while sensory localization remains intact. Cingulate cortex forms a cingulum around the genual, dorsal, and splenial parts of the corpus callosum. The human cingulate sulci can form single or double parallel patterns that make averaging across cases difficult in functional imaging studies. The multiple sulcal patterns are related in turn to different depths with the single cingulated sulcus having the greatest depth of more than 1.5 cm. In order to expedite conversations about cingulate cortex, the cingulated gyrus is routinely divided into four regions that have unique cytoarchitectures, connections, and functions. The four regions and associated areas are as follows: perigenual areas 25, 24, and 32; midcingulate areas 24’ and 32’; posterior areas 23 and 31; retrosplenial areas 29 and 30. Since early distinctions between anterior and posterior cingulated cortices are not adequate for either structural or functional studies, the designation of a midcingulate region provides a simple regional designation to avoid such concepts as a posterior anterior cingulate cortex.

title: Limbic hyperconnectivity in the vegetative state
abstract: To investigate functional connectivity between the default mode network (DMN) and other networks in disorders of consciousness.  We analyzed MRI data from 11 patients in a vegetative state and 7 patients in a minimally conscious state along with age- and sex-matched healthy control subjects. MRI data analysis included nonlinear spatial normalization to compensate for disease-related anatomical distortions. We studied brain connectivity data from resting-state MRI temporal series, combining noninferential (independent component analysis) and inferential (seed-based general linear model) methods.  In DMN hypoconnectivity conditions, a patient's DMN functional connectivity shifts and paradoxically increases in limbic structures, including the orbitofrontal cortex, insula, hypothalamus, and the ventral tegmental area.  Concurrently with DMN hypoconnectivity, we report limbic hyperconnectivity in patients in vegetative and minimally conscious states. This hyperconnectivity may reflect the persistent engagement of residual neural activity in self-reinforcing neural loops, which, in turn, could disrupt normal patterns of connectivity.

title: Functional plasticity in primate somatosensory thalamus following chronic lesion of the ventral lateral spinal cord
abstract: The long-term consequences of thoracic spinothalamic tract lesion on the physiological properties of neurons in the ventral posterior lateral nucleus of the thalamus in monkeys were assessed. Neurons responding to both compressive and phasic brush stimuli (multireceptive neurons), but not brush-specific (low-threshold) neurons, in the partially deafferented thalamus showed increased spontaneous activity, increased responses evoked by cutaneous stimuli and larger mean receptive field size than the same types of cells in the thalamus with intact innervation. The spike train properties of both the spontaneous and evoked discharges of cells were also altered so that there was an increased incidence of spike-bursts in cells of deafferented thalamus. These changes were widespread in the thalamus, and included cells in both the fully innervated forelimb representation and the partially denervated hindlimb representation ipsilateral to the lesion. The spontaneous and evoked spike trains in the ipsilateral thalamus also show increased frequency of both spike-burst and non-burst events compared to the intact thalamus. These results indicate that chronic spinothalamic tract lesion produces widespread changes in the physiological properties of a discrete cell population of the thalamus.The findings in this study indicate that the thalamic processing of somatosensory information conveyed by the lemniscal system is altered by transection of the spinothalamic tract. This change in sensory processing in the thalamus would result in altered cortical processing of innocuous somatosensory inputs following deafferentation and so possibly contribute to the generation of the central pain syndrome.

title: Hyperalgesia with reduced laser evoked potentials in neuropathic pain
abstract: Nociceptive evoked potentials to laser stimuli (LEPs) are able to detect lesions of pain and temperature pathways at peripheral, spinal and supraspinal levels. It is commonly accepted that LEP attenuation correlates with the loss of pain and temperature sensations, while pathological heat-pain hypersensitivity has been associated with increased LEP amplitude. Here we present two patients in whom increased pain sensation (hyperalgesia) to laser stimuli was, on the contrary, associated to delayed, desynchronized and attenuated LEPs. Both patients experienced increased unpleasantness and affective reactions to laser, associated to poor ability to localize the stimulus. In both cases the results may be explained by an overactivation of the 'medial pain system', in one patient due to deafferentation of cortical sensory areas by a capsular lesion, and in the other to imbalance between A-delta and C fiber excitation due to peripheral nerve injury. Our results suggest that LEPs, as currently recorded, reflect the activity of a 'lateral' pain system subserved by rapidly conducting fibers. They may therefore, assess the sensory and cognitive dimensions of pain, but may not index adequately the affective-emotional aspects of pain sensation conveyed by the 'medial' pain system. The dissociation between pain sensation and cortical EPs deserve to be added to the current semiology of LEPs, as the presence of abnormal pain to laser on the background of reduced LEPs substantiates the neuropathic nature of the pain.

title: C- and A delta-fiber components of heat-evoked cerebral potentials in healthy human subjects.
abstract: Feedback-controlled laser heat was used to stimulate the hairy skin of the hand dorsum and forearm, and heat-evoked cerebral potentials were recorded at midline (Fz, Cz, Pz) and temporal (T3, T4) scalp positions. Based on data from primary afferent electrophysiology a stimulus level (40 degrees C) was chosen, which is above C-fiber heat threshold, but clearly below A delta-nociceptor heat threshold in order to excite selectively C-fibers without concomitant excitation of A delta-fibers. Feedback-controlled stepped heat stimuli to 40 degrees C elicited ultralate laser evoked potentials (LEPs) at the vertex in a high proportion of experiments (90%). Estimates of conduction velocity calculated from latency shifts between the hand and forearm sites of ultralate LEPs (2.4 m/s) and of reaction times (2.8 m/s) confirmed mediation of ultralate potentials by unmyelinated nerve fibers (nociceptors and/or warm fibers). The ultralate LEP could be differentiated from resolution of contingent negative variation (CNV), an endogenous potential related to expectation and response preparation, by its scalp topography. Strong heat stimuli of 48 degrees C, which is suprathreshold for most A delta- and C-fiber nociceptors, elicited the well-known late LEPs mediated by nociceptive Adelta-fibers confirming previous studies. The LEP waveform to strong heat stimuli also contained an ultralate component reminiscent of an ultralate LEP following the late LEP. Ultralate and late LEP had identical scalp topography. In conclusion, the method of temperature-controlled laser heat stimuli allows the selective and reliable examination of A delta- and C-fiber-mediated afferent pathways and the related cortical processing without the complication of dissociating A-fiber nerve blocks.