Insular-limbic dissociation to intra-epidermal electrical Aδ activation: A comparative study with thermo-nociceptive laser stimulation.

Intra-epidermal electrical stimulation (IEES) has been shown to activate selectively Aδ fibers subserving spinothalamic-mediated sensations. Owing to electrically induced highly synchronous afferent volleys, IEES induces Aδ-mediated evoked potentials at nonpainful intensities, contrasting with thermo-nociceptive laser pulses which entail painful pricking sensations. Here, we recorded intracortical responses from sensory and limbic-cognitive regions of human subjects in response to IEE and laser stimuli, in order to test the hypothesis that IEES could dissociate the sensory from nonsensory networks of nociceptive processing. Intracortical evoked potentials were obtained in 11 epileptic patients with stereotactically implanted electrodes in sensory regions receiving spinothalamic afferents (posterior insula), limbic regions receiving spino-parabrachial input (amygdalar nucleus), and high-order affective-cognitive regions (anteromedial frontal cortex, including perigenual anterior cingulate and rostromedial prefrontal areas). Responses in the sensory posterior insula were of similar amplitude and latency to IEE and laser stimuli (after accounting for heat-transduction time of laser), and consistent in both cases with spinothalamic activation. However, responses to IEES in the amygdala and the anteromedial frontal regions were inconsistent and significantly smaller compared to those evoked to the laser stimulation. Thus, IEES can effectively activate the spinothalamic-sensory system with little recruitment of affective-motivational networks, including those triggered by spino-parabrachio-amygdalar projections. The fact that identical sensory responses were associated to either painful or nonpainful percepts underscores that subjective pain perception is not solely dependent on the sensory recruitment, but rather on the combined activation of sensory, limbic and cognitive areas with precise spatiotemporal relations.

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.

Thalamic Responses to Nociceptive-Specific Input in Humans: Functional Dichotomies and Thalamo-Cortical Connectivity.

While nociceptive cortical activation is now well characterized in humans, understanding of the nociceptive thalamus remains largely fragmentary. We used laser stimuli and intracerebral electrodes in 17 human subjects to record nociceptive-specific field responses in 4 human thalamic nuclei and a number of cortical areas. Three nuclei known to receive spinothalamic (STT) projections in primates (ventro-postero-lateral [VPL], anterior pulvinar [PuA], and central lateral [CL]) exhibited responses with similar latency, indicating their parallel activation by nociceptive afferents. Phase coherence analysis, however, revealed major differences in their functional connectivity: while VPL and PuA drove a limited set of cortical targets, CL activities were synchronized with a large network including temporal, parietal, and frontal areas. Our data suggest that STT afferents reach simultaneously a set of lateral and medial thalamic regions unconstrained by traditional nuclear borders. The broad pattern of associated cortical networks suggests that a single nociceptive volley is able to trigger the sensory, cognitive, and emotional activities that underlie the complex pain experience. The medial pulvinar, an associative nucleus devoid of STT input, exhibited delayed responses suggesting its dependence on descending cortico-thalamic projections. Its widespread cortical connectivity suggests a role in synchronizing parietal, temporal, and frontal activities, hence contributing to the access of noxious input to conscious awareness.

Pain networks from the inside: Spatiotemporal analysis of brain responses leading from nociception to conscious perception.

Conscious perception of painful stimuli needs the contribution of an extensive cortico-subcortical network, and is completed in less than one second. While initial activities in operculo-insular and mid-cingulate cortices have been extensively assessed, the activation timing of most areas supporting conscious pain has barely been studied. Here we used intracranial EEG to investigate the dynamics of 16 brain regions (insular, parietal, prefrontal, cingulate, hippocampal and limbic) during the first second following nociceptive-specific laser pulses. Three waves of activation could be defined according to their temporal relation with conscious perception, ascertained by voluntary motor responses. Pre-conscious activities were recorded in the posterior insula, operculum, mid-cingulate and amygdala. Antero-insular, prefrontal and posterior parietal activities started later and developed during time-frames consistent with conscious voluntary reactions. Responses from hippocampus, perigenual and perisplenial cingulate developed latest and persisted well after conscious perception occurred. Nociceptive inputs reach simultaneously sensory and limbic networks, probably through parallel spino-thalamic and spino-parabrachial pathways, and the initial limbic activation precedes conscious perception of pain. Access of sensory information to consciousness develops concomitant to fronto-parietal activity, while late-occurring responses in the hippocampal region, perigenual and posterior cingulate cortices likely underlie processes linked to memory encoding, self-awareness and pain modulation. Hum Brain Mapp 37:4301-4315, 2016. © 2016 Wiley Periodicals, Inc.

Sleep spindles and human cortical nociception: a surface and intracerebral electrophysiological study.

KEY POINTS: Sleep spindle are usually considered to play a major role in inhibiting sensory inputs. Using nociceptive stimuli in humans, we tested the effect of spindles on behavioural, autonomic and cortical responses in two experiments using surface and intracerebral electroencephalographic recordings. We found that sleep spindles do not prevent arousal reactions to nociceptive stimuli and that autonomic reactivity to nociceptive inputs is not modulated by spindle activity. Moreover, neither the surface sensory, nor the insular evoked responses were modulated by the spindle, as detected at the surface or within the thalamus. The present study comprises the first investigation of the effect of spindles on nociceptive information processing and the results obtained challenge the classical inhibitory effect of spindles. ABSTRACT: Responsiveness to environmental stimuli declines during sleep, and sleep spindles are often considered to play a major role in inhibiting sensory inputs. In the present study, we tested the effect of spindles on behavioural, autonomic and cortical responses to pain, in two experiments assessing surface and intracerebral responses to thermo-nociceptive laser stimuli during the all-night N2 sleep stage. The percentage of arousals remained unchanged as a result of the presence of spindles. Neither cortical nociceptive responses, nor autonomic cardiovascular reactivity were depressed when elicited within a spindle. These results could be replicated in human intracerebral recordings, where sleep spindle activity in the posterior thalamus failed to depress the thalamocortical nociceptive transmission, as measured by sensory responses within the posterior insula. Hence, the assumed inhibitory effect of spindles on sensory inputs may not apply to the nociceptive system, possibly as a result of the specificity of spinothalamic pathways and the crucial role of nociceptive information for homeostasis. Intriguingly, a late scalp response commonly considered to reflect high-order stimulus processing (the 'P3' potential) was significantly enhanced during spindling, suggesting a possible spindle-driven facilitation, rather than attenuation, of cortical nociception.

Asleep but aware?

Despite sleep-induced drastic decrease of self-awareness, human sleep allows some cognitive processing of external stimuli. Here we report the fortuitous observation in a patient who, while being recorded with intra-cerebral electrodes, was able, during paradoxical sleep, to reproduce a motor behaviour previously performed at wake to consciously indicate her perception of nociceptive stimulation. Noxious stimuli induced behavioural responses only if they reached the cortex during periods when mid-frontal networks (pre-SMA, pre-motor cortex) were pre-activated. Sensory responses in the opercular cortex and insula were identical whether the noxious stimulus was to evoke or not a motor behaviour; conversely, the responses in mid-anterior cingulate were specifically enhanced for stimuli yielding motor responses. Neuronal networks implicated in the voluntary preparation of movements may be reactivated during paradoxical sleep, but only if behavioural-relevant stimuli reach the cortex during specific periods of "motor awareness". These local activation appeared without any global sleep stage change. This observation opens the way to further studies on the currently unknown capacity of the sleeping brain to interact meaningfully with its environment.

Cold-evoked potentials in clinical practice: A head-to-head contrast with laser-evoked responses.

BACKGROUND: Innocuous cooling of the skin activates cold-specific Aδ fibres, and hence, the recording of cold-evoked potentials (CEPs) may improve the objective assessment of human thermo-nociceptive function. While the feasibility of CEP recordings in healthy humans has been reported, their reliability and diagnostic use in clinical conditions have not been documented. METHODS: Here, we report the results of CEP recordings in 60 consecutive patients with suspected neuropathic pain, compared with laser-evoked potentials (LEPs) which are the gold standard for thermo-algesic instrumental assessment. RESULTS: CEP recording was a well-tolerated procedure, with only ~15 min of surplus in exam duration. The reproducibility and signal-to-noise ratio of CEPs were lower than those of LEPs, in particular for distal lower limbs (LLs). While laser responses were interpretable in all patients, CEPs interpretation was inconclusive in 5/60 because of artefacts or lack of response on the unaffected side. Both techniques yielded concordant results in 73% of the patients. In 12 patients, CEPs yielded abnormal values while LEPs remained within normal limits; 3 of these patients had clinical symptoms limited to cold sensations, including cold-heat transformation. CONCLUSIONS: CEPs appear as a useful technique for exploring pain/temperature systems. Advantages are low cost of equipment and innocuity. Disadvantages are low signal-to-noise ratio for LL stimulation, and sensitivity to fatigue/habituation. Joint recording of CEPs and LEPs can increase the sensitivity of neurophysiological techniques to thin fibre- spinothalamic lesions, in particular, when abnormalities of cold perception predominate. SIGNIFICANCE: Recording of cold-evoked potentials is a well-tolerated, inexpensive and easy-to-use procedure that can be helpful in the diagnosis of abnormalities in the thin fibre- spinothalamic pathways. Supplementing LEPs with CEPs allows consolidating the diagnosis and, for some patients suffering from symptoms limited only to cold, CEPs but not LEPs may allow the diagnosis of thin fibre pathology. Optimal CEP recording conditions are important to overcome the low signal-to-noise ratio and habituation phenomena, which are less favourable than with LEPs.

The impact of shift work on pain recognition, a robust ability among intensive care nurses.

BACKGROUND: Pain empathy is essential for high-quality of care. The cognitive ability to identify and understand the pain in others remains underexplored in the context of hospital shift work. This study aimed to observe the early subliminal ability to detect pain in other faces and to investigate pain intensity evaluations during day and night shifts. METHODS: Twenty-one nurses (31 ± 7 years, 20 women) from cardio-paediatric intensive care participated in this study. Eighteen nurses completed all testing in the morning and evening hours, before and after the 12-hour day and night shift. In the first test, the nurses had to decide if facial stimuli presented subliminally showed pain or not. During the second test, they consciously determined the intensity of the painful faces on a numerical scale. Sleep, sleepiness and empathy were also measured. RESULTS: Recognition accuracy and pain sensitivity remained stable over time, only sensitivity increased following the work shift (F(1,15) = 7.10, p = 0.018). Intensity ratings remained stable. Sleepiness at the end of the night shift was negatively correlated with accuracy (ρ = -0.51, p = 0.018) and positively correlated with prior night shifts (ρ = -0.50, p = 0.022). CONCLUSION: The judgement of facial pain expressions seems robust across shift types, only individual factors such as sleepiness interfere with pain recognition. Pain sensitivity may be enhanced during working hours. SIGNIFICANCE STATEMENT: Some professions need to know how to assess pain 24/7 and a lack of sleep can disrupt the cognitive processes necessary for this assessment. Night shifts provoke a bias in pain management, and sleep deprivation, a decrease in pain evaluation. By conducting a repeated measure study in the field that applied a different paradigm (subliminal recognition of facial cues) we add evidence to the understanding of pain recognition and the impact of sleep deprivation on the early processing of pain in others.

Filtering the reality: functional dissociation of lateral and medial pain systems during sleep in humans.

Behavioral reactions to sensory stimuli during sleep are scarce despite preservation of sizeable cortical responses. To further understand such dissociation, we recorded intracortical field potentials to painful laser pulses in humans during waking and all-night sleep. Recordings were obtained from the three cortical structures receiving 95% of the spinothalamic cortical input in primates, namely the parietal operculum, posterior insula, and mid-anterior cingulate cortex. The dynamics of responses during sleep differed among cortical sites. In sleep Stage 2, evoked potential amplitudes were similarly attenuated relative to waking in all three cortical regions. During paradoxical, or rapid eye movements (REM), sleep, opercular and insular potentials remained stable in comparison with Stage 2, whereas the responses from mid-anterior cingulate abated drastically, and decreasing below background noise in half of the subjects. Thus, while the lateral operculo-insular system subserving sensory analysis of somatic stimuli remained active during paradoxical-REM sleep, mid-anterior cingulate processes related to orienting and avoidance behavior were suppressed. Dissociation between sensory and orienting-motor networks might explain why nociceptive stimuli can be either neglected or incorporated into dreams without awakening the subject.

Sympathetic skin response as an objective tool to estimate stimulus-associated arousal in a human model of hyperalgesia.

BACKGROUND: Pain is a private experience, whose assessment relies on subjective self-reporting. Inaccurate communication renders pain evaluation unreliable in individuals with alteration of consciousness, lack of verbal interaction, cognitive dysfunction or simple malingering, hence the importance of developing reliable objective assessment tools. OBJECTIVES: Since pain is associated with autonomic arousal, here we used readouts of autonomic activity to assess objectively the arousing effect of somatic stimuli in a human model of hyperalgesia. METHODS: We used topical capsaicin to induce cutaneous hypersensitivity in the right arm of 20 healthy volunteers, and recorded sympathetic skin responses (SSR) and numerical perceptive ratings (NRS) to stimulation of the sensitized region and its homologous contralateral site, using brush (Aß), pinprick (Aδ) and laser (C-Warmth) stimuli. RESULTS: Both subjective ratings and SSRs were significantly enhanced to stimulation of the sensitized region, and their respective ratios of maximal enhancement were positively correlated. At individual level, a significant association was observed between SSR and NRS behavior (χ2(1)= 11.03; p < 0.001), with a positive predictive value of 87% (CI95 [77-97%]) for SSR increase predicting enhancement of subjective reports. A "lie experiment" asking subjects to simulate elevated NRS failed to enhance SSRs. Significant habituation of SSRs appeared when stimuli were repeated at ∼15s intervals, hence decreasing their negative predictive value when several consecutive stimuli were averaged (NPV=46%; CI95 [30-62%]). CONCLUSION: The SSR may represent a rapid and reliable procedure to assess cutaneous hypersensitivity, simple to use in clinical practice and resistant to simulation. Rapid habituation is a drawback that can be countered by using few repetitions and low stimulus rates.

Cortical representation of the human hand assessed by two levels of high-resolution EEG recordings.

Increasing interest in cortical plasticity has prompted the growing use of somatosensory evoked potentials (SEPs) to estimate changes in the cortical representation of body regions. Here, we tested the effect of different sites of hand stimulation and of the density of spatial sampling in the quality of estimation of somatosensory sources. Sources of two SEP components from the primary somatosensory cortex (N20/P20 and P45) were estimated using two levels of spatial sampling (64- vs. 128-channel) and stimulation of four distal sites in the upper limbs, including single digits (first vs. fifth) and distal nerves with comparable cortical projection (superficial branch of the radial nerve and distal ulnar nerve). The most robust separation of somatosensory sources was achieved by comparing the cortical representations of the first digit and the distal ulnar nerve territories on the N20/P20 component of SEPs. Although both the 64- and the 128-electrode montages correctly discriminated these two areas, only the 128-electrode montage was able to significantly separate sources in the other cases, notably when using first versus fifth digit stimulation. Trustworthy distinction of cortical representations was not obtainable when using the P45 component, probably because of greater activation volume, radial orientation of sources in areas 1-2 and increased variability with attention and vigilance. Assessment of tangential SEP components to stimulation of first digit versus ulnar nerve appears the best option to assess plastic somatosensory changes, especially when using relatively low-electrode sampling.

Operculo-insular pain (parasylvian pain): a distinct central pain syndrome.

Central pain with dissociated thermoalgesic sensory loss is common in spinal and brainstem syndromes but not in cortical lesions. Out of a series of 270 patients investigated because of somatosensory abnormalities, we identified five subjects presenting with central pain and pure thermoalgesic sensory loss contralateral to cortical stroke. All of the patients had involvement of the posterior insula and inner parietal operculum. Lemniscal sensory modalities (position sense, graphaestesia, stereognosis) and somatosensory evoked potentials to non-noxious inputs were always preserved, while thermal and pain sensations were profoundly altered, and laser-evoked potentials to thermo-nocoiceptive stimuli were always abnormal. Central pain resulting from posterior parasylvian lesions appears to be a distinct entity that can be identified unambiguously on the basis of clinical, radiological and electrophysiological data. It presents with predominant or isolated deficits for pain and temperature sensations, and is paradoxically closer to pain syndromes from brainstem lesions affecting selectively the spinothalamic pathways than to those caused by focal lesions of the posterior thalamus. The term 'pseudo-thalamic' is therefore inappropriate to describe it, and we propose parasylvian or operculo-insular pain as appropriate labels. Parasylvian pain may be extremely difficult to treat; the magnitude of pain-temperature sensory disturbances may be prognostic for its development, hence the importance of early sensory assessment with quantitative methods.

EEG changes reflecting pain: is alpha suppression better than gamma enhancement?

OBJECTIVE: Suppression of alpha and enhancement of gamma electroencephalographic (EEG) power have both been suggested as objective indicators of cortical pain processing. While gamma activity has been emphasized as the best potential marker, its spectral overlap with pain-related muscular responses is a potential drawback. Since muscle contractions are almost universal concomitants of physical pain, here we investigated alpha and gamma scalp-recorded activities during either tonic pain or voluntary facial grimaces mimicking those triggered by pain. METHODS: High-density EEG (128 electrodes) was recorded while 14 healthy participants either underwent a cold pressor test (painful hand immersion in 10 °C water) or produced stereotyped facial/nuchal contractions (grimaces) mimicking those evoked by pain. The scalp distribution of spectral EEG changes was quantified via vector-transformation of maps and compared between the pain and grimacing conditions by calculating the cosine of the angle between the two corresponding topographies. RESULTS: Painful stimuli significantly enhanced gamma power bilaterally in fronto-temporal regions and decreased alpha power in the contralateral central scalp. Sustained cervico-facial contractions (grimaces) gave also rise to significant gamma power increase in fronto-temporal regions but did not decrease central scalp alpha. While changes in alpha topography significantly differed between the pain and grimace situations, the scalp topography of gamma power was statistically indistinguishable from that occurring during grimaces. CONCLUSION: Gamma power induced by painful stimuli or voluntary facial-cervical muscle contractions had overlapping topography. Pain-related alpha decrease in contralateral central scalp was less disturbed by muscle activity and may therefore prove more discriminant as an ancillary pain biomarker.

Cortical modulation of nociception by galvanic vestibular stimulation: A potential clinical tool?

OBJECTIVE: Vestibular afferents converge with nociceptive ones within the posterior insula, and can therefore modulate nociception. Consistent with this hypothesis, caloric vestibular stimulation (CVS) has been shown to reduce experimental and clinical pain. Since CVS can induce undesirable effects in a proportion of patients, here we explored an alternative means to activate non-invasively the vestibular pathways using innocuous bi-mastoid galvanic stimulation (GVS), and assessed its effects on experimental pain. METHODS: Sixteen healthy volunteers participated in this study. Experimental pain was induced by noxious laser-heat stimuli to the left hand while recording pain ratings and related brain potentials (LEPs). We evaluated changes of these indices during left- or right-anodal GVS (cathode on contralateral mastoid), and contrasted them with those during sham GVS, optokinetic vestibular stimulation (OKS) using virtual reality, and attentional distraction to ascertain the vestibular-specific analgesic effects of GVS. RESULTS: GVS elicited brief sensations of head/trunk deviation, inoffensive to all participants. Both active GVS conditions showed analgesic effects, greater for the right anodal stimulation. OKS was helpful to attain significant LEP reductions during the left-anodal stimulation. Neither sham-GVS nor the distraction task were able to modulate significantly pain ratings or LEPs. CONCLUSIONS: GVS appeared as a well-tolerated and powerful procedure for the relief of experimental pain, probably through physiological interaction within insular nociceptive networks. Either isolated or in combination with other types of vestibular activation (e.g., optokinetic stimuli), GVS deserves being tested in clinical settings.

Involuntary orienting of attention to nociceptive events: neural and behavioral signatures.

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

Hyperalgesia when observing pain-related images is a genuine bias in perception and enhances autonomic responses.

Observing pain in others can enhance our own pain. Two aspects of this effect remain unknown or controversial: first, whether it depends on the 'painfulness' of the visual stimulus; second, whether it reflects a genuine bias in perception or rather a bias in the memory encoding of the percept. Pain ratings and vegetative skin responses were recorded while 21 healthy volunteers received electric nociceptive shocks under three experimental conditions: (i) observing a painful contact between the body and a harmful object; (ii) observing a non-painful body contact, (iii) observing a control scene where the body and the object are not in contact. Pain reports and vegetative responses were enhanced exclusively when the subjects observed a painful body contact. The effect on perception was immediate, abated 3 sec after the shock, and positively correlated with the magnitude of vegetative arousal. This suggests that (a) hyperalgesia during observation of painful scenes was induced by their pain-related nature, and not by the simple body contact, and (b) hyperalgesia emerged from a very rapid bias in the perceptual encoding of the stimulus, and was not the result of a retrospective bias in memory recollection. Observing pain-depicting scenes can modify the processing of concomitant somatic stimuli, increasing their arousal value and shifting perception toward more painful levels.

At-Home Cortical Stimulation for Neuropathic Pain: a Feasibility Study with Initial Clinical Results.

The clinical use of noninvasive cortical stimulation procedures is hampered by the limited duration of the analgesic effects and the need to perform stimulation in hospital settings. Here, we tested the feasibility and pilot efficacy of an internet-based system for at-home, long-duration, medically controlled transcranial motor cortex stimulation (H-tDCS), via a double-blinded, sham-controlled trial in patients with neuropathic pain refractory to standard-of-care drug therapy. Each patient was first trained at hospital, received a stimulation kit, allotted a password-protected Web space, and completed daily tDCS sessions during 5 weeks, via a Bluetooth connection between stimulator and a minilaptop. Each session was validated and internet-controlled by hospital personnel. Daily pain ratings were obtained during 11 consecutive weeks, and afterwards via iterative visits/phone contacts. Twenty full procedures were completed in 12 consecutive patients (500 daily tDCS sessions, including 20% sham). No serious adverse effects were recorded. Superficial burning at electrode position occurred in 2 patients, and nausea/headache in two others, all of whom wished to pursue stimulation. Six out of the 12 patients achieved satisfactory relief on a scale combining pain scores, drug intake, and quality of life. Daily pain reports correlated with such combined assessment, and differentiated responders from nonresponders without overlap. Clinical improvement in responders could last up to 6 months. Five patients asked to repeat the whole procedure when pain resumed again, with comparable results. At-home, long-duration tDCS proved safe and technically feasible, and provided long-lasting relief in 50% of a small sample of patients with drug-resistant neuropathic pain.

Pain influences hedonic assessment of visual inputs.

It is acknowledged that the emotional state created by visual inputs can modulate the way we feel pain; however, little is known about how acute pain influences the emotional assessment of what we see. In this study healthy subjects scored affective images while receiving painful or innocuous electrical shocks. Painful stimuli did not make unpleasant images more unpleasant, but rendered pleasant pictures significantly less pleasant. Brain responses to visual inputs (64-channels electroencephalogram) mirrored behavioural results, showing pain-induced effects in the orbitofrontal cortex, the subgenual portion of the cingulate gyrus, the anterior prefrontal and the temporal cortices, exclusively during presentation of pleasant images. In addition to this specific effect on pleasant pictures, pain also produced non-specific effects upon all categories of images, engaging cerebral areas associated with attention, alertness and motor preparation (middle-cingulate, supplemental motor, prefrontal cortex). Thus, pain appears to have a dual influence on visual processing: a non-specific effect related to orienting phenomena; and a more specific action exerted on supra-modal limbic areas involved in the production of affective states. The latter correlated with changes in the subjective appraisal of visual stimuli, and may underlie not only the change in their subjective assessment but also reactive processes aimed at coping with unpleasant contexts.

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

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

Convergence of sensory and limbic noxious input into the anterior insula and the emergence of pain from nociception.

Two parallel di-synaptic routes convey nociceptive input to the telencephalon: the spino-thalamic system projecting principally to the posterior insula, and the spino-parabrachial pathway reaching the amygdalar nucleus. Interplay between the two systems underlies the sensory and emotional aspects of pain, and was explored here in humans with simultaneous recordings from the amygdala, posterior and anterior insulae. Onsets of thermo-nociceptive responses were virtually identical in the posterior insula and the amygdalar complex, but no significant functional connectivity was detected between them using coherence analysis. Anterior insular sectors responded with ~30 ms delay relative to both the posterior insula and the amygdala. While intra-insular functional correlation was significant during the whole analysis period, coherence between the anterior insula and the amygdala became significant after 700 ms of processing. Phase lags indicated information transfer initially directed from the amygdalar complex to the insula. Parallel but independent activation of sensory and limbic nociceptive networks appear to converge in the anterior insula in less than one second. While the anterior insula is often considered as providing input into the limbic system, our results underscore its reverse role, i.e., receiving and integrating very rapidly limbic with sensory input, to initiate a perceptual decision on the stimulus 'painfulness'.