Modulation of the spinal N13 SEP component by high- and low-frequency electrical stimulation. Experimental pain models matter.

OBJECTIVE: The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of cervical dorsal horn neurons. Neurophysiological studies in healthy participants showed that capsaicin-induced central sensitization causes an increase of the N13 SEP amplitude. Consequently, in human research, this spinal component may serve as a valuable readout of central sensitization. In this study, we wanted to verify if the sensitivity of the N13 SEP for detecting central sensitization is consistent across different experimental pain models inducing central sensitization and secondary hyperalgesia, namely high and low-frequency electrical stimulation (HFS and LFS). METHODS: In 18 healthy participants, we recorded SEP after bilateral ulnar nerve stimulation before and after secondary hyperalgesia was induced through HFS and LFS applied on the ulnar nerve territory of the hand of one side. The area of secondary hyperalgesia was mapped with a calibrated 128-mN pinprick probe, and the mechanical pain sensitivity with three calibrated 16-64-256-mN pinprick probes. RESULTS: Although both HFS and LFS successfully induced secondary hyperalgesia only LFS increased the amplitude of the N13 SEP. CONCLUSIONS: These findings suggest that the sensitivity of the N13 SEP for detecting dorsal horn excitability changes may critically depend on the different experimental pain models. SIGNIFICANCE: Our results indicate that LFS and HFS could trigger central sensitization at the dorsal horn level through distinct mechanisms, however this still needs confirmation by replication studies.

Modulation of the N13 component of the somatosensory evoked potentials in an experimental model of central sensitization in humans.

The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies.

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex.

OBJECTIVE: In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. METHODS: In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system. RESULTS: HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS. CONCLUSIONS: HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system. SIGNIFICANCE: Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans.

Theta-burst versus 20 Hz repetitive transcranial magnetic stimulation in neuropathic pain: A head-to-head comparison.

OBJECTIVE: High-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce neuropathic pain, but intermittent "theta-burst" stimulation (iTBS) could be a better alternative because of shorter duration and greater ability to induce cortical plasticity. Here we compared head-to-head the pain-relieving efficacy of the two modalities when applied daily for 5 days to patients with neuropathic pain. METHODS: Forty-six patients received 20 Hz-rTMS and/or iTBS protocols and 39 of them underwent the full two procedures in a random cross-over design. They rated pain intensity, sleep quality, fatigue and general health status daily during 5 consecutive weeks. RESULTS: Pain relief during the month following stimulation was superior after 20 Hz-rTMS relative to iTBS (F(1,38) = 4.645; p = 0.037). Correlation between respective levels of maximal relief showed a significant deviation toward the 20 Hz-rTMS effect. A greater proportion of individuals responded to 20 Hz-rTMS (52% vs 32%, 95 %CI[0.095-3.27]; p = 0.06), and reports of fatigue significantly improved after 20 Hz-rTMS relative to iTBS (p = 0.01). General health and sleep quality scores did not differentiate both techniques. CONCLUSIONS: High-frequency rTMS appeared superior to iTBS for neuropathic pain relief. SIGNIFICANCE: Adequate matching between the oscillatory activity of motor cortex and that of rTMS may increase synaptic efficacy, thus enhancing functional connectivity of motor cortex with distant structures involved in pain regulation.

Brain activity sustaining the modulation of pain by empathetic comments.

Empathetic verbal feedback from others has been shown to alleviate the intensity of experimental pain. To investigate the brain changes associated with this effect, we conducted 3T-fMRI measurements in 30 healthy subjects who received painful thermal stimuli on their left hand while overhearing empathetic, neutral or unempathetic comments, supposedly made by experimenters, via headsets. Only the empathetic comments significantly reduced pain intensity ratings. A whole-brain BOLD analysis revealed that both Empathetic and Unempathetic conditions significantly increased the activation of the right anterior insular and posterior parietal cortices to pain stimuli, while activations in the posterior cingulate cortex and precuneus (PCC/Prec) were significantly stronger during Empathetic compared to Unempathetic condition. BOLD activity increased in the DLPFC in the Empathetic condition and decreased in the PCC/Prec and vmPFC in the Unempathetic condition. In the Empathetic condition only, functional connectivity increased significantly between the vmPFC and the insular cortex. These results suggest that modulation of pain perception by empathetic feedback involves a set of high-order brain regions associated with autobiographical memories and self-awareness, and relies on interactions between such supra-modal structures and key nodes of the pain system.

Electrophysiology in diagnosis and management of neuropathic pain.

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

Randomized double-blind controlled study of bedtime low-dose amitriptyline in chronic neck pain.

BACKGROUND: Amitriptyline has well-established efficacy in several chronic pain conditions. While optimal treatment for chronic neck pain (CNP) remains controversial, amitriptyline was not tested for CNP. We evaluated the effect of bedtime amitriptyline in the management of CNP. METHODS: A total of 220 patients suffering from idiopathic CNP were randomized to receive either placebo pill (n = 108) or 5 mg of amitriptyline (n = 112) at bedtime for 2 months. Primary outcome measure was visual analog scale (VAS) for pain. Secondary outcome measures were neck pain disability index (NPDI), Bergen Insomnia Score (BIS) and Hospital Anxiety and Depression Scale (HAD), measured before and at the end of 2 months of treatment, with the percentage of patient satisfaction measured at the end of follow-up only. RESULTS: Eight of 112 patients (7.14%) in the amitriptyline group withdrew from the study because of intolerance. Amitriptyline group showed significantly lower VAS scores than placebo group (3.34 ± 1.45 vs. 6.12 ± 0.92; p < 0.0001), which corresponds to a 53.06 ± 20.29% of improvement from baseline pain as compared to 14.41 ± 11.05%, respectively (p < 0.0001). Similar significant improvements were observed with lesser extents for secondary outcome measures: NPDI, BIS, HAD-A, HAD-D and percentage of patient satisfaction. CONCLUSION: Low-dose amitriptyline is effective for the management of idiopathic CNP with few side effects and high patients' satisfaction. SIGNIFICANCE: This randomized controlled trial is the first to show the effectiveness and tolerance of a medication, low-dose amitriptyline, in managing idiopathic chronic neck pain and its related comorbidities. The optimal treatment of this condition was still controversial in the literature. It extends the indication of low-dose amitriptyline to another chronic pain condition.

Somatotopic effects of rTMS in neuropathic pain? A comparison between stimulation over hand and face motor areas.

BACKGROUND: The therapeutic influence of somatotopic matching between pain topography and motor cortex stimulation site for neuropathic pain (NP) remains controversial. METHODS: Thirty-two patients suffering from NP involving the upper limb (n = 20) or the face (n = 12) received two high-frequency rTMS neuronavigated sessions targeting hand and face motor cortical areas, versus placebo. The cortical target was defined by anatomical MRI and EMG responses in all patients, completed in 19 of them by functional MRI. Sessions were separated by at least 2 weeks and applied in random order. Pain relief was assessed using numerical rating scale (NRS). RESULTS: In terms of percentage of pain relief, rTMS over the hand motor area was significantly superior to both face rTMS and placebo. When comparing pre- and post-NRS scores, a significant decrease in pain was observed after hand area rTMS for the two pain localizations, while stimulation of the face area induced a slight but nonsignificant effect on upper limb pain after correction. Sham-rTMS did not exert any effect. The percentage of patients with clinically significant (>30%) or mild (15-30%) pain relief did not differ, however, between rTMS addressed to the hand or face area. CONCLUSIONS: The results do not support a somatotopic effect of motor rTMS for NP. Lack of clinically relevant somatotopic effects in upper limb or face pain suggests that much of the rTMS analgesic effect may depend on high-order mechanisms involving cognitive and affective appraisal of pain, rather than on a sensory effect related to the specific motor area stimulated. SIGNIFICANCE: Strict somatotopic targeting of rTMS does not appear warranted for the treatment of upper limb or face NP. Since the hand motor area is easier to target and provides better results, it might be privileged for both types of pain.

Does an observer's empathy influence my pain? Effect of perceived empathetic or unempathetic support on a pain test.

The physiological and behavioural effects of empathy for other's pain have been widely investigated, while the opposite situation, i.e. the influence on one's pain of empathetic feedback from others, remains largely unexplored. Here, we assessed whether and how empathetic and unempathetic comments from observers modulate pain and associated vegetative reactions. In Study 1, conversations between observers of a pain study were recorded by professional actors. Comments were prepared to be perceived as empathetic, unempathetic or neutral, and were validated in 40 subjects. In a subsequent pain experiment (Study 2), changes in subjective pain and heart rate were investigated in 30 naïve participants who could overhear the empathetic or unempathetic conversations pre-recorded in study 1. Subjective pain was significantly attenuated when hearing empathetic comments, as compared to both unempathetic and neutral conditions, while unempathetic comments failed to significantly modulate pain. Heart rate increased when hearing unempathetic remarks and when receiving pain stimuli, but heart acceleration to nociceptive stimulation was not correlated with pain ratings. These results suggest that empathetic feedback from observers has a positive influence on pain appraisal and that this effect may surpass the negative effect of unempathetic remarks. Negative remarks can either trigger feelings of guilt or induce irritation/anger, with antagonistic effects on pain that might explain inter-individual variation. As in basal conditions heart rate and pain perception are positively correlated, their dissociation here suggests that changes in subjective pain were linked to a cognitive bias rather than changes in sensory input.

EAN guidelines on central neurostimulation therapy in chronic pain conditions.

BACKGROUND AND PURPOSE: Our aim was to update previous European Federation of Neurological Societies guidelines on neurostimulation for neuropathic pain, expanding the search to new techniques and to chronic pain conditions other than neuropathic pain, and assessing the evidence with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. METHODS: A systematic review and meta-analysis of trials published between 2006 and December 2014 was conducted. Pain conditions included neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS) type I and post-surgical chronic back and leg pain (CBLP). Spinal cord stimulation (SCS), deep brain stimulation (DBS), epidural motor cortex stimulation (MCS), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct electrical stimulation (tDCS) of the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) were assessed. The GRADE system was used to assess quality of evidence and propose recommendations. RESULTS: The following recommendations were reached: 'weak' for SCS added to conventional medical management in diabetic painful neuropathy, CBLP and CRPS, for SCS versus reoperation in CBLP, for MCS in neuropathic pain, for rTMS of M1 in neuropathic pain and fibromyalgia and for tDCS of M1 in neuropathic pain; 'inconclusive' for DBS in neuropathic pain, rTMS and tDCS of the DLPFC, and for motor cortex tDCS in fibromyalgia and spinal cord injury pain. CONCLUSIONS: Given the poor to moderate quality of evidence identified by this review, future large-scale multicentre studies of non-invasive and invasive neurostimulation are encouraged. The collection of higher quality evidence of the predictive factors for the efficacy of these techniques, such as the duration, quality and severity of pain, is also recommended.

Filtering out repetitive auditory stimuli in fibromyalgia: a study of P50 sensory gating.

BACKGROUND: It has been suggested that fibromyalgia (FM) patients show increased sensory processing of nociceptive and non-nociceptive stimuli and also reduced habituation. Although this pattern of increased reactivity has been established for the somatosensory modality, its generalization to other sensory modalities remains controversial. METHODS: Auditory evoked potentials were obtained using a paired-stimuli paradigm from a sample of 52 FM female patients and 55 healthy women matched for age and socio-economic status. Sensory gating of the P50 component, as indicated by P50 suppression rates to the second identical stimuli, was analysed in relation to clinical indices of FM, including algometry of tender points and a number of self-reported questionnaires. RESULTS: Sensory gating mechanisms in FM patients proved to be normal, robust and as efficient as those recorded in control subjects. There was no correlation between P50 suppression rates and indices of clinical or experimental (threshold or tolerance) pain. In addition, P50 sensory gating was not related to the other main symptoms of FM, including fatigue, sleep dysfunction or co-morbid depression, nor to hypersensitivity to noise or headache. CONCLUSIONS: The results indicate that FM patients do not present significant deficits in early sensory gating when processing auditory stimuli, and therefore challenge the 'generalized hypersensitivity' hypothesis of FM.

Discriminating neurological from psychiatric hypersomnia using the forced awakening test.

INTRODUCTION: Sleep inertia refers to the inability to attain full alertness following awakening from sleep and is a major component of hypersomnia. As event-related potentials (ERPs) are correlated to the degree of consciousness, they allow exploring information processing in transitional states of vigilance. Their modifications during forced awakening (FA) context have been shown to reflect sleep inertia. OBJECTIVES: To assess the diagnostic value of a FA test using an oddball stimulation protocol during a nap in a representative sample of patients with excessive daytime sleepiness (EDS). METHODS: One hundred and seventy three patients [30 narcolepsy, 62 idiopathic hypersomnia, 33 sleep apnoea syndrome, and 48 other (mainly psychiatric) hypersomnia] performed an auditory target detection stimulation task during pre-, post-nap wakefulness, and during two successive intra-nap FA while the EEG was simultaneously recorded. Both the accuracy of target detection and the ERPs were evaluated. ERPs during forced awakening test were considered to reflect sleep inertia if they presented with a P300 delay and/or sleep negativities (N350/N550). RESULTS: Pre-nap behavior and ERPs were normal in all patients. Behavioral results were significantly worse during FA than during wakefulness for all groups of patients. P300 latencies were significantly delayed on FA conditions in each group of patients except the psychiatric group. Sensitivity and specificity for detection of sleep inertia were 64% and 94%, respectively, with predictive values of 96% (positive) and 50% (negative). CONCLUSIONS: Our results suggest that the FA test could be helpful as a diagnostic procedure for discriminating neurological from psychiatric hypersomnia.

Modulation of laser-evoked potentials and pain perception by transcutaneous electrical nerve stimulation (TENS): a placebo-controlled study in healthy volunteers.

OBJECTIVE: To investigate the effects of transcutaneous electrical nerve stimulation (TENS) on brain nociceptive responses (laser-evoked potentials, LEPs) and pain perception. METHODS: Twenty healthy subjects were included. Nociceptive CO(2)-laser pulses were sequentially delivered to the dorsum of both feet. The amplitude of LEPs and nociceptive thresholds were collected in three consecutive conditions: T1: "sham" TENS (2 Hz/low-intensity) positioned heterotopically, over the left thigh; T2: "active" TENS (120 Hz/low-intensity) applied homotopically, over the left common peroneal nerve; and T3: "sham" TENS (replication of condition T1). RESULTS: Compared with "sham" TENS, "active" TENS significantly decreased the LEPs amplitude. This effect was observed exclusively when "active" TENS was applied ipsilaterally to the painful stimulus. Nociceptive thresholds increased with sessions in both limbs, but the increase observed during the "active" condition of TENS (T2) exceeded significantly that observed during the condition T3 only on the foot ipsilateral to TENS. CONCLUSIONS: Compared with a credible placebo TENS, high-frequency TENS induced a significant attenuation of both the acute pain and LEPs induced by noxious stimuli applied on the same dermatome. SIGNIFICANCE: This modulation of subjective and objective concomitants of pain processing reflects a real neurophysiological TENS-related effect on nociceptive transmission.

Mechanical allodynia in neuropathic pain. Where are the brain representations located? A positron emission tomography (PET) study.

BACKGROUND: Brain areas involved in nociception have been repeatedly investigated. Therefore, brain responses to physiological pain conditions are well identified. The same is not true for allodynic pain in patients with neuropathic pain since the cortical reorganizations that are involved in the conversion of non-noxious stimuli into painful sensations still remain unknown. METHODS: The present positron emission tomography (PET) study enrolled 19 patients with dynamic mechanical allodynia to brushing or to cold rubbing of the skin. PET activations during allodynic stimulation were compared to those obtained with the same innocuous stimulation applied outside the neuropathic pain area (control). In a second comparison, they were compared with responses to a noxious heat stimulation applied outside the neuropathic pain area (experimental pain). RESULTS: Common responses to allodynia and control stimulations were found in contralateral SI, SII and insula and in ipsilateral cerebellum. Not surprisingly, heat pain condition was associated with activations in contralateral prefrontal and SII cortices and, bilaterally, in the anterior insular cortices. Distinctive cortical responses between control and allodynic conditions were restricted to one activation within the contralateral anterior insula, a region also activated by experimental heat pain. CONCLUSIONS: The insular subdivision was inappropriately activated considering the innocuous nature of the stimulus, but adequately activated with regard to pain-evoked sensation. Subcortically, the hypothesis of reorganization at any level of the somatosensory and pain pathways underlying such insular activity was supported by the observed shift of thalamic activation from a lateral-posterior to an anterior-medial position.

The posterior insular-opercular region and the search of a primary cortex for pain.

To be considered specific for nociception, a cortical region should: (a) have plausible connections with ascending nociceptive pathways; (b) be activated by noxious stimuli; (c) trigger nociceptive sensations if directly stimulated; and (d) tone down nociception when injured. In addition, lesions in this area should have a potential to develop neuropathic pain, as is the case of all lesions in nociceptive pathways. The single cortical region approaching these requirements in humans encompasses the suprasylvian posterior insula and its adjoining medial operculum (referred to as "PIMO" in this review). This region does not contain, however, solely nociceptive networks, but represents in primates the main sensory receiving area of the spinothalamic system, and as such contributes to the processing of thermo-sensory, nociceptive, C-fibre tactile, and visceral input. Nociception (and, a fortiori, pain) should therefore not be considered as a separate sensory modality, like vision or audition, but rather as one component of a global system subtending the most primitive forms of somatosensation. Although a clear functional segregation of PIMO sub-areas has not yet been achieved, some preferential distribution has been described in humans: pain-related networks appear preferentially distributed within the posterior insula, and non-noxious thermal processing in the adjacent medial operculum. Thus, spinothalamic sub-modalities may be partially segregated in the PIMO, in analogy with the separate representation of dorsal column input from joint, muscle spindle and tactile afferents in S1. Specificity, however, may not wholly depend on ascending 'labelled lines' but also on cortical network properties driven by intrinsic and extrinsic circuitry. Given its particular anatomo-functional properties, thalamic connections, and tight relations with limbic and multisensory cortices, the PIMO region deserves to be considered as a third somatosensory region (S3) devoted to the processing of spinothalamic inputs.

Objective pain diagnostics: clinical neurophysiology.

Neurophysiological techniques help in diagnosis, prognosis and treatment of chronic pain, and are particularly useful to determine its neuropathic origin. According to current standards, the diagnosis of definite neuropathic pain (NP) needs objective confirmation of a lesion or disease of somatosensory systems, which can be provided by neurophysiological testing. Lesions causing NP mostly concern the pain-temperature pathways, and therefore neurophysiological procedures allowing the specific testing of these pathways (i.e., A-delta and C-fibres, spino-thalamo-cortical tracts) are essential for objective diagnosis. Different techniques to stimulate selectively pain-temperature pathways are discussed. Of these, laser-evoked potentials (LEPs) appear as the easiest and most reliable neurophysiological method of assessing nociceptive function, and their coupling with autonomic responses (e.g., galvanic skin response) and psychophysics (quantitative sensory testing - QST) can still enhance their diagnostic yield. Neurophysiological techniques not exploring specifically nociception, such as standard nerve conduction velocities (NCV) and SEPs to non-noxious stimulation, should be associated to the exploration of nociceptive systems, not only because both may be simultaneously affected to different degrees, but also because some specific painful symptoms, such as paroxysmal discharges, may depend on specific alteration of highly myelinated A-beta fibres. The choice of techniques is determined after anamnesis and clinical exam, and tries to answer a number of questions: (a) is the pain-related to injury of somatosensory pathways?; (b) to what extent are different subsystems affected?; (c) are mechanisms and lesion site in accordance with imaging data?; (d) are results of use for diagnostic or therapeutic follow-up? Neuropathic pain (NP) affects more than 15 million people in Western countries, and its belated diagnosis leads to insufficient or delayed therapy. The use of neurofunctional approaches to obtain a "physiological photograph" of somatosensory function is therefore highly relevant, as it yields significant clues about the type and mechanisms of pain, thus prompting rapid and optimised therapy.

Enhancing non-noxious perception: behavioural and neurophysiological correlates of a placebo-like manipulation.

Sensory perception can be influenced by cognitive functions like attention and expectation. An emblematic case of this is the placebo effect, where a reduction in pain perception can be obtained by inducing expectation of benefit following a treatment. The current study assessed the behavioural and brain activity correlates of a placebo procedure inducing an enhancement of non-noxious somatic sensation. An experimental group was verbally suggested and surreptitiously conditioned about the effect of an inert cream in enhancing tactile perception, while a control group was informed about the actual inefficacy of the cream. Both groups received non-noxious electric shocks activating A-Beta fibres on the right index finger, before and after application of the cream in the same site. The behavioural and neurophysiological effects of this procedure were measured by a numerical rating scale of subjective perception and by recording cortical and subcortical somatosensory-evoked potentials (SEPs). Although the intensity of stimulation was physically identical in the two sessions, the experimental group reported stronger tactile sensation after cream treatment than before. In parallel, the experimental group showed enhanced somatosensory cortical responses (N140, P200) after treatment, whereas subcortical and early-cortical SEP components did not change. We suggest that these findings reflect top-down modulation on tactile perception probably due to an interplay between expectation and attention and might rely on interactions between prefrontal and parietal brain regions.

How the pain of others enhances our pain: searching the cerebral correlates of 'compassional hyperalgesia'.

Observing other people's pain increases our own reports to painful stimuli, a phenomenon that can be defined as 'compassional hyperalgesia' (CH). This functional magnetic resonance imaging study examined the neural correlates of CH, and whether CH could emerge when exposure to the driving stimulus was subliminal. Subjects received electric somatosensory stimuli while observing images of people undergoing painful or enjoyable somatic sensations, presented during a period allowing or not allowing conscious perception. The intensity attributed to painful stimuli increased significantly when these were delivered close to images showing human pain, but only when such images were consciously perceived. The basic core of the Pain Matrix (SI, SII, insula, mid-anterior cingulate) was activated by painful stimuli, but its activation magnitude did not increase during CH. Compassional hyperalgesia was associated with increased activity in polymodal areas involved in emotional tuning (anterior prefrontal, pregenual cingulated) and areas involved in multisensory integration and short-term memory (dorsolateral prefrontal, temporo-parieto-occipital junction). CH appears as a high-order phenomenon needing conscious appraisal of the eliciting visual stimulus, and supported by polymodal areas distinct from the basic Pain Matrix. This suggests that compassion to pain does not result from a mere 'sensory resonance' in pain networks, but rather from an interaction between the output of a first-line processing in the Pain Matrix, and the activity of a high-order network involving multisensory integration (temporo-parietal), encoding of internal states (mid-prefrontal) and short-time memory encoding (dorsolateral prefrontal). The Pain Matrix cannot be considered as an 'objective' correlate of the pain experience in all situations.

[French guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications]. / Recommandations françaises sur l'utilisation de la stimulation magnétique transcrânienne répétitive (rTMS) : règles de sécurité et indications thérapeutiques.

During the past decade, a large amount of work on transcranial magnetic stimulation (TMS) has been performed, including the development of new paradigms of stimulation, the integration of imaging data, and the coupling of TMS techniques with electroencephalography or neuroimaging. These accumulating data being difficult to synthesize, several French scientific societies commissioned a group of experts to conduct a comprehensive review of the literature on TMS. This text contains all the consensual findings of the expert group on the mechanisms of action, safety rules and indications of TMS, including repetitive TMS (rTMS). TMS sessions have been conducted in thousands of healthy subjects or patients with various neurological or psychiatric diseases, allowing a better assessment of risks associated with this technique. The number of reported side effects is extremely low, the most serious complication being the occurrence of seizures. In most reported seizures, the stimulation parameters did not follow the previously published recommendations (Wassermann, 1998) [430] and rTMS was associated to medication that could lower the seizure threshold. Recommendations on the safe use of TMS / rTMS were recently updated (Rossi et al., 2009) [348], establishing new limits for stimulation parameters and fixing the contraindications. The recommendations we propose regarding safety are largely based on this previous report with some modifications. By contrast, the issue of therapeutic indications of rTMS has never been addressed before, the present work being the first attempt of a synthesis and expert consensus on this topic. The use of TMS/rTMS is discussed in the context of chronic pain, movement disorders, stroke, epilepsy, tinnitus and psychiatric disorders. There is already a sufficient level of evidence of published data to retain a therapeutic indication of rTMS in clinical practice (grade A) in chronic neuropathic pain, major depressive episodes, and auditory hallucinations. The number of therapeutic indications of rTMS is expected to increase in coming years, in parallel with the optimisation of stimulation parameters.