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.

Functional imaging of pain.

Brain functional imaging has been applied to the study of pain since 1991. Then, a plethora of studies around the world looking at pain sensations and their brain correlates was published. Four kinds of studies can be distinguished: i) A first set investigated brain responses to noxious heat stimulations (above the pain threshold) relative to an equivalent warm innocuous stimulation (below the pain threshold). The aim of these studies was to identify the pattern of brain regions involved in the nociceptive processes and they may be considered as descriptive studies rather than explanative studies. Their value was to list for the first time every brain structure that might be playing a role. ii) Secondly, several experimental investigations have explored brain activations when subjects are confronted with unpleasant situations such as seeing or imagining other people in pain (e.g. empathy for pain). Obviously, feeling pain and representing others suffering share a common brain network, indicating that a large part of the regions showing intensity changes are not specific to nociception. iii) The third set of imaging studies is aimed at investigating the functional and structural brain abnormalities that may account for clinical pain states. Unfortunately, a relatively small number of studies provide clear findings that do not allow drawing convincing and generalized conclusions. iv) The last set of studies focused on the modulation of pain experience in humans. Several research groups conducted projects on different factors known to alter pain perception and their associated brain processes with the objective of identifying one or more key regions capable of controlling the pain sensation. In the same vein, investigations have been performed around pain therapies. From the clinician's point of view, it may be seen as complementary to assess pain and analgesic processes. All these aspects of pain research with functional imaging are considered below, including attempts to understand the functional significance of each of the observed activations. v) A special focus will be dedicated to new sophisticated approaches, vi) applied to neuroimaging (e.g. graph theory). These promising techniques and recent electrophysiological investigations bring additional information to our understanding of pain/analgesic processes, particularly for temporal dynamics and connectivity between brain regions.

The posterior insular-opercular cortex: An access to the brain networks of thermosensory and nociceptive processes?

In spite of systematic investigations, the existence of a specific cortex that could encode for the intensities of somatosensory stimuli, including within nociceptive ranges, is still a matter of debate. The present consensus is that pain is expressed in a distributed network made of thalamus, SII, insula, ACC, and, less consistently, SI. Here we argument that there must be an entrance to this network. The common denominator to every functional imaging study is that the subjects can distinguish between noxious and non-noxious stimuli, or between two different intensities of noxious stimuli. This is associated with a consistent activation of the insula-SII cortices while activations in other brain areas may be missing or sub-significant. In other words, the operculo-insular cortex activations are the most robust pain-related activations across studies, whatever the manipulation of the pain components, except the discriminative one. Intra-cerebral recordings also pointed out this piece of cortex as being able to encode for pain intensity. As a last physiological argument, stimulating directly the brain with small intensities standardized electrical shocks elicited pain sensations selectively if the electrode was in the operculo-insular cortex. Human models of disease confirmed that epileptic discharges in the insular cortex can produce ictal pain. Insular epilepsy (or propagation of discharges to the insular cortex) is the only focal epilepsy to be possibly associated with painful symptoms. Finally, unique and focal lesions of the posterior operculo-insular cortices were able to remove (or at least to impair) thermosensory and nociceptive functions. Thus, the operculo-insular area can be presented as the only area in the brain to respond to the features of a primary thermosensory and nociceptive cortex. This area is likely to be the starting point of the nociceptive-related networks. Future investigations are necessary to determine how this "pain symphony" between these different brain areas is temporally orchestrated. Developments of new targets for functional neurosurgery could benefit of such localized and initiating processes, for instance focal neurostimulations.

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.

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.

Robot-guided neuronavigated rTMS as an alternative therapy for central (neuropathic) pain: Clinical experience and long-term follow-up.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) appears as a useful tool to alleviate neuropathic pain but only few data are available for the long-term benefit of this treatment. METHODS: Here we report the effects of rTMS sessions, considered as a possible therapy for pain relief after a failure of different medications in patients with central (neuropathic) pain. We review here the prospectively collected data of the first forty patients treated as follow: 20 Hz stimulation delivered over the contralateral primary motor cortex (M1), each 3-4 weeks. RESULTS: A total of 440 rTMS sessions was collected (mean sessions number: 11, range: 1-37, follow-up 312 days on average, maximum 2.8 years). After four sessions, nine patients (22.5%) discontinued rTMS because of a lack of efficiency (<10% pain-relief). The other 31 patients (77.5%) had a cumulative effect across sessions leading to a mean pain relief of 41% for a duration of 15.6 days. A correlation was observed between pain relief in the first session and long-term pain relief (R = 0.649. p = 5.6*10(-6) ). Both intensity and duration of pain relief were significantly better for patients with persistent laser evoked potentials (LEPs, p = 0.049 and 0.0018). We did not observe any adverse-effects. CONCLUSION: These results suggest that repeated sessions of 20 Hz rTMS over M1 are interesting in clinical practice for the treatment of selected patients with central pain. Both the cumulative effects across the first sessions and the long duration of pain-relief should impact further randomized trials that are warranted to conclude formally on rTMS efficiency in central pain.

Pneumatic evoked potential. Sensory or auditive potential?

STUDY AIM: In this study, evoked potentials (EPs) to a pneumatic, innocuous, and calibrated stimulation of the skin were recorded in 22 volunteers. METHODS: Air-puff stimuli were delivered through a home-made device (INSA de Lyon, Laboratoire Ampère, CHU de Saint-Étienne, France) synchronized with an EEG recording (Micromed(®)). RESULTS: A reproducible EP was recorded in 18 out of 22 subjects (82% of cases) with a mean latency of about 120-130ms, and maximal amplitude at Cz. This EP actually consisted of two components, an auditory and a somatosensory one. Indeed, it was significantly decreased in amplitude, but did not disappear, when the noise generated by the air-puff was masked. We also verified that a stimulation close to the skin but not perceived by the subject was not associated with any EP. Conduction velocity between hand and shoulder was calculated around 25m/s. CONCLUSIONS: This preliminary study demonstrates that pneumatic EPs can be recorded in normal volunteers.

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.

Modulations of pain sensations.

Representation of time may affect pain perception. We investigated a group of volunteers looking at different clocks while they were being exposed to the same intensity of pain in two experiments. In one case, they saw the actual time, while in the other, they gazed at a clock that made it seem like the stimulation was shortened, even though it wasn't. These results show that simply believing that time is on your side can make anything more bearable. The results were not influenced by the color of the clock (red or green), or the presence of indexes such as (sad or smiling) smileys. The effects were maximal for high intensities of stimulation (pain threshold +1°C) if the stimulation lasted for at least 25s but were absent if the stimulation was short (15 min). These results suggest that pain modulation by time context is mainly available for long and intense painful stimulations. The right upper and posterior parietal cortex may support this effect. These findings are discussed with regard to previous literature of pain modulations but also with regard to the concept of the "pain matrix", its inputs and the temporal dynamics of its constitutive responses.

Functional exploration for neuropathic pain.

Neuropathic pain (NP) may become refractory to conservative medical management, necessitating neurosurgical procedures in carefully selected cases. In this context, the functional neurosurgeon must have suitable knowledge of the disease he or she intends to treat, especially its pathophysiology. This latter factor has been studied thanks to advances in the functional exploration of NP, which will be detailed in this review. The study of the flexion reflex is a useful tool for clinical and pharmacological pain assessment and for exploring the mechanisms of pain at multiple levels. The main use of evoked potentials is to confirm clinical, or detect subclinical, dysfunction in peripheral and central somato-sensory pain pathways. LEP and SEP techniques are especially useful when used in combination, allowing the exploration of both pain and somato-sensory pathways. PET scans and fMRI documented rCBF increases to noxious stimuli. In patients with chronic NP, a decreased resting rCBF is observed in the contralateral thalamus, which may be reversed using analgesic procedures. Abnormal pain evoked by innocuous stimuli (allodynia) has been associated with amplification of the thalamic, insular and SII responses, concomitant to a paradoxical CBF decrease in ACC. Multiple PET studies showed that endogenous opioid secretion is very likely to occur as a reaction to pain. In addition, brain opioid receptors (OR) remain relatively untouched in peripheral NP, while a loss of ORs is most likely to occur in central NP, within the medial nociceptive pathways. PET receptor studies have also proved that antalgic Motor Cortex Stimulation (MCS), indicated in severe refractory NP, induces endogenous opioid secretion in key areas of the endogenous opioid system, which may explain one of the mechanisms of action of this procedure, since the secretion is proportional to the analgesic effect.

In-patient versus out-patient withdrawal programmes for medication overuse headache: a 2-year randomized trial.

BACKGROUND: Medication-overuse headache (MOH) management usually includes a medication withdrawal. The choice of withdrawal modalities remains a matter of debate. METHODS: We compared the efficacy of in-patient versus out-patient withdrawal programmes in 82 consecutive patients with MOH in an open-label prospective randomized trial. The main outcome measure was the reduction in number of headache days after 2 months and after 2 years. The responders were defined as patients who had reverted to episodic headaches and to an intake of acute treatments for headache less than 10 days per month. RESULTS: Seventy-one patients had a complete drug withdrawal (n = 36 in the out-patient group; n = 35 in the in-patient group). The reduction of headache frequency and subjective improvement did not differ between groups. The long-term responder rate was similar in the out- and in- patient groups (44% and 44%; p = 0.810). The only predictive factor of a bad outcome 2 years after withdrawal was an initial consumption of more than 150 units of acute treatments for headache per month (OR = 3.1; 95% confidence interval 1.1-9.3; p = 0.044). CONCLUSION: Given that we did not observe any difference in efficacy between the in- and out-patient withdrawals, we would recommend out-patient withdrawal in the first instance for patients with uncomplicated MOH.

Episodic ataxia type 2: unusual aspects in clinical and genetic presentation. Special emphasis in childhood.

OBJECTIVE: To describe aspects in clinical and genetic presentation in five patients with episodic ataxia type 2 (EA2). METHODS: CACNA1A gene screening identified a mutation in three probands and in two of their children. RESULTS: The three probands had attacks of imbalance, associated with dizziness/vertigo and/or headache. Two of them had independent migraine attacks. Interictal oculomotor examination revealed a gaze evoked nystagmus and central oculomotor signs. Two probands had a history of strabismus. All responded well to acetazolamide. Two children were found to have both clinical and genetic abnormalities. At 23 months, one child started to have short attacks of imbalance mimicking benign paroxysmal vertigo of childhood. Then, the frequency and duration of his attacks increased and some were associated with headache. The other child developed permanent imbalance with falls at the age of 2 years, strabismus, hyperactivity and slight to moderate cognitive deficiency. When aged 10 years, this was further complicated by episodic ataxia. Genetic analysis revealed three novel mutations in the calcium channel gene CACNA1A (chromosome 19p13). The two children had the same genetic abnormality as their parents. CONCLUSION: EA2 may present with still unknown genetic mutations in adults, and with large and various phenotypes in children, such as short attacks of imbalance or permanent imbalance, cognitive deficiency, and possibly strabismus and hyperactivity.

Somatotopic organization of pain responses to direct electrical stimulation of the human insular cortex.

The question whether pain encoding in the human insula shows some somatotopic organization is still pending. We studied 142 patients undergoing depth stereotactic EEG (SEEG) exploration of the insular cortex for pre-surgical evaluation of epilepsy. 472 insular electrical stimulations were delivered, of which only 49 (10.5%) elicited a painful sensation in 38 patients (27%). Most sites where low intensity electric stimulation produced pain, without after-discharge or concomitant visually detectable change in EEG activity outside the insula, were located in the posterior two thirds of the insula. Pain was located in a body area restricted to face, upper limb or lower limb for 27 stimulations (55%) and affected more than one of these regions for all others. The insular cortex being oriented parallel to the medial sagittal plane we found no significant difference between body segment representations in the medio-lateral axis. Conversely a somatotopic organization of sites where stimulation produced pain was observed along the rostro-caudal and vertical axis of the insula, showing a face representation rostral to those of upper and lower limbs, with an upper limb representation located above that of the lower limb. These data suggest that, in spite of large and often bilateral receptive fields, pain representation shows some degree of somatotopic organization in the human insula.

Pain relief by rTMS: differential effect of current flow but no specific action on pain subtypes.

OBJECTIVES: To assess, against placebo, the pain-relieving effects of high-rate repetitive transcranial magnetic stimulation (rTMS) on neuropathic pain. METHODS: Double-blind, randomized, cross-over study of high-rate rTMS against placebo in 28 patients. The effect of a change in coil orientation (posteroanterior vs lateromedial) on different subtypes of neuropathic pain was further tested in a subset of 16 patients. Pain relief was evaluated daily during 1 week. RESULTS: High-frequency, posteroanterior rTMS decreased pain scores significantly more than placebo. Posteroanterior rTMS also outmatched placebo in a score combining subjective (pain relief, quality of life) and objective (rescue drug intake) criteria of treatment benefit. Changing the orientation of the coil from posteroanterior to lateromedial did not yield any significant pain relief. The analgesic effects of posteroanterior rTMS lasted for approximately 1 week. The pain-relieving effects were observed exclusively on global scores reflecting the most distressing type of pain in each patient. Conversely, rTMS did not modify specifically any of the pain subscores that were separately tested (ongoing, paroxysmal, stimulus-evoked, or disesthesic pain). CONCLUSIONS: Posteroanterior repetitive transcranial magnetic stimulation (rTMS) was more effective than both placebo and lateromedial rTMS. When obtained, pain relief was not specific of any particular submodality, but rather reduced the global pain sensation whatever its type. This is in accord with recent models of motor cortex neurostimulation, postulating that its analgesic effects may derive in part from modulation of the affective appraisal of pain, rather than a decrease of its sensory components.

[Central post-stroke pain]. / Les douleurs centrales post-AVC.

Central post-stroke pain (CPSP) is known since the famous Dejerine-Roussy syndrome and its description has not improved. The subject has however been revived over the last decade thanks to advances in central nervous system imaging with magnetic resonance imaging (MRI), the description of allodynia functional phenomena with fMRI, the study of opioid receptors, and above all, the analysis of pain pathways by laser-evoked potentials. Progress has also occurred in CPSP treatment with motor cortex stimulation, which probably opens a period of neuromodulation of the cortical areas controlling pain. The thalamus plays a prominent role in this disorder of central control of pain.

Central representation of the RIII flexion reflex associated with overt motor reaction: an fMRI study.

Recent neuroimaging studies precised the functions of the brain regions included in the so-called "pain-matrix". They isolated brain structures mediating attentional, emotional, anticipatory, cognitive, and discriminative aspects of pain perception. Surprisingly, little attention was devoted to isolate the cerebral network associated with the motor response to pain. In this study, we used fMRI to measure BOLD signal changes in nine volunteers while they received low- (L-) and high- (H-) intensity painful electrical shocks on the (left) lower limb. High-intensity stimulation was associated with a significantly stronger pain sensation and with a pronounced motor (withdrawal) reflex. BOLD responses common to L- and H-stimulation intensities were found in the right prefrontal and right posterior parietal cortices. These did not correlate with subjective pain ratings and probably mediate attentional processes unrelated to pain intensity and withdrawal. In contrast, signal changes in insula, left SII cortices and right amygdala did correlate with pain ratings and are therefore likely to encode for pain intensity. High-intensity shocks selectively recruited a motor network, including vermis, MI, SI, and paracentral cortices bilaterally, right premotor, right SII and posterior cingulate cortices. These responses, assessed for the first time in a functional imaging study, emphazised on the presence of a motor component in what has been described as the pain-matrix. They should be considered as a motor component of pain-related processes activated in case of intense pain.

Motor cortex stimulation for pain control induces changes in the endogenous opioid system.

BACKGROUND: Motor cortex stimulation (MCS) for neuropathic pain control induces focal cerebral blood flow changes involving regions with high density of opioid receptors. We studied the possible contribution of the endogenous opioid system to MCS-related pain relief. METHODS: Changes in opioid receptor availability induced by MCS were studied with PET scan and [(11)C]diprenorphine in eight patients with refractory neuropathic pain. Each patient underwent two preoperative (test-retest) PET scans and one postoperative PET scan acquired after 7 months of chronic MCS. RESULTS: The two preoperative scans, performed at 2 weeks interval, did not show significant differences. Conversely, postoperative compared with preoperative PET scans revealed significant decreases of [(11)C]diprenorphine binding in the anterior middle cingulate cortex (aMCC), periaqueductal gray (PAG), prefrontal cortex, and cerebellum. Binding changes in aMCC and PAG were significantly correlated with pain relief. CONCLUSION: The decrease in binding of the exogenous ligand was most likely explained by receptor occupancy due to enhanced secretion of endogenous opioids. Motor cortex stimulation (MCS) may thus induce release of endogenous opioids in brain structures involved in the processing of acute and chronic pain. Correlation of this effect with pain relief in at least two of these structures supports the role of the endogenous opioid system in pain control induced by MCS.

An fMRI study of cortical representation of mechanical allodynia in patients with neuropathic pain.

OBJECTIVE: To investigate cerebral activity associated with allodynia in patients with neuropathic pain. METHODS: The brain responses of 27 patients with peripheral (5), spinal (3), brainstem (4), thalamic (5), lenticular (5), or cortical (5) lesions were studied with fMRI as innocuous mechanical stimuli were addressed to either the allodynic territory or the homologous contralateral region. RESULTS: When applied to the normal side, brush and cold rubbing stimuli did not evoke pain and activated a somatosensory "control" network including contralateral primary (SI) and secondary (SII) somatosensory cortices and insular regions. The same stimuli became severely painful when applied to the allodynic side and activated regions in the contralateral hemisphere that mirrored the "control" network, with, however, lesser activation of the SII and insular cortices. Increased activation volumes were found in contralateral SI and primary motor cortex (MI). Whereas ipsilateral responses appeared very small and restricted after control stimuli, they represented the most salient effect of allodynia and were observed mainly in the ipsilateral parietal operculum (SII), SI, and insula. Allodynic stimuli also recruited additional responses in motor/premotor areas (MI, supplementary motor area), in regions involved in spatial attention (posterior parietal cortices), and in regions linking attention and motor control (mid-anterior cingulate cortex). CONCLUSION: On a background of deafferentation in the hemisphere contralateral to stimuli, enhanced or additional responses to innocuous stimuli in the ipsilateral hemisphere may contribute to the shift of perception from innocuous toward painful and ill-defined sensations.

Cognitive effects of precentral cortical stimulation for pain control: an ERP study.

Electrical stimulation of the motor cortex (MCS) is a promising and increasingly used neurosurgical technique for the control of refractory neuropathic pain. Although its mechanisms of action remain unknown, recent functional imaging data suggest involvement of the thalamus, brainstem and anterior cingulate/orbitofrontal cortex. Since some of these areas are also implicated in higher cognitive functions, notably attentional processes, we analysed cognitive ERPs and behavioural performance during an "oddball" auditory detection task in patients submitted to this procedure. Eleven consecutive patients undergoing MCS because of neuropathic refractory pain, ranging in age from 25 to 71 years, were included in the study. ERPs were obtained in all cases both during the application ("MCS-on") and within the 10 min that followed discontinuation of the procedure ("MCS-off"). In five patients, ERPs could also be obtained just before the start of MCS. When the patients' sample was taken as a whole, there were no consistent effects of MCS on the ERPs. There was, however, a significant interaction of MCS action with the patients' age, reflecting a significant delay during MCS of the cognitive responses N2 and P3 (N200 and P300) in the group of patients older than 50 years exclusively. This effect was rapidly reversible after MCS discontinuation. No MCS-related changes were observed in the N1 component. At the individual level, the effect of MCS on the endogenous ERPs was highly variable, ranging from a total stability of ERPs (mostly in younger subjects) to latency differences of tens of milliseconds in the older group. These results, together with recent experiments showing P300 alteration during repetitive transcranial stimulation, suggest that motor cortex stimulation may interfere with relatively simple cognitive processes such as those underlying target detection, and that the risk of abnormal cognitive effects related to cortical stimulation may increase with age. Although the procedure appears on the whole remarkably safe, complementary neuropsychological studies in this category of patients are advised, as well as caution to possible adverse cognitive effects when using MCS in the elderly, notably in the presence of pre-existent cerebral lesions.