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.

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.

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.

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.

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.

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.

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.

[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.

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.

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.

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.

Electrical stimulation of precentral cortical area in the treatment of central pain: electrophysiological and PET study.

The clinical, electrophysiological and haemodynamic effects of precentral gyrus stimulation (PGS) as a treatment of refractory post-stroke pain were studied in 2 patients. The first patient had a right hemibody pain secondary to a left parietal infarct sparing the thalamus, while the second patient had left lower limb pain developed after a right mesencephalic infarct. In both cases, spontaneous pain was associated with hyperpathia, allodynia and hypoaesthesia in the painful territory involving both lemniscal and extra-lemniscal sensory modalities in patient 1, extra-lemniscal sensory modality only in patient 2. Both patients were treated with electrical PGS by means of a 4-pole electrode, the central sulcus being per-operatively located using the phase-reversal of the N20 wave of somatosensory evoked potentials. No sensory side effect, abnormal movement or epileptic seizure were observed during PGS. The analgesic effects were somatotopically distributed according to the localization of electrode on motor cortex. A satisfactory long-lasting pain control (60-70% on visual analog scale) as well as attenuation of nociceptive reflexes were obtained during PGS in the first patient. Pain relief was less marked and only transient (2 months) in patient 2, in spite of a similar operative procedure. In this patient, in whom PGS eventually evoked painful dysethesiae, no attenuation of nociceptive RIII reflex could be evidenced during PGS. Cerebral blood flow (CBF) was studied using emission tomography (PET) with O-labeled water. The sites of CBF increase during PGS were the same in both patients, namely the thalamus ipsilateral to PGS, cingulate gyrus, orbito-frontal cortex and brainstem. CBF increase in brainstem structures was greater and lasted longer in patient 1 while patient 2 showed a greater CBF increase in orbito-frontal and cingular regions. Our results suggest that PGS-induced analgesia is somatotopically mediated and does not require the integrity of somatosensory cortex and lemniscal system. PGS analgesic efficacy may be mainly related to increased synaptic activity in the thalamus and brainstem while changes in cingulate gyrus and orbito-frontal cortex may be rather related to attentional and/or emotional processes. The inhibitory control on pain would involve thalamic and/or brainstem relays on descending pathways down to the spinal cord segments, leading to a depression of nociceptive reflexes. Painful dysesthesiae during stimulation have to be distinguished from other innocuous sensory side effects, since they may compromise PGS efficacy.

Parietal and cingulate processes in central pain. A combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) study of an unusual case.

Parietal, insular and anterior cingulate cortices are involved in the processing of noxious inputs and genesis of pain sensation. Parietal lesions may generate central pain by mechanisms generally assumed to involve the 'medial' pain system (i.e. medial thalamic nuclei and anterior cingulate cortex (ACC)). We report here PET and fMRI data in a patient who developed central pain and allodynia in her left side after a bifocal infarct involving both the right parietal cortex (SI and SII) and the right ACC (Brodmann areas 24 and 32), thus questioning the schematic representation of cortical pain processing. No rCBF increase was found in any part of the residual cingulate cortices, neither in the basal state (which included spontaneous pain and extended hypoperfusion around the infarct), nor during left allodynic pain. Thus, as previously observed in patients with lateral medullary infarct, neither spontaneous pain nor allodynia reproduce the cingulate activation observed after noxious pain in normal subjects. Conversely, both PET and fMRI data argue in favour of plastic changes in the 'lateral discriminative' pain system. Particularly, allodynia was associated with increased activity anteriorly to the infarct in the right insula/SII cortex. This response is likely to be responsible for the strange and very unpleasant allodynic sensation elicited on the left side by a non-noxious stimulation.

Electrical stimulation of motor cortex for pain control: a combined PET-scan and electrophysiological study.

Although electrical stimulation of the precentral gyrus (MCS) is emerging as a promising technique for pain control, its mechanisms of action remain obscure, and its application largely empirical. Using positron emission tomography (PET) we studied regional changes in cerebral flood flow (rCBF) in 10 patients undergoing motor cortex stimulation for pain control, seven of whom also underwent somatosensory evoked potentials and nociceptive spinal reflex recordings. The most significant MCS-related increase in rCBF concerned the ventral-lateral thalamus, probably reflecting cortico-thalamic connections from motor areas. CBF increases were also observed in medial thalamus, anterior cingulate/orbitofrontal cortex, anterior insula and upper brainstem; conversely, no significant CBF changes appeared in motor areas beneath the stimulating electrode. Somatosensory evoked potentials from SI remained stable during MCS, and no rCBF changes were observed in somatosensory cortex during the procedure. Our results suggest that descending axons, rather than apical dendrites, are primarily activated by MCS, and highlight the thalamus as the key structure mediating functional MCS effects. A model of MCS action is proposed, whereby activation of thalamic nuclei directly connected with motor and premotor cortices would entail a cascade of synaptic events in pain-related structures receiving afferents from these nuclei, including the medial thalamus, anterior cingulate and upper brainstem. MCS could influence the affective-emotional component of chronic pain by way of cingulate/orbitofrontal activation, and lead to descending inhibition of pain impulses by activation of the brainstem, also suggested by attenuation of spinal flexion reflexes. In contrast, the hypothesis of somatosensory cortex activation by MCS could not be confirmed by our results.

Association and dissociation between laser-evoked potentials and pain perception.

We investigated the relation between the subjective sensation of pain and two different components of the laser evoked potential, namely the vertex response (N220-P350) and an earlier lateralized response (middle-latency NP160). Brain responses to laser stimuli were obtained in 15 subjects under attentive and distractive conditions. Although stimulus intensity was kept constant, it was perceived as significantly higher when subjects attended the stimulation. There was a positive correlation between subjective intensity perception and the amplitude of the vertex potential, but no correlation existed with the middle-latency component. While laser vertex potentials may reflect attentional/perceptual mechanisms that determine subjective experience, the NP160 behaves as a pre-perceptual sensory response that should be advantageous in the assessment of early cortical pain processing.

Effects of GABAA receptors activation on brain glucose metabolism in normal subjects and temporal lobe epilepsy (TLE) patients. A positron emission tomography (PET) study. Part I: Brain glucose metabolism is increased after GABAA receptors activation.

Though gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the human central nervous system, the metabolic response to GABA system activation remains imperfectly known. We studied in vivo with positron emission tomography (PET) the variations of glucose metabolism in the human brain after stimulation of the GABAA receptors by systemic administration of the specific GABAA agonist, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). These investigations were performed in three normal volunteers and as part of presurgical evaluation for temporal lobe epilepsy in six patients. While clinical and electroencephalographic (EEG) monitoring showed a sedative effect and sleepiness after THIP administration, glucose metabolism was paradoxically increased in grey matter structures, which are known to have a high density of GABAA receptors. These findings suggest that the pharmacological activation of GABA pathways, although inhibitory and producing a decrease of vigilance, increases the energetic demand at least during a phase of GABA agonist action, probably at the synaptic or at the glial cell level.

Effects of GABAA receptors activation on brain glucose metabolism in normal subjects and temporal lobe epilepsy (TLE) patients. A positron emission tomography (PET) study. Part II: The focal hypometabolism is reactive to GABAA agonist administration in TLE.

Positron emission tomography (PET) using [18F]fluorodeoxyglucose (FDG) was used to study the metabolic response of focal hypometabolism to the administration of a specific GABAA agonist (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), THIP, in six temporal lobe epilepsy (TLE) patients. After THIP injection, the increase of glucose metabolism in the hypometabolic focus was larger than the mean increase reported in the whole brain (Part I; Epilepsy Res., 19 (1994) 45-54). Within the hypometabolic focus, this increase was significantly higher in regions with the lowest basal metabolic level. This metabolic response in the hypometabolic focus, observed in the absence of any epileptic discharge during FDG accumulation and PET data acquisition, suggests that GABAA receptors are up-regulated or, at least, preserved in TLE.

Functional imaging and neurophysiological assessment of spinal and brain therapeutic modulation in humans.

We summarize here our experience in the neurophysiological and neuroimaging assessment of spinal and brain neuromodulation for pain relief. Techniques reviewed include somatosensory evoked potentials (SEPs), nociceptive spinal (RIII) reflexes, and positron emission tomography (PET), which have been applied both to investigate the mechanisms and to optimize the application of neurostimulation procedures. SEPs are especially useful in the preoperative assessment of patients with neuropathic pain, as they allow the establishment of the functional state of the dorsal column system. Patients with strongly abnormal SEPs due to ganglionic or preganglionic pathology are not likely to benefit from spinal (SCS) or peripheral (TENS) neurostimulation, because ascending fibers disconnected from their soma will undergo rapid degeneration and not be excitable. In the postoperative period, nociceptive spinal reflexes yield objective data concerning the effects of neurostimulation on spinal circuitry. In our experience, the best clinical results are achieved in patients with preserved preoperative SEPs, in whom neurostimulation entails profound attenuation of nociceptive reflexes.PET-scan imaging techniques have recently been used to demonstrate changes in cerebral blood flow during new neuromodulation schemes such as motor cortex stimulation for pain control (MCS). PET studies highlight the thalamus as the key structure mediating functional MCS effects. Thalamic activation would trigger a cascade of synaptic events influencing activity in other pain-related structures including the anterior cingulate gyrus, insula, and upper brainstem. The combination of clinical electrophysiology and functional neuroimaging provides insight into the mechanisms of action of neuromodulation procedures, guides clinical decision, and contributes to optimize patient selection.

Functional imaging of brain responses to pain. A review and meta-analysis (2000).

Brain responses to pain, assessed through positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are reviewed. Functional activation of brain regions are thought to be reflected by increases in the regional cerebral blood flow (rCBF) in PET studies, and in the blood oxygen level dependent (BOLD) signal in fMRI. rCBF increases to noxious stimuli are almost constantly observed in second somatic (SII) and insular regions, and in the anterior cingulate cortex (ACC), and with slightly less consistency in the contralateral thalamus and the primary somatic area (SI). Activation of the lateral thalamus, SI, SII and insula are thought to be related to the sensory-discriminative aspects of pain processing. SI is activated in roughly half of the studies, and the probability of obtaining SI activation appears related to the total amount of body surface stimulated (spatial summation) and probably also by temporal summation and attention to the stimulus. In a number of studies, the thalamic response was bilateral, probably reflecting generalised arousal in reaction to pain. ACC does not seem to be involved in coding stimulus intensity or location but appears to participate in both the affective and attentional concomitants of pain sensation, as well as in response selection. ACC subdivisions activated by painful stimuli partially overlap those activated in orienting and target detection tasks, but are distinct from those activated in tests involving sustained attention (Stroop, etc.). In addition to ACC, increased blood flow in the posterior parietal and prefrontal cortices is thought to reflect attentional and memory networks activated by noxious stimulation. Less noted but frequent activation concerns motor-related areas such as the striatum, cerebellum and supplementary motor area, as well as regions involved in pain control such as the periaqueductal grey. In patients, chronic spontaneous pain is associated with decreased resting rCBF in contralateral thalamus, which may be reverted by 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. It is argued that imaging studies of allodynia should be encouraged in order to understand central reorganisations leading to abnormal cortical pain processing. A number of brain areas activated by acute pain, particularly the thalamus and anterior cingulate, also show increases in rCBF during analgesic procedures. Taken together, these data suggest that hemodynamic responses to pain reflect simultaneously the sensory, cognitive and affective dimensions of pain, and that the same structure may both respond to pain and participate in pain control. The precise biochemical nature of these mechanisms remains to be investigated.

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.