Review
Functional imaging of brain responses to pain. A review and meta-analysis (2000)Appréciation par l’imagerie fonctionnelle des réponses cérébrales à la douleur. Revue et méta-analyse.

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Abstract

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.

Résumé

Cette revue de la littérature concerne les réponses cérébrales à la douleur appréciées par l’imagerie fonctionnelle, soit la tomographie d’émission de positons (TEP), soit l’imagerie par résonance magnétique fonctionnelle (IRMf). La première mesure les variations de débit sanguin cérébral, la seconde les variations du signal BOLD (blood oxygen level dependent) entre deux conditions. Pour l’étude de la nociception, la douleur induite par un stimulus nocif comparée à un stimulus non nocif (en dessous du seuil) s’accompagne d’une augmentation presque constante du débit sanguin cérébral et du signal BOLD dans le cortex insulaire, l’aire SII, et le gyrus cingulaire antérieur, de façon plus inconstante dans le thalamus et l’aire SI. Les réponses insulaire/SII, thalamiques et SI sont supposées refléter l’aspect discriminatif de la douleur. La réponse du cortex SI présente dans approximativement la moitié des études, apparaît liée à la surface cutanée stimulée par unité de temps, elle semble donc dépendante des sommations temporelles et spatiales; elle est modulée par l’attention portée au stimulus. La réponse thalamique, souvent bilatérale fait probablement intervenir des phénomènes attentionnels d’« éveil » en réponse à la douleur. La réponse cingulaire antérieure (aire de Brodmann 24 et 32) ne participe vraisemblablement pas au codage de l’intensité du stimulus ni de sa localisation mais reflète certainement des processus attentionnels et émotionnels associés à la perception douloureuse. Au sein de cette structure, on distingue d’ailleurs plusieurs sub-divisions, l’une se superposant partiellement avec les activités d’orientation et de détection de cibles, l’autre, plus antérieure et rostrale, correspondant plutôt à une attention soutenue (exemple : Stroop, etc.). En plus de l’augmentation de débit cingulaire, l’attention au stimulus s’accompagne d’une activité du cortex pariétal postérieur (aire de Brodman, BA 40) et du cortex pré-frontal dorsolatéral (BA 44 à 46 ) droits qui participent au réseau cortical attentionnel et/ou mnésique. Les activations du striatum, du cervelet, de l’aire motrice supplémentaire, moins commentées, pourraient intervenir dans la réponse motrice à la douleur, l’activation péri-aqueducale pouvant être impliquée dans les contrôles inhibiteurs descendants. Chez les patients, la douleur spontanée s’accompagne d’une diminution du débit thalamique controlatéral, situation réversible sous thérapeutique analgésique. L’allodynie, douleur évoquée par un stimulus non nocif, est associée à une amplification des réponses thalamiques, insulaires et de SII, alors que la réponse cingulaire rostrale est diminuée, traduisant des anomalies de réorganisations centrales postlésionnelles. Enfin, il apparaît que des procédures antalgiques, pharmacologiques ou neurochirurgicales, augmentent le débit sanguin cérébral dans les mêmes régions que celles activées par la douleur aiguë, en particulier le gyrus cingulaire antérieur et le thalamus. Ces données suggèrent que les réponses cérébrales à la douleur reflètent à la fois les aspects sensoriel, cognitif et peut-être motivationnel de la perception douloureuse, et qu‘une même structure peut à la fois répondre à la douleur et participer à son contrôle, même si la médiation biochimique de ces activités reste à inventorier.

Section snippets

CBF studies using PET

Even though the physiological significance of rCBF changes with regard to neural activity is not clearly established, there is considerable evidence that local CBF changes are generated by metabolic products of synaptic function, and therefore reflect variations in local synaptic activity 147, 148. The short scan duration (50–120 s) and inter-scan interval (10–15 min) permit multiple studies in rapid succession, therefore allowing comparisons between consecutive functional states, including the

Responses to acute pain in normal volunteers

Table I summarises the results of previously published PET studies in normal subjects. In a decreasing order of consistency, hemodynamic responses to acute pain in normal subjects have been observed in the following brain areas: insular and SII cortices (primarily contralateral to stimulation but also ipsilateral); anterior cingulate cortex (ACC, Brodmann areas [BA] 24 and 32); thalamus (primarily contralateral to stimulation but often bilateral); SI cortex contralateral to stimulation;

Spontaneous pain in patients with neuropathic pain

Spontaneous pain is difficult to investigate using functional imaging due to the need to compare in the same subjects a painful versus a pain-free condition. This binary situation is rare in clinical practice and the literature is therefore restricted to a few reports, in patients with either cancer pain alleviated by cordotomy [48], ongoing neuropathic pain alleviated by anaesthetic blocks [76], or central pain treated with motor cortex stimulation 67, 119. One common finding in these studies

Functional imaging and subcomponents of the pain experience

Imaging studies in recent years have allowed the visualisation of a number of brain regions which consistently respond to pain with changes in blood flow. These cortical targets appear to subserve different aspects of the multidimensional pain experience; thus, the sensory-discriminative aspects of pain perception appear to implicate the lateral thalamus, primary and second somatosensory regions and the insular cortex, while the additional activation of posterior parietal and prefrontal

Conclusion

This review has shown a good deal of convergent data and promising results that should, in the next years, improve our understanding of pain processing in the brain. In spite of the remaining discrepancies and interpretive difficulties, analysis of the literature shows an overall coherent picture of brain networks involved in pain processing, in fact much more coherent than what emerges from current meta-analyses in other fields of brain imaging [55]. We believe that pain imaging studies are

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