Review
Brain mechanisms of pain affect and pain modulation

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Abstract

Recent animal studies reveal ascending nociceptive and descending modulatory pathways that may contribute to the affective–motivational aspects of pain and play a critical role in the modulation of pain. In humans, a reliable pattern of cerebral activity occurs during the subjective experience of pain. Activity within the anterior cingulate cortex and possibly in other classical limbic structures, appears to be closely related to the subjective experience of pain unpleasantness and may reflect the regulation of endogenous mechanisms of pain modulation.

Introduction

The International Association for the Study of Pain proposes that pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [1]. This definition implies that pain is a subjective experience, with both sensory and affective dimensions that are usually, but not necessarily, associated with tissue damage (see also 2., 3.). Thus, instead of being mistrusted — as implied in some studies — pain reports should be considered important indirect indices of the subjective experience of pain. By contrast, nociception refers to the ‘objective’ presence of, or potential for, tissue damage. Pain research is guided by the neurobiology of nociception, because it provides a primary structure for the analysis of pain-related brain activity. In this review, I first report selected animal studies describing recently discovered ascending nociceptive and putative descending modulatory pathways. The core of the review provides an attempt to describe the neural correlates of the subjective experience of pain in humans in the light of recent functional brain imaging studies on pain, cognitive processes, motivational and emotional states, and self-regulation.

Section snippets

Nociceptive pathways and modulatory circuits

In addition to the classical spinothalamocortical nociceptive projections, ascending nociceptive pathways originating in the spinal cord and projecting to specific areas of the brainstem and then further rostrally to various brain structures have been mapped in the rat. Recent findings indicate that one pathway projects from the dorsal horn of the spinal cord to the dorsocaudal medulla (subnucleus reticularis dorsalis), then to the ventromedian nucleus of the thalamus, and finally to the

Distributed representation of nociception underlying the experience of pain

Functional brain imaging studies in humans have focused mainly on the classical ascending spinothalamocortical pathways that convey nociceptive signals to the primary and secondary somatosensory cortices (S1 and S2/parietal operculum), the insula and the ACC (BA24) in primates (recently reviewed in [19]). Electrophysiological and electromagnetic studies in monkeys and humans have provided further evidence that these cortical areas receive contralateral nociceptive input 14., 15•., 20., 21., 22.

Cortical activity correlated with sensory and affective dimensions of pain

The functional role of pain-related brain structures in the sensory (e.g. pain intensity) and affective (e.g. pain unpleasantness) dimensions of the pain experience has been examined using combinations of pain scales that measure separately the subjective pain intensity — ‘how intense is the pain?’ — and pain unpleasantness — ‘how much does the stimulation bother you?’. One group of investigators has taken advantage of the specific increases that they observed in pain unpleasantness, but not

Role of the ACC in affective and cognitive processes

An anatomical–functional segregation of subsectors of the ACC probably depends on the type of input processed and the specific processing and output mechanisms engaged, as has been suggested previously 52., 53., 54., 55.. A recent review indicates that pain-related activation is reported most consistently in the ventral part of the supracallosal ACC (BA24), in the dorso-caudal ACC, and occasionally in the perigenual area [19]. Activation within the ventral part of the ACC is consistent with the

Pain anticipation

In many circumstances, the affective aspect of pain goes beyond its immediate unpleasantness, and emotions may be experienced in the anticipation of pain and in response to the meanings and the perceived future consequences of pain [2]. Functional brain imaging studies confirm the activation of a similar network of brain structures during pain and the anticipation of pain, although the specific sites of activation have been shown to shift slightly rostrally in the ACC and the insula in the

Emotions and motivational states

In contrast to the large body of literature on the cerebral mechanisms underlying the perception of emotions (e.g. see Adolphs, this issue), few studies have examined specifically the neural correlates of the subjective experience of emotions. One of the few recent exceptions is a study conducted by Damasio et al. [75••], in which PET scans were acquired at the specific moment when subjects indicated that they experienced an emotional feeling triggered by the autobiographical recall of an

Magnetic resonance spectroscopy of pain and anxiety

Recently, magnetic resonance spectroscopy has been applied to the investigation of pain and anxiety. Results suggest that there is a relative decrease in N-acetyl aspartate in the orbitofrontal cortex associated with anxiety [85] and in the dorsolateral prefrontal cortex in individuals with chronic low back pain [86]. Although these studies should be considered preliminary, this technique may yet make a significant contribution to our understanding of the neurophysiological correlates of pain

Self-regulation and the endogenous pain modulatory systems

One final note concerning the putative role of the ACC in pain affect and pain modulation concerns its role in self-regulation. The available anatomical data described at the beginning of this review are consistent with a role for the ACC in regulating endogenous pain modulatory mechanisms. Therefore, the ACC may not only be involved in pain perception but may also trigger subcortical pain modulatory mechanisms that may affect brainstem descending inhibitory pathways.

The modulatory effects of

Conclusions

Accepting the definition of pain as a subjective experience requires that we take a unique approach to the study the neurobiological basis of pain phenomena. Biological or information processing theories of nociception may be viewed as basic approaches that provide some primary constraints to pain theories, but these approaches alone cannot account fully for pain. The experiential approach gives a formal status to subjective experience and is not uncommon in human psychophysics and sensory

Update

Two additional important studies have been published recently. In an fMRI experiment, Büchel et al. [91•] report monotonic increases in activity with increases in pain in several areas of the ACC: in a ventral sector of the supracallosal ACC; and in the perigenual ACC within subsectors of the ACC that overlap with, but are at least partly distinct from, more dorsal areas involved in stimulus registration, orientation and pain-independent attention processes, and more posterior areas involved in

Acknowledgements

I thank Jon-Kar Zubieta and Hanna Damasio for help with preparing Fig. 2, Fig. 3, respectively, and Marie-Chantale Fortin, Jen-I Chen, Gary H. Duncan and Alice Petersen for useful comments on the manuscript. My work is supported by the Quebec FCAR.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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