Human Pain Research Group, University of Manchester Rheumatic Diseases Centre,
Hope Hospital, Salford, United Kingdom
EDUCATIONAL OBJECTIVES
The objectives of this section are to provide a justification of why we need to understand the role of the cerebral cortex in pain perception; to provide an anatomical description of the matrix of structures that contribute to pain perception with a focus on the contribution of functional imaging studies in humans; to define the division of function within this matrix and how it may be altered in pathological pain states; to speculate on how this knowledge might be used to develop new therapies.
WHY DO WE NEED TO UNDERSTAND CORTICAL MECHANISMS OF PAIN
PERCEPTION?
The experience of pain can only be defined in terms of human consciousness. However, anatomical studies in animals together with functional imaging studies in humans have made it possible to identify the main cerebral components of the human nociceptive system. These components comprise at least two main human nociceptive systems working in parallel, called the medial and lateral pain systems (Fig. 1). This anatomical evidence has provided a physical construct for the concept of the human pain matrix (Melzack 1990). In addition, other nociceptive pathways have been identified in rodents that have not yet been described in primates. Bester et al. (1999) have demonstrated projections from the parabrachial nucleus to the ventromedial nucleus of the hypothalamus, which projects densely to the dorsal periaqueductal gray (PAG). This parabrachialhypothalamus-PAG loop is thought to have a major role in aversive behaviors and thus may play an important role in motivational behavior such as defense and aggression in response to noxious stimulation. We are just beginning to understand the division of function within these systems, providing the possibility of establishing a more rational framework for pain therapy.
There is a wide spectrum of pain experience, ranging from pain that may closely reflect physical events in tissue (e.g., events leading to excitation of nociceptors and hence nociceptive pain) to pain that is generated without any peripheral physical input (e.g., psychogenic and neuropathic pain). All these pains are equally valid and can only be recorded in terms of the individual’s subjective experience. A number of electroencephalographic (EEG) and functional imaging studies have demonstrated that changing the psychological context of a stimulus, in terms of attentional instruction or anticipation, can completely alter neuronal activity within the pain matrix. The brain is therefore acting as a virtual reality system that may or may not be constrained by interactions with the body’s internal and external environment. In order to understand these interactions, we need non-invasive methods for measuring cerebral responses in human subjects. Functional imaging and electrophysiological techniques provide the means to understand some of the molecular and electrophysiological events underpinning these interactions, which have been recently reviewed (Jones
1992, 1999; Craig 1994; Apkarian 1995; Derbyshire 1999; Treede et al. 1999; Peyron et al. 2000;

Petrovic and Ingvar 2002; Rainville 2002; Jones et al. 2003; Kakigi et al. 2005). However, the interpretations of these studies are dependent on detailed knowledge of anatomy and pharmacology gained from animal studies.
This chapter summarizes how animal studies and functional imaging studies in humans have changed our understanding of normal and abnormal pain mechanisms and how they inform changes in clinical practice. Some speculation will follow on how this knowledge might eventually be used to improve human pain therapy.
No new major classes of analgesic were developed in the last century apart from the extended role of tricyclic antidepressants as adjunct analgesics and 5HT-1A agonists such as sumatriptan for migraine. There are many reasons for this disappointing progress, but one may have been the difficulty in translating animal models of pain to adequate proof-of-concept trials in humans.
Another problem relates to the assumption that modulation of nociceptive processing at any level may alter pain experience. This problem particularly applies to pharmacological agents, which may have very different effects at different sites within the nervous system. A classic example is capsaicin, which is strongly algesic at the periphery and dorsal horn of the spinal cord, but analgesic when injected intra-cerebroventricularly. Functional imaging provides the means to measure integrated nociceptive processing in the brain, to uncover pathophysiological mechanisms of some of the main clinical pain states, and to define potential new therapeutic targets. Some of these techniques have already provided well-defined targets for new classes of analgesics. For example, evidence that the endogenous opioid system is activated in two different types of chronic pain (see below) has provided a potential target for enhancing these responses. The greatest disparities between animal studies and human studies are likely to be at the cortical level, partly because that is the highest level of specialization and partly because the cortex is most susceptible to the effects of anesthetics.
Combining knowledge from human and animal experimentation therefore seems essential for the efficient development of new pain therapies. Although there is no established role for functional imaging in pain management, it may have greater applicability in patient assessment, analgesic development, and response monitoring.

SCOPE AND LIMITATIONS OF IMAGING CORTICAL FUNCTION DURING PAIN
Electrophysiological pain-evoked potentials, i.e., electroencephalographic (EEG) frequency analysis and magnetoencephalography (MEG), as well as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) provide access to nociceptive processing mainly within the brain. However, recent studies have extended some of these techniques to the spinal cord
(Gage et al. 2001). Only PET 18 F-deoxyglucose and electrophysiological techniques provide direct measurement of neuronal activity; these methods currently provide the most robust measure of drug modulation of nociceptive activity. Electrophysiological techniques, with their millisecond temporal resolution, provide the means to study early attentional and anticipatory components of nociceptive processing. Improved techniques for source localization of pain-evoked potentials have provided greatly improved spatial resolution, with millimeter reproducibility (Bentley et al. 2002a). Improved techniques for MEG analysis such as synthetic aperture magnetometry provide an advanced approach to complex data sets (Singh et al. 2002). PET has provided the means to measure both metabolic and neurochemical aspects of nociceptive processing. This technique has allowed the identification of receptor systems and changes in their occupation during acute and chronic pain (Jones et al. 1994,
1999; Zubieta et al. 2001) in addition to imaging aspects of cholinergic (Gage et al. 2001) and dopaminergic transmission (Jaaskelainen et al. 2001). The great advantage of fMRI over PET is that it is possible to make repeated measures of nociceptive responses without the constraints imposed by the use of radioactivity, allowing much more complex experimental design.
The weakness of all these techniques is that in the final analysis we are left with significant activation sites in brain volumes without directional information and without information about the ascending or descending nociceptive inputs from which they result. They can therefore only be interpreted with reference to detailed anatomical and pharmacological studies derived from animal studies (Vania et al. 1989a,b,c; Sikes and Vogt 1992) and from human post-mortem studies (Bowsher
1957). Such interpretations, together with information from evoked potentials (Chen et al. 1998) and
MEG (Hari et al. 1983) can begin to provide a working model of the circuitry concerned with nociceptive processing.
This approach has provided some significant insights into human pain perception that would not have been possible from extrapolation from studies in animals in isolation. The combined use of different techniques such as opiate receptor imaging with functional studies has already provided some important insights into the integration of different neurochemically defined systems within the brain (Liberzon et al. 2002). Electrophysiological techniques have provided some information on the temporal sequence of nociceptive processing within the pain matrix, and improved techniques will provide the greater detail required for a dynamic model of nociceptive processing (Tarkka et al. 1993).
The most important feature of functional brain imaging techniques is that they are able to measure many aspects of nociceptive processing such as anticipation of pain and neurochemical changes associated with pain, which cannot be measured by any other means.
FUNCTION OF MEDIAL AND LATERAL NOCICEPTIVE SYSTEMS IN HUMANS
Until recently, it has been unclear to what extent cortical areas subserve the experience of pain.
This uncertainty has been partly due to the sparse direct termination of anterolateral spinothalamic tract fibers to the thalamus found in human post-mortem studies (Bowsher 1957) and the even more sparse nociceptive projections to the primary somatosensory (S1) cortex (Apkarian 1995).
Uncertainty about the role of the cortex in the pain experience also dates back to early systematic cerebral stimulation studies in 16 patients by Head and Holmes (1911) that reported the difficulties in eliciting pain when stimulating S1. This finding had further support from careful studies of patients with cortical and subcortical lesions by the same authors. By contrast, more recently, other authors

have documented reduced pain sensation following cortical lesions (Marshall 1951; Ploner et al. 1999), but these reports are relatively sparse, and analgesia is often not a major feature (for a review see
Kenshalo and Willis 1991; Peters 1991).
Many years ago, single-unit recordings in the monkey established that nociceptive pathways in the somatosensory system project to areas 3b and 1 of the primary somatosensory cortex (Kenshalo and Willis 1991), as well as to the secondary somatosensory cortex (S2) and the neighboring posterior parietal cortex (Dong et al. 1989). However, nociceptive units are relatively sparse, particularly in S1, which may explain some of the variability of functional imaging studies in this area. This finding may also explain why it has taken so long for the role of the cerebral cortex in pain experience to be accepted.
It has been widely accepted that pain is a multidimensional experience that has sensorydiscriminative, affective, motivational, and evaluative components (Melzack and Casey 1968). It has been suggested that these different components are likely to be processed within a “neuromatrix,” rather than in one center (Melzack 1990). Functional imaging experiments have identified such a matrix. A number of cortical structures such as S1 and S2, the anterior insula, and cingulate and dorsolateral prefrontal cortices are reproducibly involved in nociceptive processing (Derbyshire 1999;
Peyron et al. 2000), as are subcortical structures including the amygdala (Derbyshire et al. 1997) and the thalamus and hypothalamus (Hsieh et al. 1996, 2001). The anatomical connections, with their nociceptive inputs to these areas, have been extensively reviewed elsewhere, as has the collective evidence for their involvement in human pain perception (Jones 1992, 1999; Vogt et al. 1993;
Apkarian 1995; Jones and Derbyshire 1996; Derbyshire 1999; Treede et al. 1999; Peyron et al. 2000;
Petrovic and Ingvar 2002; Rainville 2002; Jones et al. 2003; Kakigi et al. 2005). However, the concept of a matrix with parallel processing within its components is perhaps fundamental to understanding some of the human observations that have been discussed so far. If pain results from integrating processing within such a matrix, then it should not be surprising that ablation of one component of that matrix may not have immediately obvious effects, if other components of the matrix are able to compensate in some way. A clue to this possibility comes from the predominantly bilateral nociceptive inputs to most cortical components of the matrix on both anatomical and functional grounds (Schlereth et al. 2003; Youell et al. 2004). This parallel processing probably provides for considerable redundancy within this system, which is so essential for species survival. For instance, so far there is no evidence that magnetic stimulation of S1 significantly reduces pain intensity or the ability to localize pain (Kakigi et al. 2005).
A division of function between the lateral and medial components of the human pain system was originally proposed several decades ago (Bowsher 1957) and was iterated more formally by Albe-
Fessard and colleagues (1985) based on quite small numbers of human post-mortem and neurosurgical observations. The lateral pain system comprises the lateral thalamic nuclei and the somatosensory cortices. It is fast and somatotopic and may subserve the sensory-discriminative aspects of pain, which include localization, intensity, and duration. The insular cortex also has some somatotopic nociceptive inputs and may be involved in integrating them with inputs from other sensory modalities (Ostrowsky et al. 2002).
The medial pain system is slow (polysynaptic) and non-somatotopic, and is thought to process the affective components of pain (Treede et al. 1999). It includes the medial thalamic nuclei, anterior cingulate and dorsolateral prefrontal cortices, and possibly structures concerned with the processing of fear, such as the amygdala.
Further evidence for this functional division in the human brain was based on clinical observations of the effects of selective anterior cingulate lesions in alleviating the affective components of pain (Foltz and White 1962) and effects of lesions in the region of S1 on the sensorydiscriminative components of pain (Ploner et al. 1999, 2000). Deafferentation of the anterior cingulate cortex (ACC) in patients with chronic intractable pain produces a state where patients still experience

pain but it no longer bothers them (Foltz and White 1962), an observation that raises some interesting ethical and physiological issues. These effects are quite similar to the clinical observations of the effects of synthetic opiates, which are rarely pain-ablative but substantially reduce the unpleasantness of acute and chronic pain.
Functional imaging techniques have enabled researchers to investigate this division of function further. Several studies have attempted to address this issue by attentional manipulations, hypnosis, and use of the variable stimulus-response functions (Rainville et al. 1997; Bushnell et al. 1999; Peyron et al. 1999; Tölle et al. 1999; Bantick et al. 2002). These studies have used intensity of pain to access the sensory-discriminative components of pain and unpleasantness to access the affective components of pain. They have mainly identified the mid-cingulate cortex as subserving the affective processing of painful stimuli. However, it has been demonstrated that intensity is probably encoded throughout the pain matrix (Derbyshire et al. 1997; Coghill et al. 1999), although in some studies discrete intensitycoding areas have been identified within, for instance, the mid-cingulate cortex (Buchel et al. 2002) and S1 (Hofbauer et al. 2001).
Substantial psychophysical data suggest a positive correlation between unpleasantness and intensity of pain (Rainville et al. 1999). It is difficult to dissociate unpleasantness and intensity without resorting to techniques such as hypnosis. Intensity may not therefore be the best component to disclose a division of function between the sensory-discriminative and affective components of pain.
Hypnosis itself introduces issues related to monitoring of conflict between the instruction under hypnosis and what the subject may be really feeling, which is an activity also localized within the mid-cingulate cortex. An alternative approach is to use the localization of a pain stimulus as a measure of discriminatory function instead of pain intensity. This approach has been achieved using a CO
2 laser to stimulate four quadrants on the back of the arm at painful and nonpainful levels with a simple difference in instruction to attend either to the unpleasantness of the stimulus or to its localization.
This technique has very clearly identified components of the medial pain system such as the perigenual cingulate cortex, insula, and amygdala, in addition to the hypothalamus, that respond to the affective components of pain more than its localization; attending to the localization of the painful stimulus produced greater activations of S1 and inferior parietal cortex (Kulkarni et al. 2005).
Collectively, these data suggest that the main division of function between the medial and lateral pain systems is likely to be that of affective and sensory-discriminatory processing, respectively, with intensity probably being processed throughout the matrix.

WHAT FACTORS AFFECT THE PATTERN OF NOCICEPTIVE PROCESSING IN THE
BRAIN?
Anticipation.
In terms of responses to experimental pain it is now very clear that the psychological context of the stimulus in terms of anticipation and attention may be as important as the stimulus parameters. It had been previously thought that anticipation might only activate certain components of the medial system such as the medial prefrontal cortex and ACC, and that these areas were adjacent and discrete from those activated by pain (Ploghaus et al. 1999). Subsequent studies, however, suggested that these responses could be blocked by benzodiazepines and therefore may be more related to anxiety than anticipation of pain per se. More recently it has been shown that most of the nociceptive system can be activated by anticipation of a painful stimulus (Porro et al. 2002)—the anticipatory responses are just smaller than the pain intensity-related responses.
Chronicity (acute versus chronic pain).
It has been assumed for many years that the medial and lateral systems might respectively be concerned with processing chronic and acute pain (Albe-Fessard et al. 1985). Functional imaging studies have provided unequivocal evidence that this is not the case.
Both systems are involved in acute nociceptive processing and at least one type of chronic pain
(neuropathic pain), and these are processed in parallel (Jones 1999) .
It has been traditional to think of acute and chronic pain as being very distinct processes, possibly with certain types of chronic pain being processed within discrete brain regions. At a clinical level, many types of chronic pain such as arthritic pain are a mixture of recurrent acute pain and chronic ongoing pain. It is difficult to see an empirical advantage of processing each type of pain in a separate and discrete nociceptive system. So far, there is very little evidence from imaging studies for a division of function within the pain matrix on the basis of the temporal components of pain (Porro et al. 1998; Jones 1999). However, there have been claims for certain brain areas such as the perigenual cingulate cortex being concerned with certain types of pain such as allodynic pain (Lorenz et al. 2002).
However, evidence is now accumulating for this area of the cingulate cortex being involved in the affective components of experimental pain (Kulkarni et al. 2002) and psychologically induced pain
(Raij et al. 2005) in addition to chronic clinical pain.
However, there may be some more subtle differences between acute and chronic pain processing.
Components of the lateral system such as the S1 cortex do appear to be as frequently activated with tonic nonphasic experimental pain and phasic pain (67% and 69% of studies show activations, respectively). But only 23% of studies of chronic ongoing clinical pain demonstrated activation of S1
(Derbyshire 1999). There are a number of potential reasons for this. Nociceptive projections to S1 are sparse (Shi et al. 1993). Also, this is the only area where functional imaging experiments have demonstrated any convincing somatotopy for pain (Andersson et al. 1997). Therefore, spatial summation of responses to chronic pain in different locations may dilute the signal change in S1.
Some support for this proposal comes from the observation that the frequency of significant S1 activations during acute experimental somatic pain would appear to be related to the extent of the area of skin stimulated (Peyron et al. 2000). Responses within the medial system appear to be predominantly bilateral and non-somatotopic (Vogt et al. 1993; Derbyshire 1999; Jones 1999). Acute pain experiments tend to stimulate the same or adjacent locations, whereas chronic pain experiments often include patients with variable pain locations and therefore may spatially dilute an already weak signal in S1. However, nociceptive responses in S1 and other components of the lateral system may be faster and more short-lived, and therefore more difficult to detect using PET and fMRI.
Further reasons to distinguish between acute and chronic pain are the clear time-dependent neurochemical changes that occur, for instance in the spinal cord, in various subacute pain models
(Woolf 1994). Such findings have led to the general belief that there must be important pharmacotherapeutic differences between acute and chronic pain. However, so far there is no evidence for any class of analgesic only being effective in the acute or chronic phase of any type of pain. Such differences may exist, but they have yet to be clearly demonstrated in humans.

Attention.
Further evidence for the importance of top-down effects (Frith 2001) comes from a number of studies showing the effects of altered attention on nociceptive processing (Peyron et al.
1999; Bantick et al. 2002; Legrain et al. 2002; Petrovic and Ingvar 2002; Bentley et al. 2004). Altered cingulate responses during different attentional instruction have been interpreted in the context of differences in coping strategies (Hsieh et al. 1999). These observations are consistent with a largescale neurocognitive network model (Mesulam et al. 1990; Morecraft et al. 1993) that put forward the cingulate cortex as the main contributor to a motivational map that interacts with a perceptual map provided by the posterior parietal cortex. To an extent, this evidence reinforces the potential for psychological approaches to pain therapy.
Laterality .
The effect of the side of stimulation has been extensively reported on the basis of statistical thresholds yielding significant responses within the matrix, but so far only two studies have addressed this issue quantitatively using nontactile painful stimuli (Bingel et al. 2003; Youell et al.
2004). Both studies elicited bilateral responses within the pain matrix, with significantly greater contralateral responses in S1 and the thalamus.
Empathy.
Recent studies have addressed the issue of pain empathy in terms of empathy for a partner experiencing pain. An elegant experiment compared brain activations when a volunteer or her partner, who was seated next to an MRI scanner, experienced pain. The results showed activation of mid-cingulate and anterior insular cortices, brainstem, and cerebellum during pain empathizing
(Singer et al. 2004). The cortical components of these responses are within the medial pain system, providing a further example of segmentation of function within the pain matrix.
Sex.
So far there is evidence for subtle differences in cortical processing of pain between agematched men and women, with the most convincing differences being a shift of processing in women within the cingulate cortex toward the perigenual cingulate cortex (Derbyshire et al. 2002b).
Interestingly, this is one of the areas of the cortex with the highest levels of  ,  and  opioid receptor binding (Vogt et al. 1995a). Higher  -opioid receptor binding in women has been found in the temporal cortex, amygdala, and thalamus, but not so far within the cingulate cortex (Zubieta et al.
1999).
Learning.
Aversive conditioning in animals has been defined within circuitry comprising the hippocampus, anterior and posterior cingulate cortices, amygdala, striatum, and medial and anterior thalamic nuclei (Gabriel 1990, 1993; Uylings et al. 1990; Maren et al. 1991; Vogt et al. 1993). The motor outputs for these responses are by way of premotor components of the cingulate cortex and the striatum. The amygdala, thalamus, and cingulate cortices are involved in the acquisition of conditioned responses, forming a template that is compared with new sensory inputs. If there is a match, the appropriate motor response is initiated by way of the cingulate and motor cortices and the primed striatum. If there is a mismatch, the hippocampus is activated to block any motor response.
Damage to the amygdala has been associated with impairment of acquisition of conditioned autonomic responses and with impairment of affective memories without significant impairment of nonaffective cognitive functions (Cahill et al. 1995).
Functional MRI studies have allowed preliminary access to some of the processes that may be taking place in humans during aversive conditioning. Temporal difference models that allow the modeling of prediction error during the acquisition of aversive conditioning have identified the ventral striatum, anterior insular, and anterior cingulate cortices as being important in these processes
(Ploghaus et al. 2000; Seymour et al. 2004).
THE CINGULATE CORTEX, NOCICEPTION, AND THE ENDOGENOUS OPIOID SYSTEM
The role of the cingulate cortex in processing a variety of cognitive, motor, and nociceptive information has been well described (Vogt et al. 1993; Devinsky et al. 1995; Paus et al. 1998; Bush et al. 2000). Anatomical projections to the ACC from the midline thalamus and intralaminar nuclei (Vogt et al. 1979) and

ventrobasal complex have been demonstrated. The connections of these nuclei with the spinothalamic tract support the role of the ACC in nociceptive processing (Albe-Fessard et al. 1985; Boivie. et al.
1994). Single-unit recordings in rabbits (Sikes and Vogt 1992) and humans (Hutchison et al. 1999) have identified nociceptive neurons in area 24 in the posterior part of the ACC.
The observation that the ACC is the most commonly activated structure in functional imaging studies of pain (Derbyshire 1999) suggests that it has a pivotal role in nociceptive processing. There is substantial interindividual and interstudy variability of the location of anterior cingulate responses to nociceptive stimuli (Vogt et al. 1996; Derbyshire 2000). These locations were shown to extend from the more rostral perigenual cingulate to the caudal mid-cingulate cortex in studies using fMRI, PET, and EEG (Bentley et al. 2002b). Some of the most reproducible results have come from EEG studies
(Bentley et al. 2002b). The spatial distribution of pain responses within the cingulate cortex has raised the issue of both pain-specific and more generalized divisions of function within this region. The evidence for the involvement of the ACC in processing the affective components of pain has been discussed in previous sections.
Previous studies have demonstrated responses to pain within the ACC in two main clusters in the mid- and perigenual cingulate cortex (Vogt et al. 1996). The unique anatomy of the ACC, with much of the circuitry converging on the large efferent fibers of lamina V, might suggest that its general computational function is related to matching appropriate motor outputs to afferent inputs (Devinsky et al. 1995).
The perigenual cingulate cortex has been activated in studies where the pain inflicted was strong enough to be unpleasant, such as in studies using tonic cold pain (Kwan et al. 2000) or capsaicintreated skin (Lorenz et al. 2002). Such findings may explain why the perigenual cingulate is not commonly seen in most of the studies using experimental pain, except when the pain stimulus is very unpleasant allodynia, in clinical pain, or when the subjects’ attention is directed to the unpleasantness of the pain (Kulkarni et al. 2002, 2005).
There is increasing evidence that the mid-cingulate cortex is mainly concerned with executive functions such as response selection (Frith 2001), monitoring, and error detection (Devinsky et al.
1995). The mid-cingulate is also an important component of the anterior attentional system (Posner et al. 1990; Bush et al. 2000), although nociceptive responses appear to occur in discrete areas distinct from those concerned with these more general attentional functions (Davis et al. 1997; Derbyshire et al. 1998).
The perigenual cingulate, however, appears to be more concerned with affective responses
(George et al. 1996), including vocalization, autonomic control, and fear (Devinsky et al. 1995; Bush et al. 2000). The activity within the perigenual cingulate cortex during attention to unpleasantness is consistent with its relatively high concentration of opioid receptors (Jones et al. 1991b; Vogt et al.
1995a) as compared to the more executive areas of the cingulate cortex, and also with the perigenual changes in occupation by endogenous opioid peptides during chronic pain (Jones et al. 1994, 1999;
Jones and Derbyshire 1996; Spetea et al. 2002).
There are relatively high concentrations of opioid receptors in the higher association cortices and components of the limbic system, including the amygdala, and low concentrations in the S1, motor, and visual cortices. Therefore, these regions may have some function related to the modulation of selective attention in addition to their more direct role in modulation of nociception (Lewis et al.
1981). Changes in occupation of opioid receptors consistent with increased occupation by endogenous opioid peptides during pain have been demonstrated within the cortical components of the medial pain system in acute experimental pain (Zubieta et al. 2001), chronic neuropathic pain (Jones et al. 1999), and chronic arthritic pain (Jones et al. 1994).
These findings may be relevant to recent observations of shared responses within ACC to placebo and opioid analgesia (Petrovic et al. 2002). Recent observations suggest that placebo analgesia is at least partially mediated by endogenous opioid peptides (Benedetti et al. 1999). Clinical observations

suggest that synthetic opioids do not ablate pain but substantially reduce its unpleasantness. This is strikingly similar to the effects of deafferentation of the ACC (Foltz and White 1962). Opioidmediated analgesia results in significant changes in activity in the perigenual cingulate cortex in addition to other components of the medial pain system (Jones et al. 1991a; Casey et al. 2000). The cerebral mechanisms of opioid actions are still uncertain, but anatomical studies suggest  -opioid modulation of thalamocortical loops projecting through the ACC (Vogt et al. 1995b). The perigenual cingulate cortex therefore provides candidate mechanisms for some of the analgesic effects of synthetic and endogenous opioids on the affective components of pain experience.
It is proposed that the perigenual cingulate and associated structures are most likely to be concerned with processing the affective components of pain, whereas the mid-anterior cingulate is more likely to be concerned with executive processing (response selection and monitoring) and control of attention. The possibility of reducing unpleasantness while maintaining pain localization has some therapeutic appeal. The clear identification of the areas of the pain matrix processing these components raises some hope of improving on the currently limited repertoire of pain therapies.
PATTERNS OF NEURAL ACTIVITY IN DIFFERENT TYPES OF CLINICAL
PAIN SYNDROMES IN RESPONSE TO PROVOKED PAIN
Psychogenic and nociceptive pain . Some of the more recent studies on modulation of nociceptive processing may aid the interpretation of earlier clinical studies that reported substantial differences in responses to thermal pain stimuli in patients with different types of clinical pain. In general, the same areas of the pain matrix are activated during thermal and pressure-induced pain
(Gracely et al. 2002) in patients with chronic pain syndromes as in normal volunteers. The differences are in the subtle patterns of response within the matrix rather than in the presence or absence of response in any one component of the matrix. Responses to standardized acute thermal pain stimuli were reduced in patients with acute (post-dental extraction) inflammatory pain and in those with ongoing chronic arthritic pain compared to controls (Jones and Derbyshire 1997; Derbyshire et al.
1999). Patients with chronic psychogenically maintained pain (atypical facial pain) demonstrated enhanced responses to acute thermal stimulation compared to controls in the ACC, with reduced responses in the right dorsolateral prefrontal cortex (DLPF). The enhanced responses in the ACC were thought to represent abnormal attention to the affective processing of nociceptive inputs that might contribute to the perseveration of chronic pain in these individuals, perhaps resulting from a failure of supervision of attention by the prefrontal cortex (Derbyshire et al. 1994). The observation that attention can profoundly affect the pattern of nociceptive responses within the pain matrix gives some credence to this concept (Jones et al. 2002). Recent studies have shown increased correlation of catastrophizing with anterior cingulate activity in patients with fibromyalgia or chronic widespread pain (Gracely et al. 2004), which is also consistent with earlier reports (Gibson et al. 1994). The reduced activity in the DLPF in the atypical facial pain group is interesting in the context of a recent
PET study of experimental allodynia that indicated that activity in this area of the right DLPF may be negatively correlated with connectivity between midbrain and thalamus. The suggestion emerging from this study was that DLPF may be an active higher “control on pain perception by modulating corticosubcortical and corticocortical pathways” (Lorenz et al. 2003). However, studies in patients with low back pain and depression did not demonstrate significant differences in nociceptive processing between this group and pain-free controls (Derbyshire et al. 2002a).
Neuropathic pain and allodynia. Pharmacological mechanisms have been demonstrated in the dorsal horn in association with neuropathic and inflammatory pain models (Woolf 1994) that may contribute to some forms of allodynia (pain induced by sensory modalities such as touch that would not normally induce pain). However, in terms of what signals the brain sees, these spinal mechanisms convert what would normally be signaled in non-nociceptive ascending pathways to signals within the

ascending nociceptive channels (ascending spinothalamic tracts). So far there is very little evidence in humans that such pains are processed within different brain structures when acutely induced experimentally (capsaicin-induced allodynia) (Iadarola et al. 1998) or when studied in patients with chronic neuropathic pain (Hsieh et al. 1995; Peyron et al. 1998).
However, there is a trend toward reduced activity within the thalamus during ongoing neuropathic pain (Di et al. 1991; Hsieh et al. 1995; Iadarola et al. 1995). Formal comparisons with other types of pain have not been made, but it is possible that this trend may represent reduced activity of inhibitory interneurons within the thalamus.
For most types of pain, there do not appear to be specific brain areas dedicated to specific types of pain. However, interesting preliminary studies in headache may provide a possible exemption to this generalization in that there seem to be more prominent subcortical activations than cortical activations.
PET studies during headache have measured increased activity in the midbrain and pons during migraine and in the hypothalamus during cluster headache. These observations, taken together with what is known about the mechanisms of these types of headaches, “may provide evidence for a neurovascular etiology rather than a primary vascular mechanism” (Goadsby 2001). However, it should be mentioned that all these areas are activated in other types of pain, so that if there is a specific pattern to these responses, it is likely to be related to the predominance of a subcortical pattern of activity rather than to the specific structures involved.
It is too early to say whether it is possible to distinguish between different categories of pain
(nociceptive, neuropathic, psychogenic, or even imagined pain) using functional imaging. However, different patterns of response within the pain matrix are measurable in different pain syndromes and in different psychological contexts. More sophisticated methods for measuring different aspects of simultaneous processing within the pain matrix are emerging (Buchel et al. 2002). It is possible that some of these methods may be used to categorize clinical pain syndromes, match them to appropriate treatments, and monitor response to such treatments in the future. Such methods may be particularly useful as the costs of novel treatments escalate.

PHYSIOLOGICAL BASIS FOR THE SUBCLASSIFICATION OF PAIN?
The International Association for the Study of Pain has provided a classification of pain that includes 33 main groups of pain, each with subclassifications (Merskey and Bogduk 1994). Much of the classification relates to the place and system in which the pain occurs and its temporal characteristics. This publication has provided an invaluable basis for epidemiological studies and health care planning. However, in terms of nociceptive processing, the temporal and spatial features of pain may be of less importance, particularly with regard to localization, because most nociceptive processing within the medial system is non-somatotopic. There are no identifiable systems dedicated to processing pain of a particular type, location, or duration, and yet these assumptions provide a common framework for the organization of pain services, pain trials, and the teaching of medical students.
It may be more helpful to consider why certain types of pain such as neuropathic and psychogenically maintained pains (somatoform pain disorders) are more likely to become chronic, than trying to make distinctions between acute and chronic pain that so far have no biological basis in humans. The current practice of conducting separate trials in acute and chronic pain may also be questioned on the same basis.
SUMMARY OF CLINICALLY RELEVANT ISSUES
The brain does not share the construct for pain perception and treatment that the medical profession would like to impose upon it. It is premature to reclassify pain on a physiological basis.
When such a classification does become possible, it is likely to be simpler, with less emphasis on localization and duration, and with greater emphasis on the psychological context of the pain and the pathophysiological mechanisms resulting in its maintenance.
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Disclosures: Nothing to disclose; no discussion of unlabeled uses.
Correspondence to: Anthony K.P. Jones, MB, BS, Clinical Science Building, Hope Hospital, Eccles Old
Road, Salford M6 8HD, United Kingdom. Tel: 44-161-206-4266; Fax: 44-161-206-4687; email: anthony.jones@man.ac.uk.
Fig 1.
Schematic diagram of some of the main anatomical components of the “pain matrix” and their possible functional significance. PAG = periaqueductal gray matter. Additional pathways in rodents are described in the next.