Annals ofthe Rheumatic Diseases 1996; 55: 411-420 41

REVIEW: PAIN Series editor: Bruce L Kidd Ann Rheum Dis: first published as 10.1136/ard.55.7.411 on 1 July 1996. Downloaded from Cerebral mechanisms operating in the presence and absence of inflammatory pain

Anthony K P Jones, Stuart W G Derbyshire

During episodes ofinflammatory arthritic pain, surprising if such parallel processing did not the brain has the task of integrating new also exist for non-primary sensations such as information from receptors of muscle, tendon, pain. There is now growing evidence that pain and skin afferents with nociceptive information is processed by a network or 'matrix' of struc- from the joint capsule and, possibly, peri- tures in the brain (fig 1), some components of articular bone. This integration will incorpor- which could be considered to comprise parallel ate motivational, affective, discriminative, at- but integrated processing. tentional, and motor responses that may result in changes of behaviour and modification of central nervous system (CNS) processing of NEUROANATOMY OF NOCICEPTION IN ANIMALS pain. It is as yet unclear what the nature of this Studying pain in animals presents an insoluble CNS modification may be, and suggested problem. Human beings can call out and influences on pain related affective-motor express their pain in ways that are commonly responses or the inflammatory process itself understandable to other members of their remain largely speculative. species; unfortunately, there is no equivalent It is likely to be some time before we begin frame of reference when dealing with animals. to have a proper understanding of the complex Increased blood pressure, movements of integrated processes that operate during withdrawal, dilatation of the pupil, increased arthritic pain and other chronic pains. How- depth of ventilation, attacking the source of ever, we are now able to measure aspects of noxious stimulation, and cries may be common those processes in terms of measurement of to all mammals in the face of seemingly 'pain- behavioural and cerebral responses to pain. ful' stimulation, but all such responses can be These measurements are providing early clues elicited after the has been to the possible underlying CNS mechanisms destroyed, in the probable absence of any and their relation to changes in affective- subjective experience. Furthermore, the sub- http://ard.bmj.com/ motivational behaviour. This paper will review jective experiences of an animal, if it has any, the normal brain mechanisms of the conscious may be totally different from those of humans. appreciation of pain, together with working For these reasons, human interpretation of hypotheses for how these mechanisms are what is observed in another species cannot be altered during inflammatory and other types of by extrapolation from human experience. clinical pain syndromes. This is not to suggest that all 'pain' research in animals is valueless: the common ancestry on October 1, 2021 by guest. Protected copyright. between humans and animals suggests that Normal mechanisms: anatomy and some of the underlying biological processes physiology involved in human pain experience are likely to It is perhaps surprising that there should still be shared with other animals. A distinction is be debate about which areas of the brain might therefore drawn between 'nociception' and be involved in the processing of such an pain-which should not be used inter- important and commonplace sensation as pain. changeably-the term nociception being used This has come about largely because of the to refer to the biological response of receptors understanding of pain as an experience involv- in tissue to potentially damaging stimuli such ing sensory, cognitive-evaluative, and affective- as intense heat or cold, chemical irritation, or motivational components' which defies simple intense pressure. The study ofnociceptive pain explanations involving pain centres' and avoids the fact that pain in man can occur Human Physiology and specific pathways.2 without any evident nociceptor activation, as in Pain Research Whatever areas of the brain are involved in peripheral and central deafferentation pain, Laboratory, of the different Manchester University pain processing, integration and may also occur without any evidence of Rheumatic Diseases components must be accommodated. This spinothalamic tract activation, as in psycho- Centre, Clinical implies that there is unlikely to be any final genic pain. Sciences Building, common area of the brain that processes pain. The spinothalamic tract has been demon- Hope Hospital, Salford M6 8HD, Indeed, it is perhaps the search for a single strated to be 'both necessary and sufficient' for United Kingdom dominant 'pain centre' that has done more to nociception in most species studied.4 It pro- A K P Jones impair our understanding of the functional vides the major direct nociceptive input from S W G Derbyshire anatomy of pain than anything else. Parallel the spinal cord to the . As a conse- Correspondence to: Dr Jones. processing of the conscious appreciation of quence, the spinothalamic tract ascending in Accepted for publication primary sensations such as vision and touch3 the anterolateral cord is widely considered as 14 March 1996 are now well documented, and it would be the 'pain pathway'. 412 Jones, Derbyshire

Spinothalamic tracts The cortical projections of the thalamic In the early 19th century, Brown-Sequard nuclear terminations of the dorsal and ventral performed studies in which the ventrolateral spinothalamic tracts are not clearly defined in quadrants of the spinal cord were sectioned in any species. Although the cortical connections Ann Rheum Dis: first published as 10.1136/ard.55.7.411 on 1 July 1996. Downloaded from animals and the resulting effects compared of some of the more important nuclei have with sensory deficits caused by similar lesions been described in different species, it cannot be in humans.5 Sherrington and Laslett6 observed assumed that all these connections are necess- 'that the lateral column furnishes the headward arily relevant to the spinothalamic termin- path in the spinal cord for nociceptive (algesic) ations. The following descriptions of cortical arcs' and 'that this is true for these arcs, projections can only therefore be a pointer to whether they are traced from skin, muscle or some of the possible functional connections in viscera'. Lesioning of the ventral quadrant in relation to the spinothalamic tracts. monkeys results in a consistent increase in Both components ofthe spinothalamic tracts response thresholds to nociceptive stimuli on have a heavy projection to the caudal portion the contralateral side below the level of the of the ventral posterior lateral nucleus of the lesion.7 8 This analgesic response usually re- thalamus. This nucleus, in addition to the covers one to six months after the lesioning.9 ventral posterior inferior and the centrolateral The most long lasting analgesic effects were nuclei of the thalamus, have important pro- produced by the most extensive lesions includ- jections to neurones in the primary somato- ing both dorsal and ventral quadrants, indicat- sensory cortex (SI) which are probably noci- ing that other pathways may also transmit noci- ceptive.'3 There are also probable nociceptive ceptive information, or that the spinothalamic projections from thalamic nuclei (ventral tract may have important dorsal components. posterior lateral, posterior nucleus, and the Quantitative studies also have demonstrated an centrolateral nucleus) to the secondary important contribution of the dorsolateral fasci- somatosensory cortex (S2). ' Although it has culus to the spinothalamic tract.'0 The thalamus been shown that SI contains units that respond was injected with agglutinin conjugated horse- to noxious stimuli,'5 Shi et al'3 have argued that radish peroxidase (HRP) in the presence and 'nociception does not seem to be a sensory absence of thoracic spinal lesions to preserve modality that is prominently represented in either the ipsilateral or contralateral ventral either the first or the second somatic sensory quadrant or dorsolateral fasciculus: 25-30% of area of the parietal cortex. Since the terminals the cells staining for HRP in the lumbar of the [spinothalamic tract] are scattered in segments were accounted for by retrograde small patches, since the cortical projections transport of stain down the contralateral dorso- from the VPLC (caudal section of the ventral lateral tract. These authors also found signifi- posterior lateral nucleus) are restricted to small cant differences in the distributions of cells of areas,'6 since VPLC cells in a given somatotopic origin of these two pathways. The most striking area project to multiple cortical zones and not observation was the predominance of laminae all VPLC cells project to the cortext'7. ..'. http://ard.bmj.com/ I-III of the dorsal horn as the main sites of The pulvinar oralis and the suprageniculate origin of the dorsolateral funiculus and laminae nucleus have been termed the posterior region VII-X as the main sites of origin of the ventral of the thalamus, and this region receives over- quadrant of the spinothalamic tract. Laminae lapping terminations from both spinothalamic IV-VI made a variable and often significant components. This area in turn projects to the contribution, dependent on the species of insular cortices in primates'8 which, because of monkey. An ipsilateral origin was demonstrated its connections with the amygdala, has been on October 1, 2021 by guest. Protected copyright. for 17% of both components of the spino- implicated in the autonomic responses to thalamic tracts.'0 nociceptive stimuli. A subdivision of the The terminations of the spinothalamic tracts ventral medial nucleus of the thalamus in the in different thalamic nuclei have also been ventroposterior part of the lateral thalamus has studied using anterograde transport of HRP recently been identified as being a relay nucleus injected into the lumbar segments in monkeys.'" for nociceptive specific information from Extensive termination of both components of lamina I of the dorsal horn in primates."' This the spinothalamic tracts was demonstrated in nucleus also projects to the anterior insula both the lateral and medial thalamic nuclei. The cortex, and may be a source of nociceptive lateral terminations were predominantly to the inputs to the insula parallel to those from the suprageniculate nucleus, pulvinar oralis, the medial thalamic nuclei. The cortical projec- caudal and oral divisions of the ventral posterior tions of the medial thalamic nuclei are de- lateral nucleus, the ventral posterior inferior scribed below. nucleus, and the zona incerta. In the medial thalamus, the main terminations were in the Spinoreticulothalamic tracts medial dorsal, intralaminar nuclei of the centrl Studies in the macaque monkey20 21 have lateral, central median, and parafascicular demonstrated that fibres in the anterior part of nuclei. There was extensive overlap between the the anterolateral spinothalamic tract originate regions innervated by the ventral and dorsal in the contralateral posterior horns and end in quadrants of the spinothalamic tracts. However, the gigantocellular part of the medulla and there were more extensive projections of the pons, and in the lateral reticular nucleus. ventral spinothalamic tract to the medial Fibres or collaterals from these areas terminate thalamic nuclei. Other anterograde degeneration in the medial geniculate body, the posterior studies have also shown extensive spinothalamic group, and the intralaminar nuclei of the projections to the midline thalamic nuclei.'2 thalamus. The fibres of the spinoreticulo- Cerebral mechanisms operating in the presence and absence ofinflammatory pain 413

thalamic tract may be divided into a ccaudal and been considered on anatomical grounds to be ventral group of fibres: the cauidal fibres a cranial extension of the brain stem reticular terminate in the central median, paraLfascicular, formation.24 In addition to the mediodorsal centrolateral, and dorsomedial nuc-lei of the nucleus, they have been found to have Ann Rheum Dis: first published as 10.1136/ard.55.7.411 on 1 July 1996. Downloaded from thalamus, while the ventral group s:ynapses in important connections with both the cingu- the subthalamus and the hypothalanaus. There late25 and prefrontal cortex26 in the monkey. is also a connection with the Edingerr-Westphal Cells within these medial thalamic nuclei nucleus, which may be the pathway mediating respond to nociceptive stimuli and often have the pupillary dilatation in response 1to noxious large and often bilateral receptive fields with a stimuli. Fibres from the ventrolateral spino- non-somatotopic organisation.2 For these thalamic tract have a crossed arid double reasons, these structures are considered to crossed projection to a reticular nucleus in the subserve the so called 'medial pain system', medulla-the subnucleus reticularis dorsalis. as distinct from the somatotopically arranged This nucleus appears to have ntociceptive projections to the ventral posterior lateral specific inputs that are totally consvergent on nucleus which are thought to subserve the units with hemi or whole body recep)tive fields. 'lateral pain system'.26a Vogt et al consider- Efferent projections are to the parafascicular ably extended the concept of the medial pain and ventromedian nuclei of the thalamus.22 23 system by demonstrating projections of the Projections via the dorsal accessory olive to medial thalamic group of nuclei to area 24 of motor areas such as motor and premotor the anterior cingulate cortex.27 28 The anterior cortices and striatum suggest possible involve- cingulate cortex is an extensive area of the ment in arousal and motor reactions limbic cortex overlying the corpus callosum which is involved in the integration of cog- Cortical projections of the medial thalarmic nuclei: nition, affect, and response selection.29 There medial v lateralpain systems is also evidence for medial thalamic nociceptive The intralaminar group of nuclei are an projections to the prefrontal cortex.30 The important group of medial thalamic:nuclei that descending connections of the anterior cingu- were originally described as those rauclei that late cortex to the medial thalamic nuclei and lay within the internal medullary lannina of the to the periaqueductal grey in the brain stem thalamus. However, they are now (considered suggest that this system may also be involved to comprise the central medial nucleus located in the modulation of reflex responses to in the midline and the more lateral p)aracentral noxious stimuli.28 and central lateral nuclei, and a third more The lateral pain system is subserved by posterior group that includes the posterior monosynaptic projections from the dorsal horn intralaminar, centromedian and parafascicular and is therefore rapid compared with the poly- nuclei. These structures have for nnany years synaptic medial pain system. This makes it a more likely candidate for processing infor- MEDIAL PAIN SYSTEMS LATERAL mation about acute pain. Certainly 'first pain', http://ard.bmj.com/ which is that first well defined pricking or Schema retrieval Attention Pain stabbing sensation, would require such a Attention supervision Emotion/Memory localisation relatively rapid system. However, acute pain Motor inhibition incorporates both first pain and second pain. The former is important for avoidance of potentially damaging stimuli. 'Second pain',

Somato- on October 1, 2021 by guest. Protected copyright. sensory which is that more enduring, often burning and cortex unpleasant, slow component ofpain, is likely to be of greater relevance to the experience of most acute clinical pain. Groups of neurones have been identified in the contralateral pri- mary and secondary sensory cortices of unan- aesthetised primates capable of responding to ) noxious stimuli.31 These have traditionally been considered to derive from the ventral posterior Localisation lateral nucleus of the thalamus, and their presence has reinforced the classical idea that dingdistration the 'lateral pain system' is the main system for processing acute pain, whereas the medial pain system is the main system processing chronic pain. An alternative hypothesis is that the lateral pain system is dealing primarily with the sensory discriminative aspects of pain, whereas ontralateral the medial pain system is concerned mainly pinothalamic with the motivational-affective components of pain response.

THE CEREBRAL NETWORK FOR PAIN PROCESSING IN MAN

Figure 1 Schematic diagram ofsome ofthe main anatomical components ofthe 'pain The cerebral neural substrate mediating matrix', and their possiblefunctional significance. PAG = Periaqueductal grey matter. painful response to noxious stimuli in man has 414 Jones, Derbyshire

been poorly understood until recently. Studies developed to quantitate changes in blood flow in man to identify the principal areas of the in man as an index of neuronal activity in brain involved in the response to pain have response to physiological StimUli.45 The under- Ann Rheum Dis: first published as 10.1136/ard.55.7.411 on 1 July 1996. Downloaded from relied predominantly either on stimulating lying assumption in applying these techniques specific areas of the brain in order to relieve33 is that there is a close relationship between or elicit pain known to have inputs from the blood flow and neuronal function. There is spinothalamic tracts,34 or on observing the good evidence from animal studies that there effects ofbrain lesions resulting from an infarct is such a relationship, and that changes in or surgery."-38 These different approaches have blood flow are closely related to neuronal provided some very important insights into energy metabolism.46 These methods therefore human pain physiology, but have not identified provide the exciting possibility of defining those areas of the brain germane to the inte- functional neuroanatomical substrates of dif- grated response to painful stimuli in normal ferent internally or externally generated physio- individuals. Penfield and Boldrey observed that logical stimuli, and have been extended to only 11 of800 cortical locations in the studies of response to non-painful and painful primary motor sensory cortex elicited pain thermal stimuli in normal volunteers, to deter- when stimulated,39 and none of these sites mine which areas of the brain respond specific- produced severe pain, but mostly a sharp ally to acutely painful thermal stimuli applied to burning pain. This observation has generated the back of the right hand, compared with non- considerable debate as to the relative import- painful thermal stimuli applied to the same spot. ance of the cerebral cortex to pain sensation in Expefiments were therefore designed specific- man. In more recent studies in patients under- ally to exclude the temporal and spatial localisa- going craniotomy for severe intractable pain, tion components of the response. The hypothe- pain was elicited by stimulating the primary sis to be tested was that pain is a predominantly and secondary sensory cortices and in some emotional experience and therefore substantial cases this has reproduced the type of chronic specific responses to pain are more likely to be pain experienced by the subject.40Y2 It is diffi- seen in the cortical and subcortical structures cult to know whether these experiences in relating to the 'medial pain system'. response to this type of stimulation result from An initial group ofexperiments examined the local neuronal excitation or as a result of acti- non-sensory discriminative components of the vation of corticothalamic pathways. Because cerebral response to an acute painful stimulus. these studies are difficult to reproduce, it is A series ofpainful or non-painful phasic stimuli difficult to assess how relevant these findings were given for two minutes while regional are to normal pain physiology or to the majority cerebral blood flow was measured. The effect of patients suffering from different types of of non-painful heat was subtracted from the chronic pain. Experiments in primates suggest effect of painful heat so that the temporal and that the cingulate cortex plays an important spatial discriminatory components of the pain part in conditioning responses to painful were controlled, leaving only the motivational- http://ard.bmj.com/ stimuli,43 while it has been observed that affective and cognitive components of the pain removal of the frontal or cingulate cortex in response. The subjects did not move during the patients with intractable pain may ameliorate delivery of the stimuli and were therefore its unpleasant emotional component without possibly suppressing the desire to withdraw the necessarily abolishing the pain itself37 or the hand. The results in a number ofgroups ofpain perception of acute nociceptive stimuli.35 41 It free volunteers have shown that there is a is interesting that Foltz and White37 had also unique network of structures activated by the on October 1, 2021 by guest. Protected copyright. observed that, after frontal cingulumotomy, no non-discriminatory components of pain which patient who had been addicted to opioids is not activated during other cognitive, motor, before surgery required opioids after the or sensory tasks. operation. Of the 14 patients who had been The non-discriminatory components of an addicted, nine had no withdrawal symptoms acute thermal pain stimulus activate predomi- and only five had mild withdrawal symptoms, nantly the contralateral thalamus, anterior suggesting that this operation may attenuate insula, lentiform nucleus and anterior cingu- opioid withdrawal symptoms. The significance late cortex, ipsilateral dorsolateral prefrontal of these structures to the integrated normal cortex (Brodman area 9 and 10), and inferior human pain response has been unknown until parietal cortex (areas 39 and 40) (table).47 50 recently because of the lack of non-invasive Subsignificant activations have also been seen techniques for observing such responses in specific brain regions. Summary ofthe areas ofsignificant (p < 005) increases in regional cerebral bloodflow (rCBF) in response to painfor Electrophysiological techniques have been each ofthe studies indicated extensively reviewed by Chen.' Much current information the network is the Significant regarding pain rCBF increase result of recent studies using functional imaging techniques such as positron emission Region Ref: 47 48 49 50 tomography (PET) and functional magnetic Thalamus v / Lentiform nucleus / V resonance imaging (fMRI). These techniques, Insula / V which offer exciting possibilities for theoretical Anterior cingulate cortex / / / / Prefrontal cortex / advancement, enable imaging of events in the Inferior parietal cortex / grey matter of the brain, giving a 'snapshot' of SiI / the actual function of the brain. They are non- S2 / / invasive techniques that have recently been SI, S2 = Primary and secondary somatosensory cortex. Cerebral mechanisms operating in the presence and absence ofinflammatory pain 415

in the region of the periaqueductal grey in the the medial pain system-the anterior insula brain stem. A similar pattern of activation has cortex, lentiform nucleus, mid- and perigenual been observed in normal volunteers subjected cingulate cortices, inferior parietal cortex, and to a tonic heat stimulus to the back of the right prefrontal cortex (dorsolateral prefrontal Ann Rheum Dis: first published as 10.1136/ard.55.7.411 on 1 July 1996. Downloaded from hand.48 Confirmation of these areas being (DLPF) areas 9, 10, and 46). activated by acute pain has come from a The cingulate cortex is involved in a number number of different laboratories including of integrated tasks including cognition, affect, groups from Ann Arbor,49 Montreal,50 Rome,5" and response selection.29 Although injection of and Stockholm (Hsieh JC, et al; submitted for local anaesthetic into the cingulum bundle publication). However, there is also some induces analgesia in animals,56 removal or important variability. In addition to the mid- deafferentation of the anterior cingulate cortex cingulate area previously described, a recent in patients with severe intractable pain did not study has demonstrated an additional highly abolish the pain: rather, the patients reported significant area at the perigenual cingulate.52 that the pain was no longer bothersome.37 This Studies disagree as to the laterality of cingulate suggests that the cingulate cortex is not response, some indicating bilateral responses; necessary for the registration of pain, but may there are also reports of bilateral thalamic be responsible for the attentional and affective activation.52 The possibility arises that there responses to pain. Cognitive tasks which make may be a bilateral component to thalamic, severe attentional demands, such as the Stroop insula, and basal ganglia processing, though conflict task, commonly activate the right the contralateral component may well be quan- anterior cingulate cortex. The Stroop task titatively more important. Nociceptive re- consists of asking subjects to call out the ink sponse in units in area 24 of the anterior colour of colour words which are incongruent cingulate often exhibit whole body receptive with their colour (such as the word 'red' fields. Some bilaterality of response might written in green ink). therefore be expected in this region. Although To what extent the anterior cingulate re- PET studies suggest that acute pain responses sponses to pain involve the 'attentional net- are mainly contralateral, chronic neurogenic work' is not established. A series ofexperiments pain appears to be processed ipsilaterally." It to determine whether similar areas of cingulate should be remembered that the effective spatial cortex are activated by an attentionally resolution of activation studies is about 16 mm demanding task (Stroop) and pain in the same and therefore there always remains some individuals suggested that both pain and uncertainty about the distinction between attention activate structures within the mid structures either side of the midline. However, cingulate cortex, but that only pain activates the fMRI studies also suggest that there is bilateral more anterior perigenual cingulate cortex.29 50 anterior cingulate activation in response to However, the same networks within the mid- pain.54 cingulate are not involved in both tasks, and the There is also unexpected variability of anterior cingulate responses to pain appear to http://ard.bmj.com/ responses in the somatosensory cortex. The be more than just attentional processing. There Manchester/Hammersmith group have been is some evidence that the perigenual cingulate unable to elicit consistent responses in S1, is involved in affective, vocalisation, and auto- finding both increases and decreases in flow in nomic responses to pain.32 It is possible that the response to pain. Apkarian et al have found anterior cingulate responses comprise a linked decreases in flow in response to tonic pain in attentional and affective network concerned S1/S2.55 Both the Montreal and Ann Arbor with response selection, the mid-cingulate on October 1, 2021 by guest. Protected copyright. groups have documented responses in this area response being concerned with motor response of cortex,49 50 and contralateral responses in S2 selection, and the passive attentional and to phasic pain 49 and tonic pain48 have also been affective components of the response being described. These inconsistencies most prob- processed more anteriorly. In support of this ably reflect differences in experimental design: suggestion, there are important connections for example, all the groups except the betwen mid-cingulate cortex and the DLPF Hammersmith/Manchester group moved a cortex which has been associated with the heat probe at a given temperature from one generation of willed actions and response location to another on the forearm in order to inhibition.57 minimise the effect of habituation. This is The inferior parietal cortical involvement in likely to increase attention to the discriminat- the pain response may be concerned with the ory components ofthe stimulus; this is unlikely posterior attentional system that Posner and to be matched in the control condition. There Petersen suggested is involved in directed is little doubt that S1 is involved in the sensory spatial attention.58 However, with its connec- discriminatory components of pain processing tions to the posterior cingulate cortex, where (Anderson J, et al; submitted for publication). substantial reductions in flow in response to However, the presence or absence of pain is pain have been recorded, it is more likely that unlikely to be the main determinant ofwhether this represents a nociceptive visual orientation there is an increase in flow in this area. response, as has been demonstrated in animals. It would appear, therefore, that the non- discriminatory components of acute pain are mainly processed in the region of the peri- Altered functional anatomy during acute aqueductal grey and thalamus, and subse- and chronic inflammatory pain quently in structures which may be the Jones et al studied the cerebral responses to the principal subcortical and cortical projections of non-discriminatory components of phasic 41646ones, Derbyshire

thermal pain (as described earlier) in a group of the various components of the anterior cingu- six patients with active rheumatoid arthritis late response to be discriminated. However, it (RA) according to American Rheumatism Asso- is likely that the reduced responses to phasic ciation criteria and compared their responses in pain may be related to enhanced coping and Ann Rheum Dis: first published as 10.1136/ard.55.7.411 on 1 July 1996. Downloaded from the presence of artritic pain with a group of attentional strategies63 related to altered pain free normal volunteers.59 All patients with response selection. Support for this concept RA had involvement of the metacarpo- comes from observations in patients with phalangeal joints, but none of the patients had atypical facial pain who have no identifiable active synovitis under the area of skin stimu- source of nociceptive input, but poor coping lated. Sensory testing and thermal threshold strategies, with frequent depression. They measurements were normal. The same group show enhanced anterior cingulate responses to (Jones AKP, et al; submitted for publication) standardised experimental heat pain.64 How- found that patients with RA demonstrated ever, patients with acute pain attributable to a significantly reduced frontal (BA 10) and definite nociceptive input from the face four anterior cingulate (BA 24 and 32) responses to hours after molar extraction have reduced experimental pain compared with controls (fig anterior cingulate and prefrontal cortical re- 2), in addition to reduced responses in the sponses, with intact thalamic and lentiform anterior insula and inferior parietal cortex. In the nucleus responses to a standardised thermal patients with RA, there was a generally damped pain stimulus (Derbyshire SWG, et al; sub- cortical and subcortical response to phasic mitted for publication). These different thermal pain (fig 3). patterns of cortical response suggest that adap- These differences are likely to represent an tation may be mainly at the level of the important cortical adaptation in the presence thalamocortical projections of the medial of continuing inflammatory pain. It is not thalamic nuclear group. possible to determine the level at which these There are extensive projections from the cortical responses are modified by ascending dorsolateral prefrontal cortex, including areas inputs. The anterior insula receives projections 9, 46, and 1065 to the anterior cingulate cortex from nociceptive specific components of the in primates. Reduced response in the DLPF ventromedial nucleus of the thalamus."9 Both cortex has also been found in patients suffering the anterior cingulate and frontal cortices are atypical facial pain66 and dental pain, and innervated by the parafascicular and medial depression.67 The DLPF cortex has been impli- thalamic group of nuclei. The cingulate cortex cated in the normal supervision of attentional is also implicated in avoidance conditioning,60 processes,68 depressed mood (areas 9, 46) and attention,16 mood,62 and willed actions. Study willed actions (areas 46, 10). The decreased design and spatial resolution have not enabled flow seen in the patients studied may be related http://ard.bmj.com/ on October 1, 2021 by guest. Protected copyright.

Figure 2 Pain versus heat-female controls. Data averagedfrom a group ofsix women. At the top are transverse images ofthe brain after stereotaxic normalisation, with the distancesfrom the anterior commissure-posterior commissure plane indicated. A: Anatomicalfeatures obtained by averaging aUl bloodflow scansfrom the six women. B: Arithmetical difference between adjusted mean bloodflowsforpainful hot and non-painful hot stimuli. C: Statistical parametric map t values derivedffrom theformalpixel by pixel comparison ofthe adjusted mean bloodflows and variancesfor each ofthe two conditions. The colour scale is arbitrary; threshold significance is indicated by the lower leftpixelfor each plane. D: Orthogonalprojections ofthe statistical comparison at p < 0-001 (Z threshold 3.09). The areas showing significant increases in bloodflow are within the region ofperiaqueductal grey, lentiform nucleus, insula, frontal areas 32 and 9, parietal area 40, and anterior cingulate cortex. Cerebral mechanisms operating in the presence and absence ofinflammatory pain 417 Ann Rheum Dis: first published as 10.1136/ard.55.7.411 on 1 July 1996. Downloaded from

Figre 3 Pain versus heat-rheumatoid arthritis. Data averagedfrom a group ofsix RA patients. At the top are trahsverse images ofthe brain after stereotaxic normalisation, with the distances from the anterior commissure-posterior commissure plane indicated. A: Anatomicalfeatures obtained by averaging all bloodflow scansfrom the six patients. B: Arithmetical difference between adjusted mean bloodflowsforpainful hot and non-painful hot stimuli. C: Statistical parametric map t values derivedfrom thefornalpixel by pixel comparison of the adjusted mean bloodflows and variances for each ofthe two conditions. The colour scale is arbitrary; threshold significance is indicated by the lower left pixelfor each plane. No area shows significant increase in regional cerebral bloodflow.

to the collapse of this supervisory function and found larger numbers of units with prolonged subsequent automatic attempts to recruit afterdischarges in response to movement or coping strategies or catastrophising schemes, light pressure of the inflamed joint in the depending on the beliefs and expectations of ventrobasal complex ofthe thalamus and S 1 up the patients. In this context, it is interesting that to one day after induced inflammation. These Hsieh et al have shown that prefrontal re- interesting effects were substantially blocked sponses to pain are critically dependent on the by both morphine and non-steroidal anal- psychological state of the subject: if the subject gesics. This group made a further interesting is preconditioned by a painful stimulus and observation that the total proportion of units knows when to expect the painful stimulus, excited by non-joint inputs (brush and pinch) there are reduced rather than increased pre- was considerably decreased after induction of frontal (ventromedial) responses.69 Further arthritis,67 and this effect was most marked for sequential studies are in progress to resolve the cortex. However, on the current evidence http://ard.bmj.com/ these issues. Recently developed surface it is not clear that these responses are noci- electrophysiological mapping techniques allow ceptive specific, as control non-nociceptive frontal responses to pain to be studied in detail. stimulation was not performed. It is possible The late vertex pain evoked potential, which that joint movement may comprise consider- probably corresponds to cingulate response, able non-nociceptive proprioceptive stimu- has been shown to be dependent on pain lation and pinch will also contain considerable

intensity.70 Sequential studies in patients with touch stimulation. It is also a concern that on October 1, 2021 by guest. Protected copyright. inflammatory pain using these techniques may noxious pressure on the joint may frequently well be the most sensitive and oost effective way not elicit any thalamic or primary somato- of correlating behaviour with physiological sensory cortical response (Guilbaud G; events in the forebrain. personal communication). The possibility A striking reduction in response is thus therefore exists that, whereas these obser- clearly demonstrated in frontal and anterior vations are undoubtedly related to the presence cingulate cortical responses during of inflammatory pain, they may not be related inflammatory pain and is distinct from to pain processing but to altered proprioceptive previously reported increased cingulate processing. It seems likely that the primary responses in patients with psychogenically somatosensory cortex is mainly involved in the maintained pain, suggesting different cortical localisation of pain in both time and space- substrates of these two types of pain that is, the sensory discriminative components experience. At present it is difficult to explain of pain. Adaptive motor responses during these observations in terms of any mechanisms inflammatory arthritis will certainly require that have been described in animal studies more precise proprioceptive processing. An because no equivalent experiment has been expansion of receptive fields to non- done. Studies in rodents with induced hindpaw nociceptive stimuli such as touch within the inflammatory arthritis have demonstrated cortex would be consistent with this process. neurones with expanded receptive fields and Human studies are necessary to validate this prolonged afterdischarges to touch in S1, but hypothesis. not in the ventrobasal complex of the The involvement of the anterior cingulate thalamus.66 This increase in the and frontal cortices in addition to medial of a unit was correlated with its increased thalamic nuclei in continuing inflammatory spontaneous activity. The same group also pain in animals has been recently established in 4184ones, Derbyshire

freely moving rodents using 2-deoxyglucose pain have been demonstrated in patients with autoradiography. This was performed at arftritis,72 consistent with increased cortical different stages ofthe development of the acute opioid peptide release demonstrated in animals inflammation in response to injection of with arthritis." To date, the principal cerebral Ann Rheum Dis: first published as 10.1136/ard.55.7.411 on 1 July 1996. Downloaded from formalin into a single paw of rats, and demon- neuropharmacological studies on inflammatory strated the sequence of metabolic changes pain in man have been performed using PET resulting from increased neuronal activity in the scanning. This technique was used to quantitate spinal cord, brain stem7" and telencephalic accurately the regional cerebral kinetics oftracer structures (Porro CA, et a4 personal communi- quantities of carbon-l labelled diprenorphine cation). In addition to significant activation of for 90 minutes after intravenous injection. This bilateral medullary, pontine reticular forma- tracer binds to available L, 8, and K opioid tion, and superior colliculi, several higher struc- binding sites; the radioactivity retained is tures were activated bilaterally, including directly proportional to the concentration of medial and lateral posterior thalamic nuclei, available opioid binding sites.74 Binding is parietal, anterior cingulate, anterior insula, and quantitated by fitting the regional kinetic data S1 and S2 cortices. Interestingly, the medial obtained with the PET camera to the thalamic nuclei were activated throughout the continuously sampled arterial plasma period of study (two, 30, and 60 minutes). radioactivity after correcting for metabolism of Frontal, orbitofrontal, S1, S2, anterior cingu- the tracer. The error on the fitted values for late cortex, and portions of the basal ganglia regional "C-diprenorphine binding has been were activated during the second phase of the minimised in these studies by injecting a response. These patterns may obviously be saturating dose of the opiate antagonist, influenced by motor response, but they are very naloxone, 30 minutes after the injection of different from the pattern of activation during tracer. At that point in the fitting routine, the repetitive motor response (Porro CA, et al; assumption can be made that there is no further personal communication). binding of "'C-diprenorphine to specific binding sites, reducing the number of variables by one. The kinetics of each of a number of brain Pharmacology regions are fitted to derive quantitative values of The neuropharmacological basis of the differ- in vivo " C-diprenorphine binding. These ences of cortical responses to pain are not measurements are made in each subject on one known, but indirect evidence implicates the occasion while they are in considerable pain and endogenous opioid system. Substantial changes on a second after substantial pain relief. The in opioid receptor binding during inflammatory changes in "1C-diprenorphine binding are expressed as a volume of distribution of specific binding and are assumed to reflect changes in occupancy of opioid receptors by endogenous opioid peptides, reducing the chances of trace http://ard.bmj.com/ quantitites of "C-diprenorphine associating with those receptors. A group of patients with active rheumatoid arthritis was studied during a period of active inflammation and, subsequently, substantially pain free as a result of either natural remission of their disease or intra-articular injection of on October 1, 2021 by guest. Protected copyright. locally injected and retained steroid. Pain free patients and patients in pain were also compared with non-age-matched controls. All patients who were studied twice showed a substantial reduction in the Ritchie index, erythrocyte sedimentation rate, C reactive protein concentration, or all three parameters, at the time of the second study, suggesting a considerable reduction in inflammation. Visual analogue scale pain scores (both affective and sensory components) for the 24 hours before the scan were reduced by 100% in three patients and by 62% in one patient at the time ofthe second scan. There was very little change in pain threshold, though there was an increase in pain tolerance consistent with the reduction in arthritic pain. Figure 4 Datafrom two single subjects in which the magnetic resonance images shown on Within group analysis of the four patients the left, have been coregistered and superimposed with the positron emission tomography scanned in two pain states showed substantial images on the right. A medial slice through the left hemisphere is depicted. TOP: Cerebral changes in "C-diprenorphine binding in most response to a phasic heatpain stimulus compared with a non-painful heat stimulus, showing increased regional cerebral bloodflow in the anterior cingulate cortex, thalamus, and brain regions analysed except for inferior periaqueductal grey matter in the brain stem. BELOW: Distribution ofopiate receptors temporal, inferior and mid-occipital cortices, imaged with "C-diprenorphine (binding to ,u, 8, K subtypes), displayed as a parametric the primary (cuneus), and map ofvolume ofdistribution ofreceptor binding. The concentration ofopiate receptors is maximal in the thalamus and is also high in the anterior parts ofthe cingulate cortex and in posterior putamen.72 Significant decreases in the periaqueductal grey. binding were observed in the superior and Cerebral mechanisms operating in the presence and absence ofinflammatory pain 419

inferior frontal cortices, straight gyrus, anterior to medial thalamic and periaqueductal grey in and posterior cingulate, superior, and mid- the brain stem, result in a resetting of temporal cortices. None of the changes seen in thresholds for ascending nociceptive inputs to the subcortical structures achieved significance. these higher centres. A series of prospective Ann Rheum Dis: first published as 10.1136/ard.55.7.411 on 1 July 1996. Downloaded from In this particular study, no distinction can be and longitudinal studies are now planned to made between the effects of inflammation and test these hypotheses. pain. It is therefore possible that all the changes observed may have been attributable to the 1 Melack R, Wall P. The chalenge of pain. Harmondsworth: Penguin Books, 1991. inflammation alone. However, a similar pattern 2 Boring E G. Sensation and perception in the history of of changes in opiate receptor binding has been experimental psychology. 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