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Neurophysiology and Functional Neuroanatomy of Pain Perception A. Schnitzler and M. Ploner Department of Neurology, Heinrich–Heine University, Du ¨sseldorf, Germany Summary: The traditional view that the cerebral cortex is not involved in pain processing has been abandoned during the past decades based on anatomic and physiologic investigations in animals, and lesion, functional neuroimaging, and neu- rophysiologic studies in humans. These studies have revealed an extensive central network associated with nociception that consistently includes the thalamus, the primary (SI) and secondary (SII) somatosensory cortices, the insula, and the anterior cingulate cortex (ACC). Anatomic and electrophysiologic data show that these cortical regions receive direct nociceptive thalamic input. From the results of human studies there is growing evidence that these different cortical structures contribute to different dimensions of pain experience. The SI cortex appears to be mainly involved in sensory-discriminative aspects of pain. The SII cortex seems to have an important role in recognition, learning, and memory of painful events. The insula has been proposed to be involved in autonomic reactions to noxious stimuli and in affective aspects of pain-related learning and memory. The ACC is closely related to pain unpleasantness and may subserve the integration of general affect, cognition, and response selection. The authors review the evidence on which the proposed relationship between cortical areas, pain-related neural activations, and components of pain perception is based. Key Words: Pain representation–Somatosensory cortex–SI–SII–Insula–Anterior cingulate cortex–Functional neuroimaging–Neurophysiology. Pain is an unpleasant sensory and emotional experi- ence associated with actual or potential tissue damage. It is mostly accompanied by the desire to stop and to avoid stimuli causing it. Pain can be modulated by cognitive factors like previous experiences and attention. The in- teraction of sensory, affective, and cognitive factors, and the indispensability for the physical integrity of the individual distinguish pain from other sensory experi- ences. From the peripheral receptor to the cerebral cortex, noxious stimuli are processed by specialized neural path- ways termed the nociceptive system. Peripherally, nox- ious stimuli activate specific receptors (nociceptors) of thinly myelinated Ad- and unmyelinated C-fibers termi- nating in the spinal cord dorsal horn (Raja et al., 1999). In the dorsal horn, neurons responding specifically to noxious stimuli (nociceptive specific [NS]) or to both noxious and innoxious stimuli (wide dynamic range [WDR]) are found. NS neurons are mainly located in the superficial aspects of the dorsal horn (lamina I) whereas WDR neurons are located predominantly in the deep dorsal horn (laminae IV–V) (Craig and Dostrovsky, 1999). The axons of both types of neurons cross the midline within one or two segments and ascend in the spinothalamic tract (STT). In the lateral STT, most axons originate from lamina I neurons whereas axons in the anterior STT originate from deep dorsal horn neurons. Supported by grants from the Volkswagen-Stiftung (I/73240), the Deutsche Forschungsgemeinschaft (SFB 194), and the Ute-Huneke- Stiftung. Address correspondence and reprint requests to Dr. Alfons Schnitzler, Department of Neurology, Heinrich–Heine University, Moorenstrasse. 5, D-40225 Du ¨sseldorf, Germany; e-mail: [email protected] Journal of Clinical Neurophysiology 17(6):592– 603, Lippincott Williams & Wilkins, Inc., Philadelphia © 2000 American Clinical Neurophysiology Society 592

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Neurophysiology and Functional Neuroanatomy of PainPerception

A. Schnitzler and M. Ploner

Department of Neurology, Heinrich–Heine University, Du¨sseldorf, Germany

Summary: The traditional view that the cerebral cortex is not involved in painprocessing has been abandoned during the past decades based on anatomic andphysiologic investigations in animals, and lesion, functional neuroimaging, and neu-rophysiologic studies in humans. These studies have revealed an extensive centralnetwork associated with nociception that consistently includes the thalamus, theprimary (SI) and secondary (SII) somatosensory cortices, the insula, and the anteriorcingulate cortex (ACC). Anatomic and electrophysiologic data show that these corticalregions receive direct nociceptive thalamic input. From the results of human studiesthere is growing evidence that these different cortical structures contribute to differentdimensions of pain experience. The SI cortex appears to be mainly involved insensory-discriminative aspects of pain. The SII cortex seems to have an important rolein recognition, learning, and memory of painful events. The insula has been proposedto be involved in autonomic reactions to noxious stimuli and in affective aspects ofpain-related learning and memory. The ACC is closely related to pain unpleasantnessand may subserve the integration of general affect, cognition, and response selection.The authors review the evidence on which the proposed relationship between corticalareas, pain-related neural activations, and components of pain perception is based.KeyWords: Pain representation–Somatosensory cortex–SI–SII–Insula–Anterior cingulatecortex–Functional neuroimaging–Neurophysiology.

Pain is an unpleasant sensory and emotional experi-ence associated with actual or potential tissue damage. Itis mostly accompanied by the desire to stop and to avoidstimuli causing it. Pain can be modulated by cognitivefactors like previous experiences and attention. The in-teraction of sensory, affective, and cognitive factors, andthe indispensability for the physical integrity of theindividual distinguish pain from other sensory experi-ences.

From the peripheral receptor to the cerebral cortex,

noxious stimuli are processed by specialized neural path-ways termed the nociceptive system. Peripherally, nox-ious stimuli activate specific receptors (nociceptors) ofthinly myelinated Ad- and unmyelinated C-fibers termi-nating in the spinal cord dorsal horn (Raja et al., 1999).In the dorsal horn, neurons responding specifically tonoxious stimuli (nociceptive specific [NS]) or to bothnoxious and innoxious stimuli (wide dynamic range[WDR]) are found. NS neurons are mainly located in thesuperficial aspects of the dorsal horn (lamina I) whereasWDR neurons are located predominantly in the deepdorsal horn (laminae IV–V) (Craig and Dostrovsky,1999). The axons of both types of neurons cross themidline within one or two segments and ascend in thespinothalamic tract (STT). In the lateral STT, most axonsoriginate from lamina I neurons whereas axons in theanterior STT originate from deep dorsal horn neurons.

Supported by grants from the Volkswagen-Stiftung (I/73240), theDeutsche Forschungsgemeinschaft (SFB 194), and the Ute-Huneke-Stiftung.

Address correspondence and reprint requests to Dr. Alfons Schnitzler,Department of Neurology, Heinrich–Heine University, Moorenstrasse. 5,D-40225 Dusseldorf, Germany; e-mail: [email protected]

Journal of Clinical Neurophysiology17(6):592–603, Lippincott Williams & Wilkins, Inc., Philadelphia© 2000 American Clinical Neurophysiology Society

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These STT neurons project to the thalamus, with thelatter terminating mainly in lateral nuclei, whereas me-dial nuclei receive input predominantly from lamina Ineurons. Cells in these thalamic nuclei in turn project tovarious distributed areas of the cortex. Medial and lateralthalamic nuclei and their particular cortical projectiontargets are summarized as medial and lateral pain sys-tems respectively. Obviously, the nociceptive systemconsists of different, partially independent pathways as-cending in parallel from the spinal cord dorsal horn to thecortex. At all levels these ascending parts of the noci-ceptive system can be modulated by descending projec-tions.

Involvement of the cerebral cortex in pain processinghas been doubted for many decades. Henry Head ob-served that “pure cortical lesions cause no increase ordecrease of sensibility to measured painful stimuli”(Head and Holmes, 1911, p. 154). Accordingly, electricalstimulation of the human cortex only rarely elicitedpainful sensations (Penfield and Boldrey, 1937). Thesehistorical findings were taken as evidence against aparticipation of the cerebral cortex in human pain pro-cessing. Later, various lesion studies contradicted thesefindings (for reviews see Kenshalo and Willis [1991] andSweet [1982]). However, the observed clinical deficitswere inconsistent, partly because information about le-sion extent or presence of additional lesions was oftenscant before high-resolution structural brain imagingbecame available. More unequivocal evidence for aninvolvement of the cerebral cortex in pain processingcame from animal experiments. Anatomic studies re-vealed parallel nociceptive thalamocortical projections tovarious cortical areas where corresponding neurophysi-ologic studies demonstrated pain-evoked neuronal re-sponses.

Eventually, these findings were complemented by hu-man lesion studies using computed tomography andMRI, and by functional neuroimaging studies using sin-gle-photon emission computed tomography (SPECT),positron emission tomography (PET), and functionallyMRI (fMRI). These studies noninvasively demonstratedinvolvement of distributed cerebral areas in human painprocessing comprising a variety of subcortical and cor-tical regions. More recently, the topographic aspects ofpain representations in the cerebral cortex have beenextended to the temporal domain by results of neuro-physiologic studies using whole-scalp magnetoencepha-lography (MEG) and EEG.

Analysis of both temporal and spatial aspects of cor-tical activity allows inferences on the hierarchical orga-nization of pain processing. Moreover, new stimuli andrefined experimental paradigms allow one to investigate

the nociceptive system selectively, without concurrentstimulation of tactile afferents, and to dissociate differentaspects of the pain experience.

In some aspects, the results of these studies are not yetunequivocal. However, concerning the relevance ofsome essential cortical areas there is growing consensusbetween human and experimental animal studies. Theseareas are the primary (SI) and secondary (SII) somato-sensory cortices of the lateral pain system, the anteriorcingulate cortex (ACC) of the medial pain system, andthe insular cortex, which cannot be assigned clearly toone of these systems. The current review summarizes themain findings indicating participation of these areas inthe processing of pain. In addition, the relationshipbetween the function of these areas and different aspectsof pain perception is demonstrated.

PRIMARY SOMATOSENSORY CORTEX

The role of SI in pain perception has long been indispute. Lesions of SI have been reported to cause eitherhypoalgesia or hyperalgesia, or to affect pain perceptionnot at all (for reviews see Kenshalo and Willis [1991]and Sweet [1982]).

In contrast, results from experimental animal studiesclearly indicate participation of SI in pain processing.Anatomic studies revealed nociceptive projections fromlateral thalamic nuclei, particularly from the ventral pos-terior lateral nucleus (VPL), to SI (Gingold et al., 1991;Kenshalo et al., 1980). Electrophysiologically, single cellrecordings in rats (Lamour et al., 1983), and anesthetized(Chudler et al., 1990; Kenshalo and Isensee, 1983) andawake (Kenshalo et al., 1988) monkeys demonstratedneurons in SI that responded to noxious stimuli. Theywere found much less frequently than cells responsive totactile stimuli and were localized at the borders betweenthe cytoarchitectonic areas 3b and 1, and 1 and 2 respec-tively (Chudler et al., 1990; Kenshalo and Isensee,1983). Most of these nociceptive SI neurons were ar-ranged somatotopically and had restricted receptivefields (Chudler et al., 1990; Kenshalo and Isensee, 1983;Kenshalo et al., 1988; Lamour et al., 1983). The activityof these neurons correlated with duration and intensity ofthe stimulus (Chudler et al., 1990; Kenshalo et al., 1988;Kenshalo and Isensee, 1983; Lamour et al., 1983) as wellas with the intensity of stimulus perception (Kenshalo etal., 1988). Psychophysical data suggest that these find-ings most probably also apply to humans (Chudler et al.,1990). Thus, functionally, nociceptive SI neurons arepredestinated to encode sensory-discriminative aspectsof pain.

In contrast to these animal studies but corresponding

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to the inconsistent clinical observations of human lesionstudies, the first functional neuroimaging studies pub-lished in the beginning of the 1990s have producedgreatly different results demonstrating pain-evoked in-crease, decrease, or no change of SI activity. By usingPET and repeated heat stimuli presented to six spots onthe arm, Talbot et al. (1991) found a notable activationfocus in SI contralateral to the stimulated arm. By usingSPECT, Apkarian et al. (1992) found that submergingfingers in hot water led to a decrease in SI activity.Finally, by using similar heat stimuli, but presented to asingle spot on the dorsal hand, Jones et al. (1991a) failedto observe notable activation in SI. However, morerecent PET, fMRI, and MEG/EEG studies (Andersson etal., 1997; Casey et al., 1994; Coghill et al., 1994, 1999;Craig et al., 1996; Derbyshire et al., 1997; Iadarola et al.,1998; Ploner et al., 1999b, 2000; Rainville et al., 1997;Tarkka and Treede, 1993) have provided convergentevidence for participation of SI in human pain process-ing. Furthermore, the results of several investigationspoint to a specific role of SI in sensory-discriminativefunctions of pain perception, such as spatial discrimina-tion (Andersson et al., 1997; Tarkka and Treede, 1993)and intensity coding (Coghill et al., 1999; Porro et al.,1998). Tarkka and Treede (1993) reported results con-sistent with a somatotopic organization of cerebral re-sponses along the central sulcus in a study modelingevoked potentials arising from laser pulses of painfulheat. Using PET, Andersson et al. (1997) demonstrated asimilar somatotopic organization of activations along thecentral sulcus during sustained pain on the dorsum of thehand or foot elicited by intracutaneous injection of cap-saicin. Somatotopic arrangement of pain in SI stronglysuggests that this region is involved in localization ofpainful stimuli on the body surface.

In agreement with this notion, a recent case reportdemonstrated that localization of painful stimuli may begrossly impaired when SI is damaged (Ploner et al.,1999a). In that study painful laser stimuli were deliveredto a patient with a right postcentral stroke as documentedby high-resolution MRI. When the dorsum of the af-fected left hand was stimulated, the patient reported anintense unpleasant sensation that was only poorly local-ized anywhere in the left upper limb.

Studies combining brain imaging with psychophysicalassessment of graded painful stimuli have revealed pos-itive correlations between perceived pain intensity andactivation of a functionally diverse group of brain re-gions, including the contralateral SI (Coghill et al., 1999;Porro et al., 1998). These results indicate that the inten-sity of different aspects of pain may be processed pref-

erentially in different regions. For example, SI activationcorrelates with the intensity of pain sensation (Bushnellet al., 1999) but not with the intensity of pain unpleas-antness (Rainville et al., 1997).

Taken together, these findings indicate an essentialrole of SI for the sensory-discriminative pain component.Nevertheless, the inconsistency of results of early lesionand functional imaging studies remains remarkable. Thismay be due in part to different net effects of excitationand inhibition within SI (Apkarian, 1995; Bushnell et al.,1999): Neurophysiologic recordings revealed that somenociceptive neurons in SI had very large receptive fields(Kenshalo and Isensee, 1983; Lamour et al., 1983;Mountcastle and Powell, 1959), did not code stimulusintensity or duration, or were even suppressed by nox-ious stimuli (Chudler et al., 1990; Kenshalo et al., 1988;Lamour et al., 1983). Such inhibitory effects within SIhave also been demonstrated simultaneously with (Tom-merdahl et al., 1996, 1998) as well as after excitation(Backonja et al., 1991). Inhibition has been observedwithin (Tommerdahl et al., 1996, 1998) as well as out-side the somatotopically appropriate regions of SI (Der-byshire et al., 1997). These inhibitory effects on theneurophysiologic level may account for pain-inducedimpairments in tactile perception on the behavioral level(Apkarian et al., 1994), and it has been proposed thatinhibition within SI optimizes the utilization of SI pro-cessing circuits for pain perception. Regardless of thefunctional role of inhibitory phenomena, the net effect ofexciting some neurons and inhibiting the spontaneousactivity of others could have different effects on regionalcerebral blood flow (as measured by PET) or on venousblood oxygenation (as measured by fMRI), depending onsuch variables as timing, duration, location, and intensityof the painful stimulus (Bushnell et al., 1999). Anotherconfounding variable that may account for inconsistentpain-evoked SI activations is its modulation by cognitivefactors. Attention to the sensory aspects of pain has beenshown to yield increases in SI activity (Bushnell et al.,1999) as well as in the intensity of stimulus perception(Bushnell et al., 1985, 1999). Furthermore, anticipationof a painful stimulus yields decreases in blood flow inareas of SI outside the representation of the anticipatedstimulus (Drevets et al., 1995). Thus, neurons that showinhibition to noxious stimuli and do not encode stimulusintensity or location may participate in cognitive modu-lation of SI activity and pain perception.

Anatomically, SI consists of four cytoarchitectonicallydefined areas, each of which contains a separate repre-sentation of the body surface with a, at least partially,

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serial information flow and hierarchical organization inthe tactile modality (for review see Iwamura [1998]). Bycomparing neuromagnetic responses to nociceptive andtactile stimuli delivered to the same skin site of thedorsum of the hand, Ploner et al. (2000) studied theprecise representation of pain within the parietal cortexin a group of normal subjects. In agreement with previ-ous anatomic and physiologic investigations (for reviewsee Iwamura [1998]), they found serial activations ofthree parietal sources to tactile stimuli: Brodmann area3b, representing the first cortical stage of a processingcascade, followed by activation of area 1 and the poste-rior parietal cortex. By contrast, nociceptive stimuli ac-tivated only a single parietal source, which was located atthe site of the tactile area 1 source (Fig. 1). This findingagrees with results of monkey studies (Chudler et al.,

1990; Kenshalo and Isensee, 1983), and suggests thatnociceptive processing does not share the elaborate andhierarchical organization of tactile processing that prob-ably evolved during evolution in parallel with an im-provement in tactile capacities of the hands.

Taken together, a considerable amount of evidencesuggests that SI has a pivotal role in sensory-discrimina-tive aspects of pain. Within SI, pain processing appearsto be less hierarchically organized than tactile process-ing. Cognitive factors can alter the perceived intensity ofpain and, accordingly, can modulate SI activity in func-tional imaging studies. Physiologically, inhibition of no-ciceptive neurons and neurons with nonsensory-discrim-inative response characteristics may be involved in thiscognitive modulation and in the interaction of pain andtouch.

FIG. 1. Comparison of tactile and no-ciceptive responses in a single subject.Tactile and nociceptive afferents sup-plying the dorsum of the hand werestimulated. Tactile afferents were stim-ulated with 0.3-msec constant voltagepulses delivered to the superficialbranch of the radial nerve just proximalto the wrist. Cutaneous nociceptive af-ferents were stimulated selectively by1-msec pulses of a Tm:YAG laser. (A)Magnetic field patterns at 30, 49, and68 msec (tactile), and 145 msec (noci-ceptive); corresponding current sourc-es; and source strength waveforms. Thehelmet-shaped sensor array is viewedfrom the upper left. Shaded areas indi-cate fields directed into the head. Ar-rows represent location and directionof current sources; correspondingsource strengths as a function of timeare shown on the right of the sensorarrays. (B) Location of sources super-imposed on the subject’s brain surfacerendering. Note that, along the postcen-tral gyrus, the nociceptive primary so-matosensory cortex source is locatedmore medially than the tactile area 3bresponse. Its location corresponds wellto the tactile area 1 source. Note alsothat tactile stimuli elicited a responsearising from the posterior parietal cor-tex, whereas no corresponding activitywas recorded to nociceptive stimuli.Adapted from Ploner M, Schmitz F,Freund H-J, Schnitzler A. Differentialorganization of touch and pain in hu-man primary somatosensory cortex.J Neurophysiol2000;83:1770–6.

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SECONDARY SOMATOSENSORY CORTEX

The second somatosensory area is located in the pari-etal operculum in the upper bank of the Sylvian fissureand its existence has been known since the early corticalstimulation studies during epileptic surgery (Penfield andJasper, 1954).

Several clinical observations of patients with opercu-lar lesions suggest that SII is relevant to the perception ofpain. Patients with lesions in the parietal operculum havemainly been reported to show impaired pain thresholds(Greenspan and Winfield, 1992; Greenspan et al., 1999;Kenshalo and Willis, 1991; Sweet, 1982). However,macroscopically, SII and the insular cortex are difficultto separate. Thus, based on lesion studies alone, infer-ences about the role of SII in pain are not unequivocal.

Anatomic studies indicate that SII receives nocicep-tive projections from lateral thalamic nuclei (Friedmanand Murray, 1986; Stevens et al., 1993). These projec-tions originate mostly from the ventral posterior inferior(VPI) thalamic nucleus (Friedman and Murray, 1986;Stevens et al., 1993), whereas nociceptive projections toSI originate predominantly from the VPL (Gingold et al.,1991; Kenshalo et al., 1980). Differences in spinal inputand response characteristics of VPL and VPI neurons(Apkarian and Hodge, 1989; Apkarian and Shi, 1994;Dong et al., 1989; Kenshalo and Willis, 1991) indicateanatomic and functional segregation of nociceptive path-ways from the spinal cord to SI and SII. Correspond-ingly, contrary to most SI cells, nociceptive neurons inSII including the neighboring area 7b and the retroinsularcortex have mostly large, bilateral receptive fields (Donget al., 1989, 1994; Robinson and Burton, 1980; Whitselet al., 1969) and encode stimulus intensity poorly (Donget al., 1989, 1994; Robinson and Burton, 1980). How-ever, only very few neurons have been found in theseareas, mainly in the caudal part of SII, that responded tonoxious stimuli (Dong et al., 1989, 1994; Robinson andBurton, 1980; Whitsel et al., 1969). Some of thesenociceptive neurons have multisensory properties andrespond additionally to stimuli from other modalities,particularly to threatening visual stimuli from locationscorresponding to the nociceptive receptive field (Dong etal., 1994; Whitsel et al., 1969). Thus, although SIIreceives appropriate spinothalamic projections, evidencefrom single cell recordings for nociceptive neurons inthis area is sparse.

The paucity of nociceptive SII neurons in animalstudies contrasts with results of human neurophysiologicand neuroimaging studies in which SII is one of theregions that is found most consistently to be activated.SII has been implicated in a number of PET and fMRI

studies on experimental pain (Casey et al., 1994; Coghillet al., 1994, 1999; Craig et al., 1996; Davis et al., 1998;Derbyshire et al., 1997; Gelnar et al., 1999; Iadarola etal., 1998; Rainville et al., 1997; Talbot et al., 1991) aswell as in neuromagnetic recordings of cortical activity(Hari et al., 1983, 1997; Huttunen et al., 1986; Kakigi etal., 1995; Ploner et al., 1999b, 2000) or scalp-evokedpotentials (Bromm and Chen, 1995; Spiegel et al., 1996;Tarkka and Treede, 1993) using different painful stimulisuch as thermal heat or laser-radiant heat. Generally,activations are observed bilaterally in the upper bank ofthe Sylvian fissure. Recordings of laser-evoked poten-tials from subdural grids (Lenz et al., 1998) confirm theresults of these noninvasive studies. A recent investiga-tion using stereotactically implanted depth electrodes(Frot et al., 1999) suggests that the generator of laser-evoked potentials may be located at the inner surface ofthe parietal operculum on the outer bank of the circularsulcus of the insula, which would be outside the classicSII area. If the nociceptive area was separate from thetactile area, then the discrepancy between animal andhuman studies could have a simple explanation: Becauseelectrophysiologic studies in SII usually use mechanicalsearch stimuli, they may have missed the nociceptiveneurons systematically.

In humans, the temporal activation pattern of SI andSII strongly supports direct thalamocortical distributionof nociceptive information to SII: MEG recordings re-vealed nearly simultaneous activation onsets of SI andSII to selective nociceptive stimuli indicating parallelactivation of these areas (Ploner et al., 1999b) (Fig. 2).This contrasts with the sequential activation of SI and SIIafter innocuous tactile stimuli (Hari et al., 1993; Ploneret al., 2000; Schnitzler et al., 1999), which reflect a serialorganization of these cortices in human tactile processing(for review see Iwamura [1998]). Thus, temporal activa-tion patterns suggest fundamentally different processingmodes in humans for tactile and nociceptive information,the former following a serial processing scheme fromthalamus via SI to SII and the latter underlying parallelprocessing in SI and SII. Interestingly, this parallel or-ganizational mode of SI and SII in human pain process-ing corresponds to the parallel cortical organization oftactile processing in lower primates and nonprimates(Garraghty et al., 1991; Turman et al., 1992), which hasshifted to serial processing during evolution in higherprimates and humans. Obviously, the basic mammalianparallel organizational scheme has been preserved inhuman pain processing. Assuming that the hierarchicalorganization of somatosensory cortices in human tactileprocessing allows for sophisticated discriminative capac-ities, these appear to be of less importance in human pain

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processing than in tactile processing. Instead, preserva-tion of direct access to SII emphasizes the relevance ofSII in human pain processing.

The anatomic connections of SII and inferences fromits proposed function in tactile processing suggest animportant role of SII in pain-associated learning andmemory. SII projects via the insula to the temporal lobelimbic structures (Friedman et al., 1986; Shi and Cassell,1998a). These corticolimbic projections have been pro-posed to subserve tactile learning and memory (Fried-man et al., 1986; Mishkin, 1979). Similarly, SII may playa key role in relaying nociceptive information to thetemporal lobe limbic structures (Dong et al., 1989; Lenzet al., 1997).

For the tactile system, there is evidence that areas inthe parietal operculum may be involved in feature ex-traction such as roughness discrimination and object sizedetection (Ledberg et al., 1995). Single neurons in SIIoften exhibit weak responses to passively presented tac-tile stimuli and larger receptive fields than those in SI,but display specificity for spatial patterns such as grat-ings and are activated specifically during active touchtasks (Sinclair and Burton, 1993). As such, one of thefunctions of SII may be tactile object recognition. Forthis function, most of the input to SII is assumed toderive from SI, and the output is directed toward theinsular cortex and the parahippocampal gyrus (Friedmanet al., 1986). This pattern of connections is similar to thatof the inferior temporal cortex, which is implicated in thevisual discrimination of objects (Ungerleider and Mish-kin, 1982).

By analogy, one of the functions of SII in pain per-ception may be the recognition of the noxious nature ofa stimulus. Consistent with this idea, patients with le-sions in the parietal operculum have both impaired tactileobject recognition (Caselli, 1993) and deficits in painperception (Biemond, 1956; Greenspan and Winfeld,1992; Greenspan et al., 1999; Ploner et al., 1999a). Thecase study by Ploner et al. (1999a) represents strikingsupport in favor of this notion. They report a patient withan ischemic lesion of the left SII (and SI). Besides beinggrossly impaired in localizing a painful laser stimulusdelivered on the affected hand, this patient was totallyunable to recognize the noxious nature of the stimuluseven when appropriate terms were presented to him.When asked to pick terms that might describe his sen-sation from a list that included “hot,” “burning,” and“pain,” the patient chose none. However, he perceived anintense unpleasantness and showed appropriate motorreactions and avoidance behavior.

In summary, neurophysiologic and functional imagingdata clearly indicate participation of SII in human painprocessing. Preserved, direct thalamic access of nocicep-tive information to SII, supported by anatomic thalamo-cortical connections and by parallel activation of somato-sensory cortices, suggests a particular relevance of thisarea in pain processing. Functionally, SII may be in-volved in recognition, learning, and memory of painfulevents. By contrast, in animal studies only very few SIIneurons respond to noxious stimuli. The relevance of thisconflict currently remains uncertain.

INSULA

Until recently, evidence for participation of the insulain human pain processing was scarce. However, during

FIG. 2. Cortical responses to cutaneous laser stimuli (see Fig. 1)applied to the right hand. (A) Location of cortical sources superposedon MR images. (Left ) Axial slice through the primary somatosensorycortex (SI) hand area viewed from above. (Middle, right ) Coronal andaxial slice through the secondary somatosensory cortex (SII). (B)Source strength as a function of time. Group mean (6standard error ofthe mean) source activities across six subjects are shown. Note thevirtually simultaneous activation of contralateral SI and SII, indicatingparallel thalamocortical organization of nociceptive information flow.Contra, contralateral; ipsi, ipsilateral. Adapted from Ploner M, SchmitzF, Freund H-J, Schnitzler A. Parallel activation of primary and sec-ondary somatosensory cortices in human pain processing.J Neuro-physiol1999b;81:3100–4.

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the last decade this has changed dramatically. Lesionstudies have shown that damage restricted to the insulaapparently reduces pain affect and appropriate reactionsto painful and threatening visual and auditory stimuli butdoes not influence pain threshold (Berthier et al., 1988;Greenspan et al., 1999). In addition, functional imagingstudies in particular demonstrated consistently pain-re-lated activations of the insula (Andersson et al., 1997;Binkofski et al., 1998; Casey et al., 1994, 1996; Coghillet al., 1994, 1999; Craig et al., 1996; Davis et al., 1998;Derbyshire et al., 1997; Gelnar et al., 1999; Iadarola etal., 1998; Rainville et al., 1997; Talbot et al., 1991; Tolleet al., 1999). These results motivated complementaryinvestigations in experimental animals. Indeed, singlecell recordings and local field potentials in rats (Hana-mori et al., 1998; Ito, 1998) and monkeys (Dostrovskyand Craig 1996; Robinson and Burton, 1980; Zhang etal., 1999) revealed nociceptive responses in the insula.These nociceptive neurons had large receptive fields(Robinson and Burton, 1980; Zhang et al., 1999) andresponded partially to multimodal stimulation, in partic-ular to visceral stimuli (Hanamori et al., 1998; Ito, 1998;Zhang et al., 1999).

Together, these results clearly indicate participation ofthe insula in the processing of pain. The response char-acteristics of nociceptive neurons in the insula pointagainst sensory-discriminative functions.

So far, considerations of the functional importance ofthe insula in pain processing have to rely mainly onindirect evidence. The insula consists of anatomicallyand functionally different areas (for reviews see Augus-tine [1996] and Mesulam and Mufson [1985]). Thalamicand cortical connectivity as well as results from physio-logic studies suggest that the posterior granular parts ofthe insula are related mainly to auditory, visual, andsomatosensory functions, whereas the anterior dysgranu-lar parts of the insula are related predominantly to limbic,olfactory, gustatory, and viscero-autonomic functions(Augustine, 1996; Mesulam and Mufson, 1985). Thus,the anterior insula processes predominantly intrapersonalinformation, and the posterior insula processes mainlyextrapersonal information.

Most functional imaging studies agree that pain-re-lated activations are located in the anterior parts of theinsula (Andersson et al., 1997; Binkofski et al., 1998;Casey et al., 1994, 1996; Coghill et al., 1994, 1999;Craig et al., 1996; Davis et al., 1998; Derbyshire et al.,1997; Gelnar et al., 1999; Iadarola et al., 1998; Rainvilleet al., 1997; Talbot et al., 1991; Tolle et al., 1999). Incontrast, tactile activations are located more posteriorly(Burton et al., 1993; Coghill et al., 1994). Thus, pain-related activity appears to be spatially distinct from

tactile activity and to be located in parts of the insulawhere mainly intrapersonal information is processed.This is supported by single cell recordings showingnociceptive neurons in the mid/anterior insula(Dostrovsky and Craig, 1996). However, an earlier in-vestigation that did not explore the anterior insulashowed nociceptive neurons in the posterior insula (Rob-inson and Burton, 1980). Therefore, further investiga-tions are needed to clarify the distribution of nociceptiveneurons and their spatial relationship to neurons con-cerned with other functions.

Recently, the mid/anterior insula has been shown toreceive afferents from a distinct posterior thalamic nu-cleus termed the posterior portion of the ventral medialnucleus (VMpo) (Craig, 1995). This newly describedthalamic nucleus has been shown to contain almostexclusively thermoreceptive and nociceptive neurons,and to receive predominantly afferents from lamina I ofthe spinal cord dorsal horn (Craig et al., 1994). Thus, anociceptive and thermoreceptive spinothalamocorticalpathway from lamina I of the spinal cord dorsal horn viaVMpo to the insula has been proposed (Craig et al.,1994). This pathway has been suggested to mediateenteroceptive information (i.e., information on the phys-iologic condition of the body itself, including the specificsensations of pain and temperature) (Craig, 1996). Dis-ruption of this pathway has been proposed to disinhibitactivity in a parallel nociceptive pathway to the ACCand, by this means, to be involved in the generation ofcentral pain (Craig, 1998). However, these findings re-main to be integrated with results from previous ana-tomic, physiologic and functional imaging studies. Par-ticularly the correspondence between an insular regiondefined by connectivity and single cell responses inmonkeys to pain-related activations of the anterior insulain humans has not yet been demonstrated unequivocally.Nevertheless, connections of the insula to widespreadthalamic and cortical regions related to all sensory mo-dalities and autonomic and limbic functions suggest asupramodal integrative role of the insula subservingappropriate, particularly autonomic, responses to stimulifrom various modalities including pain. In addition, theinsula receives afferents from SII and projects to theamygdala and hippocampal formation, and has thus beenproposed to subserve tactile and pain-related learningand memory (Friedman et al., 1986; Lenz et al., 1997;Mesulam and Mufson, 1985; Shi and Cassell, 1998a, b).Therefore, the insula may integrate pain-related inputfrom SII and the thalamus with contextual informationfrom other modalities before relaying this information tothe temporal lobe limbic structures.

In summary, numerous functional imaging studies

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indicate participation of anterior insular cortex in humanpain processing. Experimental animal studies suggestinvolvement of the insula in a wide variety of functionswith anatomic and functional differences between ante-rior and posterior insula. Recent findings indicating adedicated pain and temperature pathway to the insulaneed to be integrated with previous experimental animaland functional imaging data. Functionally, the insulamay be involved in autonomic reactions to noxiousstimuli and in pain-related memory and learning.

ANTERIOR CINGULATE CORTEX

Traditionally the cingulate gyrus has been regarded aspart of the limbic system, and was thus associated withthe motivational-affective component of pain. Accord-ingly, surgical lesions of the cingulate cortex (Hurt andBallantine, 1974) and the neighboring white matter(Foltz and White, 1962) reduce the emotional value andthe motivation to avoid painful stimuli but do not impairdetection of painful stimuli. Such effects have also beenobserved in experimental animals (Vaccarino and Mel-zack, 1989). Thus, these results confirm the relativeindependence of different aspects of pain perception aswell as of the corresponding anatomic substrates.

However, the cingulate cortex is an anatomically andfunctionally heterogenous area. Cytoarchitectonically, itis divided into the ACC, which has an agranular appear-ance similar to motor cortex, and a posterior part con-sisting of granular layers II and IV typical of areasreceiving primary afferent input (Brodmann, 1909). Ingeneral, the ACC receives little afferent supply fromother cortical areas whereas the posterior cingulate hasextensive input from the frontal, parietal, temporal, andoccipital lobes. Nevertheless the two cingulate parts arewell interconnected. Differences in input are especiallystriking in connections with the amygdala, whichprojects reciprocally to the anterior but not to the poste-rior cingulate. Because a major role of the amygdala isthe storage of emotional memory, its connections withthe ACC may serve to relate ongoing with past emotionalexperience.

Anterior and posterior cingulate are also functionallydistinct (Vogt et al., 1992). Particularly, the ACC ap-pears to be involved in pain processing: This part re-ceives input mainly from the medial thalamic nuclei(midline and intralaminar nuclei, central, parafascicular,reuniens, and mediodorsal nuclei) (Baleydier and Mau-guiere, 1980; Sikes and Vogt, 1992; Vogt et al., 1979,1987), which in turn receive afferents from the STT(Albe-Fessard et al., 1985; Apkarian, 1995; Dong et al.,1978).

Single cell recordings in the ACC of animals (Koyamaet al., 1998; Sikes and Vogt, 1992; Yamamura et al.,1996) revealed nociceptive neurons that are not orga-nized somatotopically and that have large receptivefields that often include the entire animal (Sikes andVogt, 1992; Yamamura et al., 1996). A substantial pro-portion of neurons has nociceptive-specific characteris-tics whereas others behave like polymodal nociceptors inthat they respond to noxious heat and noxious pressure.The only innocuous stimulus that activates these neuronsis tap stimuli. The large receptive fields and activation byinnocuous tap are similar to nociceptive neurons in themedial thalamic nuclei (Bushnell and Duncan, 1989;Dong et al., 1978), which suggests that ACC nociceptiveactivity arises from these nuclei. This is corroboratedfurther by the finding that activity of nociceptive neuronsin the ACC can be almost completely blocked withlidocaine injections into the medial and intralaminarthalamic nuclei (Sikes and Vogt, 1992).

In a recent study, single-neuron recordings and micro-stimulation were carried out in the ACC of patients underlocal anesthesia who underwent cingulotomy for thetreatment of psychiatric disease (Hutchison et al., 1999).In agreement with animal data neurons were identifiedthat responded selectively to painful thermal and me-chanical stimuli (Figs. 3B and C), thus providing directsupport, on the single-neuron level, for a role of the ACCin human pain sensation. Most neurons were activatedand very few were inhibited. None of these cells re-sponded to innocuous mechanical or thermal stimuli.Receptive fields were usually large and often bilateral.

Surprisingly, electrical stimulation even with high cur-rents at sites in the ACC, where pain-sensitive neuronswere recorded, failed to elicit painful or unpleasantsensations. As possible explanations the authors proposethat pain may be perceived only with simultaneousactivation of other cortical regions (for example, SI,insula) or that it requires bilateral activation of the ACC.Furthermore, electrical activation may not mimic normalpain-related firing patterns adequately. Additionally, it isconceivable that pain-related activity in the ACC mayalso represent descending modulation of pain rather thanperception of pain.

The location of pain-related neurons in the study ofHutchison et al. (1999) is in good agreement with anumber of functional neuroimaging studies showing con-sistent ACC activation during application of noxiousstimuli to various parts of the body (Figs. 3A and B)(Binkofski et al., 1998; Casey et al., 1994; Coghill et al.,1994, 1999; Craig et al., 1996; Davis et al., 1997;Derbyshire et al., 1994, 1998; Gelnar et al., 1999; Hsiehet al., 1995; Iadarola et al., 1998; Jones et al., 1991a;

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Porro et al., 1998; Rainville et al., 1997; Silverman et al.,1997; Talbot et al., 1991; Tolle et al., 1999; Vogt et al.,1992, 1996). It is also consistent with the location ofpain-evoked potentials in humans obtained both fromintracranial (Lenz et al., 1998) and extracranial record-ings (Bromm et al., 1995; Tarkka and Treede, 1993;Valeriani et al., 2000).

In addition to the clinical reports that patients withcingulotomies sometimes still feel pain but report it asless distressing or bothersome, and that there is a highlevel of opioid binding in the ACC (Jones et al., 1991b;Vogt et al., 1995), there is now also convincing evidencethat pain affect (i.e., the unpleasantness of pain) isencoded in the ACC. By using hypnosis, Rainville et al.(1997) selectively altered the unpleasantness of noxiousthermal stimuli without changing the perceived painintensity. Analysis of cerebral activation pattern as mea-sured by PET revealed that the modulation of pain affectwas paralleled by activation changes in the ACC but notin other brain areas (Rainville et al., 1997) (Fig. 3A).

However, it should be mentioned that the ACC cannotbe considered a mere pain center because it is alsoactivated by various other conditions such as duringperformance of the Stroop task (Bench et al., 1993;Pardo et al., 1990) and other cognitively challengingtasks (Corbetta et al., 1991; Petersen et al., 1988). More-over, the ACC appears to be involved in regulation ofautonomic functions and response selection and initia-tion as well as in attention (for review see Devinsky et al.[1995]). Therefore, pain-associated activations may rep-resent a nonpain-specific effect (for example, of atten-

tion). However, direct comparison of pain- and attention-related activations revealed that these activations do notcorrespond spatially to each other (Davis et al., 1997;Derbyshire et al., 1998). Thus, pain-related activations ofthe ACC are unlikely to be the result, exclusively, ofattention effects. On the other hand, some studiesshowed more than one activation focus in the ACC(Derbyshire et al., 1998; Tolle et al., 1999; Vogt et al.,1996). This and the proximity of the nociceptive, motor,and cognitive regions of the ACC suggests possible localinterconnections that may allow the output of the ACCpain area to command immediate behavioral reactions.

CONCLUSIONS

During the last decade, advances in functional brainimaging techniques have led to the identification ofneuroanatomic substrates of pain perception. SI and SII,the insula, and the ACC are involved essentially incortical processing of painful stimuli. Conceptual andmethodological refinements have allowed for character-ization and selective investigation of different compo-nents of pain perception. Taken together, accumulatingevidence suggests that each of the previously mentionedcortical areas is concerned with processing of specificaspects of pain. On the behavioral level, these differentaspects of pain perception are partly independent of eachother. Accordingly, on the anatomic level, the pain-related areas and pathways are organized predominantlyin parallel. However, well-orchestrated cooperation be-tween these distributed areas is required to unify the

FIG. 3. Activation of human anterior cingulate cortex (ACC) by painful stimuli. (A) Changes in pain-related positron emission tomographic(PET) activity associated with hypnotic suggestions of high unpleasantness. Sagittal slice through the ACC. The red circle indicates the locationand size of the activated ACC area. The image represents the subtraction of PET data recorded when the hand was submerged in thermallyneutral water (35°C) from data recorded when the hand was submerged in painfully hot water (47°C). PET data were averaged across 11experimental sessions, and are illustrated against the average MRI for that subject group (Reprinted with permission from American Associationfor the Advancement of Science. Source: Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC. Pain affect encoded in human anteriorcingulate but not somatosensory cortex.Science1997;277:968–71.) (B, C) Responses and locations of ACC neurons recorded from patientsduring neurosurgical treatment (cingulotomy) for psychiatric illness. (Adapted from Hutchison WD, Davis KD, Lozano AM, Tasker RR,Dostrovsky JO. Pain-related neurons in the human cingulate cortex.Nat Neurosci1999;2:403–5.) (B) Diagram showing the locations ofpain-related neurons (red circles) on a sagittal map 3 mm lateral to the midline. The dashed outline shows the region in which neurons weretested. VAC, vertical line through the ACC; VPC, vertical line through the posterior commissure. (C) ACC neuron fromB responding to thermalstimuli in the noxious range. Note that stimuli reported by the patient as warm but nonpainful (44°C, 46°C) did not activate the unit. (Top trace)Thermode temperature. (Below) Firing-rate histogram (bin width, 200 msec). The location of the thermode was on the contralateral volarforearm.

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different aspects of pain perception into the unique andindispensable experience of pain. The advances in ourunderstanding of normal pain perception have createdthe basis for studying the pathophysiology of abnormalpain states (e.g., chronic pain syndromes) that may resultfrom imbalances within the pain-related cerebral net-work.

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