Journal of Clinical Neurophysiology
17(6):592– 603, Lippincott Williams & Wilkins, Inc., Philadelphia
© 2000 American Clinical Neurophysiology Society
Neurophysiology and Functional Neuroanatomy of Pain
Perception
A. Schnitzler and M. Ploner
Department of Neurology, Heinrich–Heine University, Düsseldorf, 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 neurophysiologic 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 experience 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 interaction of sensory, affective, and cognitive factors, and
the indispensability for the physical integrity of the
individual distinguish pain from other sensory experiences.
From the peripheral receptor to the cerebral cortex,
noxious stimuli are processed by specialized neural pathways termed the nociceptive system. Peripherally, noxious stimuli activate specific receptors (nociceptors) of
thinly myelinated A␦- and unmyelinated C-fibers terminating 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-HunekeStiftung.
Address correspondence and reprint requests to Dr. Alfons Schnitzler,
Department of Neurology, Heinrich–Heine University, Moorenstrasse. 5,
D-40225 Düsseldorf, Germany; e-mail: schnitza@uni-duesseldorf.de
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These STT neurons project to the thalamus, with the
latter terminating mainly in lateral nuclei, whereas medial nuclei receive input predominantly from lamina I
neurons. Cells in these thalamic nuclei in turn project to
various distributed areas of the cortex. Medial and lateral
thalamic nuclei and their particular cortical projection
targets are summarized as medial and lateral pain systems respectively. Obviously, the nociceptive system
consists of different, partially independent pathways ascending in parallel from the spinal cord dorsal horn to the
cortex. At all levels these ascending parts of the nociceptive system can be modulated by descending projections.
Involvement of the cerebral cortex in pain processing
has been doubted for many decades. Henry Head observed that “pure cortical lesions cause no increase or
decrease of sensibility to measured painful stimuli”
(Head and Holmes, 1911, p. 154). Accordingly, electrical
stimulation of the human cortex only rarely elicited
painful sensations (Penfield and Boldrey, 1937). These
historical findings were taken as evidence against a
participation of the cerebral cortex in human pain processing. Later, various lesion studies contradicted these
findings (for reviews see Kenshalo and Willis [1991] and
Sweet [1982]). However, the observed clinical deficits
were inconsistent, partly because information about lesion extent or presence of additional lesions was often
scant before high-resolution structural brain imaging
became available. More unequivocal evidence for an
involvement of the cerebral cortex in pain processing
came from animal experiments. Anatomic studies revealed parallel nociceptive thalamocortical projections to
various cortical areas where corresponding neurophysiologic studies demonstrated pain-evoked neuronal responses.
Eventually, these findings were complemented by human lesion studies using computed tomography and
MRI, and by functional neuroimaging studies using single-photon emission computed tomography (SPECT),
positron emission tomography (PET), and functionally
MRI (fMRI). These studies noninvasively demonstrated
involvement of distributed cerebral areas in human pain
processing comprising a variety of subcortical and cortical regions. More recently, the topographic aspects of
pain representations in the cerebral cortex have been
extended to the temporal domain by results of neurophysiologic studies using whole-scalp magnetoencephalography (MEG) and EEG.
Analysis of both temporal and spatial aspects of cortical activity allows inferences on the hierarchical organization of pain processing. Moreover, new stimuli and
refined experimental paradigms allow one to investigate
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the nociceptive system selectively, without concurrent
stimulation of tactile afferents, and to dissociate different
aspects of the pain experience.
In some aspects, the results of these studies are not yet
unequivocal. However, concerning the relevance of
some essential cortical areas there is growing consensus
between human and experimental animal studies. These
areas are the primary (SI) and secondary (SII) somatosensory cortices of the lateral pain system, the anterior
cingulate cortex (ACC) of the medial pain system, and
the insular cortex, which cannot be assigned clearly to
one of these systems. The current review summarizes the
main findings indicating participation of these areas in
the processing of pain. In addition, the relationship
between the function of these areas and different aspects
of pain perception is demonstrated.
PRIMARY SOMATOSENSORY CORTEX
The role of SI in pain perception has long been in
dispute. Lesions of SI have been reported to cause either
hypoalgesia or hyperalgesia, or to affect pain perception
not at all (for reviews see Kenshalo and Willis [1991]
and Sweet [1982]).
In contrast, results from experimental animal studies
clearly indicate participation of SI in pain processing.
Anatomic studies revealed nociceptive projections from
lateral thalamic nuclei, particularly from the ventral posterior lateral nucleus (VPL), to SI (Gingold et al., 1991;
Kenshalo et al., 1980). Electrophysiologically, single cell
recordings in rats (Lamour et al., 1983), and anesthetized
(Chudler et al., 1990; Kenshalo and Isensee, 1983) and
awake (Kenshalo et al., 1988) monkeys demonstrated
neurons in SI that responded to noxious stimuli. They
were found much less frequently than cells responsive to
tactile stimuli and were localized at the borders between
the cytoarchitectonic areas 3b and 1, and 1 and 2 respectively (Chudler et al., 1990; Kenshalo and Isensee,
1983). Most of these nociceptive SI neurons were arranged somatotopically and had restricted receptive
fields (Chudler et al., 1990; Kenshalo and Isensee, 1983;
Kenshalo et al., 1988; Lamour et al., 1983). The activity
of these neurons correlated with duration and intensity of
the stimulus (Chudler et al., 1990; Kenshalo et al., 1988;
Kenshalo and Isensee, 1983; Lamour et al., 1983) as well
as with the intensity of stimulus perception (Kenshalo et
al., 1988). Psychophysical data suggest that these findings most probably also apply to humans (Chudler et al.,
1990). Thus, functionally, nociceptive SI neurons are
predestinated to encode sensory-discriminative aspects
of pain.
In contrast to these animal studies but corresponding
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A. SCHNITZLER AND M. PLONER
to the inconsistent clinical observations of human lesion
studies, the first functional neuroimaging studies published in the beginning of the 1990s have produced
greatly different results demonstrating pain-evoked increase, decrease, or no change of SI activity. By using
PET and repeated heat stimuli presented to six spots on
the arm, Talbot et al. (1991) found a notable activation
focus in SI contralateral to the stimulated arm. By using
SPECT, Apkarian et al. (1992) found that submerging
fingers in hot water led to a decrease in SI activity.
Finally, by using similar heat stimuli, but presented to a
single spot on the dorsal hand, Jones et al. (1991a) failed
to observe notable activation in SI. However, more
recent PET, fMRI, and MEG/EEG studies (Andersson et
al., 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 convergent
evidence for participation of SI in human pain processing. Furthermore, the results of several investigations
point to a specific role of SI in sensory-discriminative
functions of pain perception, such as spatial discrimination (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 consistent with a somatotopic organization of cerebral responses along the central sulcus in a study modeling
evoked potentials arising from laser pulses of painful
heat. Using PET, Andersson et al. (1997) demonstrated a
similar somatotopic organization of activations along the
central sulcus during sustained pain on the dorsum of the
hand or foot elicited by intracutaneous injection of capsaicin. Somatotopic arrangement of pain in SI strongly
suggests that this region is involved in localization of
painful stimuli on the body surface.
In agreement with this notion, a recent case report
demonstrated that localization of painful stimuli may be
grossly impaired when SI is damaged (Ploner et al.,
1999a). In that study painful laser stimuli were delivered
to a patient with a right postcentral stroke as documented
by high-resolution MRI. When the dorsum of the affected left hand was stimulated, the patient reported an
intense unpleasant sensation that was only poorly localized anywhere in the left upper limb.
Studies combining brain imaging with psychophysical
assessment of graded painful stimuli have revealed positive correlations between perceived pain intensity and
activation of a functionally diverse group of brain regions, including the contralateral SI (Coghill et al., 1999;
Porro et al., 1998). These results indicate that the intensity of different aspects of pain may be processed prefJ Clin Neurophysiol, Vol. 17, No. 6, 2000
erentially in different regions. For example, SI activation
correlates with the intensity of pain sensation (Bushnell
et al., 1999) but not with the intensity of pain unpleasantness (Rainville et al., 1997).
Taken together, these findings indicate an essential
role of SI for the sensory-discriminative pain component.
Nevertheless, the inconsistency of results of early lesion
and functional imaging studies remains remarkable. This
may be due in part to different net effects of excitation
and inhibition within SI (Apkarian, 1995; Bushnell et al.,
1999): Neurophysiologic recordings revealed that some
nociceptive neurons in SI had very large receptive fields
(Kenshalo and Isensee, 1983; Lamour et al., 1983;
Mountcastle and Powell, 1959), did not code stimulus
intensity or duration, or were even suppressed by noxious stimuli (Chudler et al., 1990; Kenshalo et al., 1988;
Lamour et al., 1983). Such inhibitory effects within SI
have also been demonstrated simultaneously with (Tommerdahl et al., 1996, 1998) as well as after excitation
(Backonja et al., 1991). Inhibition has been observed
within (Tommerdahl et al., 1996, 1998) as well as outside the somatotopically appropriate regions of SI (Derbyshire et al., 1997). These inhibitory effects on the
neurophysiologic level may account for pain-induced
impairments in tactile perception on the behavioral level
(Apkarian et al., 1994), and it has been proposed that
inhibition within SI optimizes the utilization of SI processing circuits for pain perception. Regardless of the
functional role of inhibitory phenomena, the net effect of
exciting some neurons and inhibiting the spontaneous
activity of others could have different effects on regional
cerebral blood flow (as measured by PET) or on venous
blood oxygenation (as measured by fMRI), depending on
such variables as timing, duration, location, and intensity
of the painful stimulus (Bushnell et al., 1999). Another
confounding variable that may account for inconsistent
pain-evoked SI activations is its modulation by cognitive
factors. Attention to the sensory aspects of pain has been
shown 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, anticipation
of a painful stimulus yields decreases in blood flow in
areas of SI outside the representation of the anticipated
stimulus (Drevets et al., 1995). Thus, neurons that show
inhibition to noxious stimuli and do not encode stimulus
intensity or location may participate in cognitive modulation of SI activity and pain perception.
Anatomically, SI consists of four cytoarchitectonically
defined areas, each of which contains a separate representation of the body surface with a, at least partially,
PAIN PERCEPTION
595
FIG. 1. Comparison of tactile and nociceptive responses in a single subject.
Tactile and nociceptive afferents supplying the dorsum of the hand were
stimulated. Tactile afferents were stimulated with 0.3-msec constant voltage
pulses delivered to the superficial
branch of the radial nerve just proximal
to the wrist. Cutaneous nociceptive afferents were stimulated selectively by
1-msec pulses of a Tm:YAG laser. (A)
Magnetic field patterns at 30, 49, and
68 msec (tactile), and 145 msec (nociceptive); corresponding current sources; and source strength waveforms. The
helmet-shaped sensor array is viewed
from the upper left. Shaded areas indicate fields directed into the head. Arrows represent location and direction
of current sources; corresponding
source strengths as a function of time
are shown on the right of the sensor
arrays. (B) Location of sources superimposed on the subject’s brain surface
rendering. Note that, along the postcentral gyrus, the nociceptive primary somatosensory cortex source is located
more medially than the tactile area 3b
response. Its location corresponds well
to the tactile area 1 source. Note also
that tactile stimuli elicited a response
arising from the posterior parietal cortex, whereas no corresponding activity
was recorded to nociceptive stimuli.
Adapted from Ploner M, Schmitz F,
Freund H-J, Schnitzler A. Differential
organization of touch and pain in human primary somatosensory cortex.
J Neurophysiol 2000;83:1770 – 6.
serial information flow and hierarchical organization in
the tactile modality (for review see Iwamura [1998]). By
comparing neuromagnetic responses to nociceptive and
tactile stimuli delivered to the same skin site of the
dorsum of the hand, Ploner et al. (2000) studied the
precise representation of pain within the parietal cortex
in a group of normal subjects. In agreement with previous anatomic and physiologic investigations (for review
see Iwamura [1998]), they found serial activations of
three parietal sources to tactile stimuli: Brodmann area
3b, representing the first cortical stage of a processing
cascade, followed by activation of area 1 and the posterior parietal cortex. By contrast, nociceptive stimuli activated only a single parietal source, which was located at
the site of the tactile area 1 source (Fig. 1). This finding
agrees with results of monkey studies (Chudler et al.,
1990; Kenshalo and Isensee, 1983), and suggests that
nociceptive processing does not share the elaborate and
hierarchical organization of tactile processing that probably evolved during evolution in parallel with an improvement in tactile capacities of the hands.
Taken together, a considerable amount of evidence
suggests that SI has a pivotal role in sensory-discriminative aspects of pain. Within SI, pain processing appears
to be less hierarchically organized than tactile processing. Cognitive factors can alter the perceived intensity of
pain and, accordingly, can modulate SI activity in functional imaging studies. Physiologically, inhibition of nociceptive neurons and neurons with nonsensory-discriminative response characteristics may be involved in this
cognitive modulation and in the interaction of pain and
touch.
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A. SCHNITZLER AND M. PLONER
SECONDARY SOMATOSENSORY CORTEX
The second somatosensory area is located in the parietal operculum in the upper bank of the Sylvian fissure
and its existence has been known since the early cortical
stimulation studies during epileptic surgery (Penfield and
Jasper, 1954).
Several clinical observations of patients with opercular lesions suggest that SII is relevant to the perception of
pain. Patients with lesions in the parietal operculum have
mainly 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 difficult
to separate. Thus, based on lesion studies alone, inferences about the role of SII in pain are not unequivocal.
Anatomic studies indicate that SII receives nociceptive projections from lateral thalamic nuclei (Friedman
and Murray, 1986; Stevens et al., 1993). These projections originate mostly from the ventral posterior inferior
(VPI) thalamic nucleus (Friedman and Murray, 1986;
Stevens et al., 1993), whereas nociceptive projections to
SI originate predominantly from the VPL (Gingold et al.,
1991; Kenshalo et al., 1980). Differences in spinal input
and response characteristics of VPL and VPI neurons
(Apkarian and Hodge, 1989; Apkarian and Shi, 1994;
Dong et al., 1989; Kenshalo and Willis, 1991) indicate
anatomic and functional segregation of nociceptive pathways from the spinal cord to SI and SII. Correspondingly, contrary to most SI cells, nociceptive neurons in
SII including the neighboring area 7b and the retroinsular
cortex have mostly large, bilateral receptive fields (Dong
et al., 1989, 1994; Robinson and Burton, 1980; Whitsel
et al., 1969) and encode stimulus intensity poorly (Dong
et al., 1989, 1994; Robinson and Burton, 1980). However, only very few neurons have been found in these
areas, mainly in the caudal part of SII, that responded to
noxious stimuli (Dong et al., 1989, 1994; Robinson and
Burton, 1980; Whitsel et al., 1969). Some of these
nociceptive neurons have multisensory properties and
respond additionally to stimuli from other modalities,
particularly to threatening visual stimuli from locations
corresponding to the nociceptive receptive field (Dong et
al., 1994; Whitsel et al., 1969). Thus, although SII
receives appropriate spinothalamic projections, evidence
from single cell recordings for nociceptive neurons in
this area is sparse.
The paucity of nociceptive SII neurons in animal
studies contrasts with results of human neurophysiologic
and neuroimaging studies in which SII is one of the
regions that is found most consistently to be activated.
SII has been implicated in a number of PET and fMRI
J Clin Neurophysiol, Vol. 17, No. 6, 2000
studies on experimental pain (Casey et al., 1994; 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; Rainville et al., 1997; Talbot et al., 1991) as
well as in neuromagnetic recordings of cortical activity
(Hari et al., 1983, 1997; Huttunen et al., 1986; Kakigi et
al., 1995; Ploner et al., 1999b, 2000) or scalp-evoked
potentials (Bromm and Chen, 1995; Spiegel et al., 1996;
Tarkka and Treede, 1993) using different painful stimuli
such as thermal heat or laser-radiant heat. Generally,
activations are observed bilaterally in the upper bank of
the Sylvian fissure. Recordings of laser-evoked potentials from subdural grids (Lenz et al., 1998) confirm the
results of these noninvasive studies. A recent investigation using stereotactically implanted depth electrodes
(Frot et al., 1999) suggests that the generator of laserevoked potentials may be located at the inner surface of
the parietal operculum on the outer bank of the circular
sulcus of the insula, which would be outside the classic
SII area. If the nociceptive area was separate from the
tactile area, then the discrepancy between animal and
human studies could have a simple explanation: Because
electrophysiologic studies in SII usually use mechanical
search stimuli, they may have missed the nociceptive
neurons systematically.
In humans, the temporal activation pattern of SI and
SII strongly supports direct thalamocortical distribution
of nociceptive information to SII: MEG recordings revealed nearly simultaneous activation onsets of SI and
SII to selective nociceptive stimuli indicating parallel
activation of these areas (Ploner et al., 1999b) (Fig. 2).
This contrasts with the sequential activation of SI and SII
after innocuous tactile stimuli (Hari et al., 1993; Ploner
et al., 2000; Schnitzler et al., 1999), which reflect a serial
organization of these cortices in human tactile processing
(for review see Iwamura [1998]). Thus, temporal activation patterns suggest fundamentally different processing
modes in humans for tactile and nociceptive information,
the former following a serial processing scheme from
thalamus via SI to SII and the latter underlying parallel
processing in SI and SII. Interestingly, this parallel organizational mode of SI and SII in human pain processing corresponds to the parallel cortical organization of
tactile processing in lower primates and nonprimates
(Garraghty et al., 1991; Turman et al., 1992), which has
shifted to serial processing during evolution in higher
primates and humans. Obviously, the basic mammalian
parallel organizational scheme has been preserved in
human pain processing. Assuming that the hierarchical
organization of somatosensory cortices in human tactile
processing allows for sophisticated discriminative capacities, these appear to be of less importance in human pain
PAIN PERCEPTION
FIG. 2. Cortical responses to cutaneous laser stimuli (see Fig. 1)
applied to the right hand. (A) Location of cortical sources superposed
on MR images. (Left) Axial slice through the primary somatosensory
cortex (SI) hand area viewed from above. (Middle, right) Coronal and
axial slice through the secondary somatosensory cortex (SII). (B)
Source strength as a function of time. Group mean (⫾standard error of
the mean) source activities across six subjects are shown. Note the
virtually simultaneous activation of contralateral SI and SII, indicating
parallel thalamocortical organization of nociceptive information flow.
Contra, contralateral; ipsi, ipsilateral. Adapted from Ploner M, Schmitz
F, Freund H-J, Schnitzler A. Parallel activation of primary and secondary somatosensory cortices in human pain processing. J Neurophysiol 1999b;81:3100 – 4.
processing than in tactile processing. Instead, preservation of direct access to SII emphasizes the relevance of
SII in human pain processing.
The anatomic connections of SII and inferences from
its proposed function in tactile processing suggest an
important role of SII in pain-associated learning and
memory. SII projects via the insula to the temporal lobe
limbic structures (Friedman et al., 1986; Shi and Cassell,
1998a). These corticolimbic projections have been proposed to subserve tactile learning and memory (Friedman et al., 1986; Mishkin, 1979). Similarly, SII may play
a key role in relaying nociceptive information to the
temporal lobe limbic structures (Dong et al., 1989; Lenz
et al., 1997).
597
For the tactile system, there is evidence that areas in
the parietal operculum may be involved in feature extraction such as roughness discrimination and object size
detection (Ledberg et al., 1995). Single neurons in SII
often exhibit weak responses to passively presented tactile stimuli and larger receptive fields than those in SI,
but display specificity for spatial patterns such as gratings and are activated specifically during active touch
tasks (Sinclair and Burton, 1993). As such, one of the
functions of SII may be tactile object recognition. For
this function, most of the input to SII is assumed to
derive from SI, and the output is directed toward the
insular cortex and the parahippocampal gyrus (Friedman
et al., 1986). This pattern of connections is similar to that
of the inferior temporal cortex, which is implicated in the
visual discrimination of objects (Ungerleider and Mishkin, 1982).
By analogy, one of the functions of SII in pain perception may be the recognition of the noxious nature of
a stimulus. Consistent with this idea, patients with lesions in the parietal operculum have both impaired tactile
object recognition (Caselli, 1993) and deficits in pain
perception (Biemond, 1956; Greenspan and Winfeld,
1992; Greenspan et al., 1999; Ploner et al., 1999a). The
case study by Ploner et al. (1999a) represents striking
support in favor of this notion. They report a patient with
an ischemic lesion of the left SII (and SI). Besides being
grossly impaired in localizing a painful laser stimulus
delivered on the affected hand, this patient was totally
unable to recognize the noxious nature of the stimulus
even when appropriate terms were presented to him.
When asked to pick terms that might describe his sensation from a list that included “hot,” “burning,” and
“pain,” the patient chose none. However, he perceived an
intense unpleasantness and showed appropriate motor
reactions and avoidance behavior.
In summary, neurophysiologic and functional imaging
data clearly indicate participation of SII in human pain
processing. Preserved, direct thalamic access of nociceptive information to SII, supported by anatomic thalamocortical connections and by parallel activation of somatosensory cortices, suggests a particular relevance of this
area in pain processing. Functionally, SII may be involved in recognition, learning, and memory of painful
events. By contrast, in animal studies only very few SII
neurons respond to noxious stimuli. The relevance of this
conflict currently remains uncertain.
INSULA
Until recently, evidence for participation of the insula
in human pain processing was scarce. However, during
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the last decade this has changed dramatically. Lesion
studies have shown that damage restricted to the insula
apparently reduces pain affect and appropriate reactions
to painful and threatening visual and auditory stimuli but
does not influence pain threshold (Berthier et al., 1988;
Greenspan et al., 1999). In addition, functional imaging
studies in particular demonstrated consistently pain-related activations of the insula (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; Rainville et al., 1997; Talbot et al., 1991; Tolle
et al., 1999). These results motivated complementary
investigations in experimental animals. Indeed, single
cell recordings and local field potentials in rats (Hanamori et al., 1998; Ito, 1998) and monkeys (Dostrovsky
and Craig 1996; Robinson and Burton, 1980; Zhang et
al., 1999) revealed nociceptive responses in the insula.
These nociceptive neurons had large receptive fields
(Robinson and Burton, 1980; Zhang et al., 1999) and
responded partially to multimodal stimulation, in particular to visceral stimuli (Hanamori et al., 1998; Ito, 1998;
Zhang et al., 1999).
Together, these results clearly indicate participation of
the insula in the processing of pain. The response characteristics of nociceptive neurons in the insula point
against sensory-discriminative functions.
So far, considerations of the functional importance of
the insula in pain processing have to rely mainly on
indirect evidence. The insula consists of anatomically
and functionally different areas (for reviews see Augustine [1996] and Mesulam and Mufson [1985]). Thalamic
and cortical connectivity as well as results from physiologic studies suggest that the posterior granular parts of
the insula are related mainly to auditory, visual, and
somatosensory functions, whereas the anterior dysgranular 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 intrapersonal
information, and the posterior insula processes mainly
extrapersonal information.
Most functional imaging studies agree that pain-related activations are located in the anterior parts of the
insula (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; Rainville
et al., 1997; Talbot et al., 1991; Tolle et al., 1999). In
contrast, tactile activations are located more posteriorly
(Burton et al., 1993; Coghill et al., 1994). Thus, painrelated activity appears to be spatially distinct from
J Clin Neurophysiol, Vol. 17, No. 6, 2000
tactile activity and to be located in parts of the insula
where mainly intrapersonal information is processed.
This is supported by single cell recordings showing
nociceptive neurons in the mid/anterior insula
(Dostrovsky and Craig, 1996). However, an earlier investigation that did not explore the anterior insula
showed nociceptive neurons in the posterior insula (Robinson and Burton, 1980). Therefore, further investigations are needed to clarify the distribution of nociceptive
neurons and their spatial relationship to neurons concerned with other functions.
Recently, the mid/anterior insula has been shown to
receive afferents from a distinct posterior thalamic nucleus termed the posterior portion of the ventral medial
nucleus (VMpo) (Craig, 1995). This newly described
thalamic nucleus has been shown to contain almost
exclusively thermoreceptive and nociceptive neurons,
and to receive predominantly afferents from lamina I of
the spinal cord dorsal horn (Craig et al., 1994). Thus, a
nociceptive and thermoreceptive spinothalamocortical
pathway from lamina I of the spinal cord dorsal horn via
VMpo to the insula has been proposed (Craig et al.,
1994). This pathway has been suggested to mediate
enteroceptive information (i.e., information on the physiologic condition of the body itself, including the specific
sensations of pain and temperature) (Craig, 1996). Disruption of this pathway has been proposed to disinhibit
activity in a parallel nociceptive pathway to the ACC
and, by this means, to be involved in the generation of
central pain (Craig, 1998). However, these findings remain to be integrated with results from previous anatomic, physiologic and functional imaging studies. Particularly the correspondence between an insular region
defined by connectivity and single cell responses in
monkeys to pain-related activations of the anterior insula
in humans has not yet been demonstrated unequivocally.
Nevertheless, connections of the insula to widespread
thalamic and cortical regions related to all sensory modalities and autonomic and limbic functions suggest a
supramodal integrative role of the insula subserving
appropriate, particularly autonomic, responses to stimuli
from various modalities including pain. In addition, the
insula receives afferents from SII and projects to the
amygdala and hippocampal formation, and has thus been
proposed to subserve tactile and pain-related learning
and 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 input
from SII and the thalamus with contextual information
from other modalities before relaying this information to
the temporal lobe limbic structures.
In summary, numerous functional imaging studies
PAIN PERCEPTION
indicate participation of anterior insular cortex in human
pain processing. Experimental animal studies suggest
involvement of the insula in a wide variety of functions
with anatomic and functional differences between anterior and posterior insula. Recent findings indicating a
dedicated pain and temperature pathway to the insula
need to be integrated with previous experimental animal
and functional imaging data. Functionally, the insula
may be involved in autonomic reactions to noxious
stimuli and in pain-related memory and learning.
ANTERIOR CINGULATE CORTEX
Traditionally the cingulate gyrus has been regarded as
part of the limbic system, and was thus associated with
the motivational-affective component of pain. Accordingly, surgical lesions of the cingulate cortex (Hurt and
Ballantine, 1974) and the neighboring white matter
(Foltz and White, 1962) reduce the emotional value and
the motivation to avoid painful stimuli but do not impair
detection of painful stimuli. Such effects have also been
observed in experimental animals (Vaccarino and Melzack, 1989). Thus, these results confirm the relative
independence of different aspects of pain perception as
well as of the corresponding anatomic substrates.
However, the cingulate cortex is an anatomically and
functionally heterogenous area. Cytoarchitectonically, it
is divided into the ACC, which has an agranular appearance similar to motor cortex, and a posterior part consisting of granular layers II and IV typical of areas
receiving primary afferent input (Brodmann, 1909). In
general, the ACC receives little afferent supply from
other cortical areas whereas the posterior cingulate has
extensive input from the frontal, parietal, temporal, and
occipital lobes. Nevertheless the two cingulate parts are
well interconnected. Differences in input are especially
striking in connections with the amygdala, which
projects reciprocally to the anterior but not to the posterior cingulate. Because a major role of the amygdala is
the storage of emotional memory, its connections with
the ACC may serve to relate ongoing with past emotional
experience.
Anterior and posterior cingulate are also functionally
distinct (Vogt et al., 1992). Particularly, the ACC appears to be involved in pain processing: This part receives input mainly from the medial thalamic nuclei
(midline and intralaminar nuclei, central, parafascicular,
reuniens, and mediodorsal nuclei) (Baleydier and Mauguiere, 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).
599
Single cell recordings in the ACC of animals (Koyama
et al., 1998; Sikes and Vogt, 1992; Yamamura et al.,
1996) revealed nociceptive neurons that are not organized somatotopically and that have large receptive
fields that often include the entire animal (Sikes and
Vogt, 1992; Yamamura et al., 1996). A substantial proportion of neurons has nociceptive-specific characteristics whereas others behave like polymodal nociceptors in
that they respond to noxious heat and noxious pressure.
The only innocuous stimulus that activates these neurons
is tap stimuli. The large receptive fields and activation by
innocuous tap are similar to nociceptive neurons in the
medial thalamic nuclei (Bushnell and Duncan, 1989;
Dong et al., 1978), which suggests that ACC nociceptive
activity arises from these nuclei. This is corroborated
further by the finding that activity of nociceptive neurons
in the ACC can be almost completely blocked with
lidocaine injections into the medial and intralaminar
thalamic nuclei (Sikes and Vogt, 1992).
In a recent study, single-neuron recordings and microstimulation were carried out in the ACC of patients under
local anesthesia who underwent cingulotomy for the
treatment of psychiatric disease (Hutchison et al., 1999).
In agreement with animal data neurons were identified
that responded selectively to painful thermal and mechanical stimuli (Figs. 3B and C), thus providing direct
support, on the single-neuron level, for a role of the ACC
in human pain sensation. Most neurons were activated
and very few were inhibited. None of these cells responded to innocuous mechanical or thermal stimuli.
Receptive fields were usually large and often bilateral.
Surprisingly, electrical stimulation even with high currents at sites in the ACC, where pain-sensitive neurons
were recorded, failed to elicit painful or unpleasant
sensations. As possible explanations the authors propose
that pain may be perceived only with simultaneous
activation of other cortical regions (for example, SI,
insula) or that it requires bilateral activation of the ACC.
Furthermore, electrical activation may not mimic normal
pain-related firing patterns adequately. Additionally, it is
conceivable that pain-related activity in the ACC may
also represent descending modulation of pain rather than
perception of pain.
The location of pain-related neurons in the study of
Hutchison et al. (1999) is in good agreement with a
number of functional neuroimaging studies showing consistent ACC activation during application of noxious
stimuli 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; Hsieh
et al., 1995; Iadarola et al., 1998; Jones et al., 1991a;
J Clin Neurophysiol, Vol. 17, No. 6, 2000
600
A. SCHNITZLER AND M. PLONER
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 location
and size of the activated ACC area. The image represents the subtraction of PET data recorded when the hand was submerged in thermally
neutral water (35°C) from data recorded when the hand was submerged in painfully hot water (47°C). PET data were averaged across 11
experimental sessions, and are illustrated against the average MRI for that subject group (Reprinted with permission from American Association
for the Advancement of Science. Source: Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC. Pain affect encoded in human anterior
cingulate but not somatosensory cortex. Science 1997;277:968 –71.) (B, C) Responses and locations of ACC neurons recorded from patients
during 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 Neurosci 1999;2:403–5.) (B) Diagram showing the locations of
pain-related neurons (red circles) on a sagittal map 3 mm lateral to the midline. The dashed outline shows the region in which neurons were
tested. VAC, vertical line through the ACC; VPC, vertical line through the posterior commissure. (C) ACC neuron from B responding to thermal
stimuli 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 volar
forearm.
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 of
pain-evoked potentials in humans obtained both from
intracranial (Lenz et al., 1998) and extracranial recordings (Bromm et al., 1995; Tarkka and Treede, 1993;
Valeriani et al., 2000).
In addition to the clinical reports that patients with
cingulotomies sometimes still feel pain but report it as
less distressing or bothersome, and that there is a high
level of opioid binding in the ACC (Jones et al., 1991b;
Vogt et al., 1995), there is now also convincing evidence
that pain affect (i.e., the unpleasantness of pain) is
encoded in the ACC. By using hypnosis, Rainville et al.
(1997) selectively altered the unpleasantness of noxious
thermal stimuli without changing the perceived pain
intensity. Analysis of cerebral activation pattern as measured by PET revealed that the modulation of pain affect
was paralleled by activation changes in the ACC but not
in other brain areas (Rainville et al., 1997) (Fig. 3A).
However, it should be mentioned that the ACC cannot
be considered a mere pain center because it is also
activated by various other conditions such as during
performance of the Stroop task (Bench et al., 1993;
Pardo et al., 1990) and other cognitively challenging
tasks (Corbetta et al., 1991; Petersen et al., 1988). Moreover, the ACC appears to be involved in regulation of
autonomic functions and response selection and initiation as well as in attention (for review see Devinsky et al.
[1995]). Therefore, pain-associated activations may represent a nonpain-specific effect (for example, of attenJ Clin Neurophysiol, Vol. 17, No. 6, 2000
tion). However, direct comparison of pain- and attentionrelated activations revealed that these activations do not
correspond spatially to each other (Davis et al., 1997;
Derbyshire et al., 1998). Thus, pain-related activations of
the ACC are unlikely to be the result, exclusively, of
attention effects. On the other hand, some studies
showed 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 local
interconnections that may allow the output of the ACC
pain area to command immediate behavioral reactions.
CONCLUSIONS
During the last decade, advances in functional brain
imaging techniques have led to the identification of
neuroanatomic substrates of pain perception. SI and SII,
the insula, and the ACC are involved essentially in
cortical processing of painful stimuli. Conceptual and
methodological refinements have allowed for characterization and selective investigation of different components of pain perception. Taken together, accumulating
evidence suggests that each of the previously mentioned
cortical areas is concerned with processing of specific
aspects of pain. On the behavioral level, these different
aspects of pain perception are partly independent of each
other. Accordingly, on the anatomic level, the painrelated areas and pathways are organized predominantly
in parallel. However, well-orchestrated cooperation between these distributed areas is required to unify the
PAIN PERCEPTION
different aspects of pain perception into the unique and
indispensable experience of pain. The advances in our
understanding of normal pain perception have created
the basis for studying the pathophysiology of abnormal
pain states (e.g., chronic pain syndromes) that may result
from imbalances within the pain-related cerebral network.
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