Brain, Vol. 126, No. 2, 438-450,
February 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg032
Dual representation of pain in the operculo-insular cortex in humans
Department of Functional Neurology and Epileptology, Hôpital Neurologique, Lyon, France
Correspondence to: Maud Frot, Department of Functional Neurology and Epileptology, Hôpital Neurologique, 59 boulevard Pinel, 69003, Lyon, France E-mail: timo{at}hydromail.com
Received July 20, 2002. Accepted September 5, 2002.
 |
Summary |
|---|
 Top Summary IntroductionPatients and methodsResultsDiscussionReferences |
|---|
We report the response properties of the suprasylvian opercular and insular cortices to a painful stimulation delivered by a CO2 laser recorded by depth intracerebral electrodes in epileptic patients. We defined two cortical areas of activation in the operculo-insular cortex in response to a painful laser stimulation: a suprasylvian opercular area, where we recorded responses peaking 140–170 ms after a painful stimulation (N140–P170), and a deeper insular area, where responses with a similar pattern peaked 180–230 ms after the stimulus (N180–P230). The average delay of 50 ms measured between the opercular and insular responses may reflect either sequential activation of the suprasylvian cortex then of the insula via corticocortical connections, or direct activation of the insula by inputs conveyed via thalamocortical projections through distinct fibres with different conduction times. We also recorded similar insular and opercular responses in the hemisphere ipsilateral to the stimulation, peaking 15 ms later than contralateral responses; this delay is compatible with transcallosal input transmission between these cortices. The mean stereotactic coordinates of the suprasylvian opercular N140–P170 and insular N180–P230 responses were found to be very similar to those of the maximal blood-flow responses to pain reported by previous PET and functional MRI studies in these cortical areas. We were able to distinguish the suprasylvian opercular and insular cortices in terms of response latencies evoked by a painful stimulus and in terms of stereotactic coordinates of the sources of these responses. The sequential timing of activation of the suprasylvian and insular cortices shown in this study thus complements in the time domain the spatial information provided by neuroimaging studies of the cortical processing of pain. It strongly suggests that these cortical areas are those responding with the shortest latency to peripheral pain inputs in the human brain.
Keywords: pain; insula; SII area; intracerebral recordings; evoked potentials
Abbreviations: AC-PC = anterior commissure–posterior commissure; fMRI = functional MRI; LEP = laser-evoked potential; SII = secondary somatosensory area; SEEG = stereotactic EEG
|
Introduction |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
On the basis of numerous anatomical and microelectrode studies in monkeys (Burton 1986
; Burton et al., 1995; Krubitzer et al., 1995), it is now accepted that the secondary somatosensory area (SII) and the insular cortex play a major role in the processing of painful and non-painful inputs (Robinson and Burton, 1980a, b, c; Mesulam and Mufson, 1982; Friedman and Murray, 1986; Cusick et al., 1989; Burton and Sinclair, 1990, 1991; Schneider et al., 1993; Zhang et al., 1999). Several clinical observations have confirmed these data. Some observations of ictal pain sensation have been reported in patients with epileptic seizures originating in SII (Young et al., 1986). Greenspan and colleagues (Greenspan and Winfield, 1992; Greenspan et al., 1999) have observed reversible loss or decrease of pain and tactile sensation in patients with focal lesions involving the posterior and parietal operculum, confirming the role of these cortices in normal pain and tactile perception. Moreover, recent studies from our department have reported painful somatic sensations during direct electrical stimulation of the posterior insular cortex in epileptic patients with intracerebral electrodes. Pain evoked by insular stimulation with intracerebral electrodes was lateralized to the opposite half of the body in epileptic patients (Ostrowsky et al., 2000, 2002). In most cases these painful sensations were elicited by stimulating the hemisphere that was not dominant for language. During the past 20 years, many functional imaging studies have been in accordance with all these anatomical and clinical data and have converged on the conclusion that the operculo-insular cortex is involved in the processing of pain in humans. PET and functional MRI (fMRI) studies showed bilateral pain-related activation in a broad region, comprising the depth of the sylvian fissure and the parietofrontal opercular cortex (for a review see Peyron et al., 2000). These studies highlighted two distinct sites of activations in this region: (i) an antero-inferior activation in the vicinity of the anterior insular cortex, and (ii) a posterior activation at the boundary between SII cortex and the posterior insula (Casey et al., 1994; Svensson et al., 1997; Xu et al., 1997; Davis et al., 1998; Paulson et al., 1998; Baron et al., 1999; Becerra et al., 1999; Sawamoto et al., 2000). Moreover, some electrophysiological studies in humans have localized in the SII/insular cortex the sources of activities peaking on the scalp between 160 and 200 ms after a painful CO2 laser skin stimulus (Tarkka and Treede, 1993; Bromm and Chen, 1995; Kakigi et al., 1995, 1996; Valeriani et al., 1996, 2000). These studies combined scalp recordings of electrical or magnetic fields evoked by a painful stimulation with the estimation, by dipole source modelling, of the localization of the dipolar intracerebral sources of these activities. Lenz and colleagues (Lenz et al., 1998) have recorded, by means of a subdural grid of electrodes, CO2 laser-evoked potentials (LEPs) peaking between 162 and 340 ms. The spatial distribution of this response over the cortical surface of the perisylvian cortex was considered to be compatible with generators located in the parietal operculum and/or in the insular cortices. Using depth intracerebral recordings in humans, we have been able to demonstrate the existence of sources of pain-evoked potentials in the SII cortex (Frot et al., 1997, 1999, 2001). However, the anatomical boundary between SII and insular cortex is not easy to draw in functional neuroimaging studies, especially along the depth axis from lateral to medial cortical structures [the x axis in Talairach’s system of stereotactic coordinates (Talairach and Tournoux, 1988)]. Moreover, functional neuroimaging lacks the temporal resolution required to separate in time the activities of the suprasylvian opercular (SII) and insular cortices. Such a separation could make it possible to differentiate these two cortices by their response characteristics and to know how these areas, which are intimately interconnected (Friedman et al., 1986), act in the processing of nociceptive inputs. In this study, we report the response properties of the electrical potentials evoked in the suprasylvian opercular and insular cortices by a painful skin stimulation delivered by a CO2 laser. These potentials were recorded by depth intracerebral multicontact electrodes with a separation of 1.5 mm between two adjacent contacts (each 2 mm long) along the lateral medial axis (depth axis), with millisecond time resolution. In this way we were able to separate in time and space the suprasylvian opercular and insular responses to pain.
|
Patients and methods |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patients
We recorded CO2 LEPs in 13 patients (aged 24–47 years, mean age 35 years, nine females, four males). All patients included in this study presented with refractory temporal lobe epilepsy and were investigated using stereotactically implanted intracerebral electrodes before functional surgery. Among other sites (Table 1), these patients had electrodes chronically implanted in the operculo-insular cortex for the recording of their seizures and cortical functional mapping using electric stimulation and evoked potentials recordings (for a description of the stimulation procedure see Ostrowsky et al., 2002
). The decision to explore this area resulted from the observation during scalp video-EEG recordings of ictal manifestations, suggesting the possibility of suprasylvian and/or insular spreading of seizures, such as lip and face paraesthesiae or tonic–clonic movements, laryngeal contraction, gustatory illusions, hypersalivation (for a complete description of the rationale of electrode implantation see Isnard et al., 2000). This procedure, as well as the recording of somatosensory evoked potentials, is part of the functional mapping of eloquent cortical areas that is performed routinely before epilepsy surgery in patients implanted with depth electrodes. According to the French regulations concerning invasive investigations with a direct individual benefit, patients were fully informed about the electrode implantation, stereotactic EEG (SEEG) and evoked potential (EP) recordings and the cortical stimulation procedures used to localize the epileptogenic and eloquent brain areas, and they gave their consent. The CO2 laser stimulation paradigm has been approved by the local ethics committee.
|
At the time of the LEP recordings, the patients were under monotherapy with one of the following major anti-epileptic drugs: carbamazepine, phenytoin, valproate, lamotrigine and topiramate. The LEP recordings were performed at the end of the SEEG monitoring, once pertinent seizures had been recorded, so that the daily doses of anti-epileptic drugs were at or slightly under the minimum of their therapeutic range. Handedness was determined using the Edinburgh Handedness Inventory (Oldfield, 1971
); 10 patients were right-handed and three were left-handed. The hemisphere that was dominant for speech was determined using an intracarotid amobarbital test in 11 patients and by cortical stimulation in two. In the 10 right-handed patients the left hemisphere was dominant for language; two left-handed patients had bilateral hemispheric representation of language, and in the third left-handed patient language was found to be represented in the right hemisphere. A complete description of the cortical structures explored by depth electrodes and of the cortical areas found to be involved in seizure propagation is given in Table 1. In all patients but one (Patient 12), several spontaneous seizures could be recorded, all of which originated in the mesial structures of the temporal lobe. In these 12 patients, ictal discharges were propagating outside the mesiotemporal cortex. The areas most frequently involved in seizure propagation were the temporal pole, the temporal neocortex, the cingulate gyrus and the orbitofrontal cortex. In Patient 12 (Table 1) no spontaneous seizure occurred during SEEG monitoring; however, seizures could be triggered by stimulating the left hippocampus and these spread to the orbitofrontal cortex and spared the suprasylvian operculo-insular cortex.
In seven patients, the suprasylvian operculum showed rhythmic spike-wave activity during the spread of the discharges; in four of these patients this type of activity was also observed in the insular cortex. The possibility remains that, in these seven patients, the suprasylvian opercular and insular cortices show some degree of interictal hyper-excitability which might modify their responsiveness to somatosensory or pain inputs. However, this possibility seems unlikely for the following reasons: (i) none of the patients included in this study showed ictal discharge onset in the operculo-insular cortex and no low-voltage fast activity was recorded in this cortex during spontaneous seizures; (ii) no sustained afterdischarge was elicited by electrical stimulation of the operculo-insular cortex in any of the patients; (iii) in terms of latency and amplitude, the somatosensory and pain EPs recorded in the operculo-insular cortex of the patients who showed ictal spike-wave activity were not different from those recorded in patients whose seizures were not propagating to these cortical areas.
Electrode implantation
Intracerebral electrodes were implanted orthogonally using Talairach’s stereotactic frame (Talairach and Tournoux, 1988). The cortical targets were identified on the patient’s MRI, which had been enlarged at scale 1 before surgery. The implanted procedure has been described in detail elsewhere (Frot and Mauguière, 1999; Frot et al., 1999, 2001). Each electrode had a diameter of 0.8 mm and 10–15 contacts, each 2 mm long, separated by 1.5 mm; they could be left in place up to 15 days. Each of the contacts could be localized in Talairach space using its stereotactic coordinates: x for the lateral medial axis, x = 0 being the coordinate of the sagittal interhemispheric plane; y for the rostrocaudal axis, y = 0 being the coordinate of the vertical plane through the anterior commissure (VAC); and z for the inferior–superior axis, z = 0 being the coordinate of the horizontal anterior commissure–posterior commissure (AC-PC) plane.
In the opercular region, electrodes were implanted caudal and rostral to the VAC plane (y = 0). The deepest contacts of the electrodes implanted in the suprasylvian opercular cortex explored the insula proper. As shown in Table 1, five patients were implanted with a single opercular electrode exploring either the pre-rolandic (one patient) or the post-rolandic (four patients) suprasylvian cortex. In the eight other patients, the frontal operculum and the parietal operculum were each implanted with one electrode exploring the insular cortex. Thus, our data were collected using a total of 21 electrodes. Forty-two contacts explored the insular cortex, distributed along the rostrocaudal axis, 14 mm rostral and 25 mm caudal to the VAC plane (y coordinates).
Intracerebral LEPs from regions other than the operculo-insular cortex were also recorded in these patients, such as the hippocampus, the amygdala, the anterior cingulate gyrus, the temporal pole, the orbitofrontal cortex and, in a few cases, the supplementary motor area (Frot et al., 1999).
CO2 laser stimulation
The LEP recordings were performed 
10 days after electrode implantation. During the recordings, the patient lay relaxed on a bed in a semidarkened room. Cutaneous heat stimuli were delivered by a CO2 laser (wavelength 10.6 µm, output power 10 W). The power output being fixed, the amount of thermal energy delivered depended on the duration of the pulse. Thresholds for innocuous and painful sensations were first determined in each patient. The intensity of pain perception (pinprick) was rated by the patients as between 4 and 7 on a 0–10 visual analogue scale. The energy density of the laser beam varied between 6.3 and 10.9 mJ/mm2, delivered on a skin surface of 16 mm2. The stimuli were applied to the dorsum of the hand in the radial nerve territory. A red helium–neon (He-Ne) laser was combined with the CO2 laser to visualize the stimulated skin area. Two runs of 30 stimuli were performed. For each run of stimuli, the continuous EEG was divided into 30 epochs (each EEG epoch began 12 ms before the stimulus and ended 500 ms after it). All these epochs were averaged to remove the noise and to bring out the evoked potentials. The two runs were averaged after we had checked that the averaged waveforms were reproducible. The interstimulus interval varied randomly between 4500 and 5500 ms. The laser beam was moved slightly between two successive stimuli to avoid habituation and especially to avoid peripheral nociceptor fatigue (Schwarz et al., 2000). The analysis time was 512 ms; the signal was bandpass-filtered between 1 and 250 Hz and sampled at 500 Hz. The reference electrode was at the earlobe ipsilateral to the stimulated hand and the ground was a circular wrapped electrode on the forearm ipsilateral to stimulation.
Responses were labelled according to the polarity–latency nomenclature, in which the letter N or P, referring to the polarity of the potential in the contacts close to the scalp surface, is followed by the mean latency in milliseconds. In all figures, negative potentials at the intracortical recording site are represented upwards. In the text and tables, mean voltages, latencies and time intervals are given ±1 SD.
|
Results |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Polarity, latency and voltage of operculo-insular responses
Responses from the suprasylvian opercular cortex
The CO2 laser stimulus consistently evoked in the suprasylvian cortex an N140 negative response followed by a P170 positivity (Fig. 1). Latencies and voltages of these potentials are given in Table 2. These responses, which have been described in detail elsewhere (Frot et al., 1999
, 2001), were picked up by all of the 21 electrodes implanted in the suprasylvian opercular cortex and were not recorded in the other areas that were explored, including the amygdala, hippocampus, anterior cingulate gyrus, temporal pole, orbitofrontal cortex and supplementary motor area (Frot et al., 1999). Similar responses were recorded from the electrodes implanted in the homologous cortex ipsilateral to the painful stimulus, peaking 17 ± 7.5 ms (P = 0.003) and 16 ± 12.9 ms (P = 0.03) later than contralateral N140 and P170, respectively (Table 2). This latency difference between ipsi- and contralateral responses was not different for N140 and P170 potentials (P = 0.75).
|
|
Responses from the insular cortex.
Two potentials contralateral to stimulation were recorded in the insular cortex, consisting of a N180 negative response followed by a P230 positivity (Fig. 1). The N180 and P230 responses, the latencies and voltages of which are given in Table 2, were recorded 49.5 ± 16.3 and 55.5 ± 13.5 ms later than the opercular N140 and P170 potentials, respectively. Figure 2 illustrates these opercular and insular responses on several recordings of different patients.
|
Negative–positive LEPs were also recorded ipsilateral to stimulus from all contacts located in the insular cortex. They had a similar waveform to those recorded contralateral to stimulation but peaked 15 ± 6.6 and 17 ± 9.5 ms later than the contralateral N180 and P230, respectively. This difference between contra- and ipsilateral responses was statistically significant for each of the two components (P = 0.02 for N180 and P = 0.03 for P230; Student’s t test), but there was no difference in this interhemispheric transit time between N180 and P230 potentials (P = 0.78).
Stereotactic localization of the operculo-insular responses
The maximal amplitude of the N/P deflection was taken to determine the contact likely to be the closer to the source.
Responses from the suprasylvian opercular cortex
The N140–P170 responses were recorded along the trajectory of all electrodes penetrating the suprasylvian opercular cortex between vertical planes at 14 mm rostral and 20 mm caudal (y coordinates) to the VAC, and between horizontal planes 3 mm and 21 mm above (z coordinates) the AC-PC. These responses were picked up by the majority of these electrode contacts, between 38 and 63.5 mm from the midsagittal vertical plane (x coordinates) (Table 3).
|
The cortical volume where opercular LEPs were distributed was assessed using the mean and standard deviations of the x, y and z coordinates of the N140–P170. This volume was 0.25 cm3 using a confidence interval of ±1 SD and 1.98 cm3 with a confidence interval of ±2 SD (Fig. 3).
|
Responses from the insular cortex
The N180–P230 responses were picked up by the depth contacts of the electrodes penetrating the opercular cortex between vertical planes 14 mm rostral and 25 mm caudal (y coordinates) to the VAC, and between horizontal planes 1 mm below and 21 mm above (z coordinates) the horizontal AC-PC. The contacts recording these responses were distributed between 29 and 45 mm from the median line (x coordinates). The average coordinates of these contacts are given in Table 3. The cortical volume where insular LEPs were distributed was 0.35 cm3 using a confidence interval of ±1 SD and 2.8 cm3 with a confidence interval of ±2 SD (Fig. 3).
In the seven patients in whom the insular cortex was explored with several electrodes (two or three) along the rostrocaudal axis (y), we did not observe any intra-individual differences in the N180–P230 responses between contacts in terms of latency and amplitude. No significant correlation was observed between the localization of the implanted electrodes along the rostrocaudal axis (y) and the latencies of the N180 (r = 0.17, P = 0.5) and P230 (r = 0.003, P = 0.99) responses (Fig. 4). Moreover, there was no significant correlation between the localization of the electrodes along the rostrocaudal axis (y) and the amplitudes of the N180 (r = 0.22, P = 0.39) and P230 (r = 0.22, P = 0.39) responses (Fig. 4). Thus, we could not define distinct populations of nociceptive neurons along this axis only on the basis of the responses recorded in this cortex.
|
As illustrated in Figs 1 and 2, the first insular negativity peaked clearly later than the SII P170 potential (P = 0.03, Student’s t test). However, in two cases (Patients C and D in Fig. 2) this first insular negativity was preceded by a positive potential, the latency of which was the same as that of the SII N140 potential. In these two patients the polarity reversal was observed at the contact located at the border between the insular contact and the deepest SII contact, so that it was difficult to decide on which side of the circular sulcus the N140 source was located. This difficulty had already been encountered in our previous studies (Frot and Mauguière, 1999
; Frot et al., 1999, 2001). Moreover, in one patient (Patient E in Fig. 2) the insular N180 was preceded by a positivity peaking later than the SII N140 and a few milliseconds earlier than the SII P170 (7 ms for the frontal operculum and 14 ms for the parietal operculum). Due to the low spatial electrode sampling in the insular cortex, we cannot formulate any firm hypothesis concerning this individual variation in insular responses. However, neither the N180 nor the P230 insular potentials showed any polarity reversal at more superficial contacts located in the SII area. Moreover, when the N180 spread to the SII contacts, as in Patient E (Fig. 2), its amplitude was decreased regularly from the deepest insular contact to the more superficial SII sites. Therefore we considered that these two potentials were the only consistent components that could be considered as originating in the insula proper. |
Discussion |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
In this study we were able to separate two cortical areas in the operculo-insular cortex that were responsive to a painful laser stimulation (Fig. 3): a suprasylvian opercular area, where we recorded a response peaking 140–170 ms after a painful stimulation, and a deeper insular area, where we recorded a response with a similar pattern but peaking 180–230 ms after the stimulus. The latency range of the operculo-insular responses recorded directly in the cortex is consistent with that of the earliest CO2 laser potentials recorded on the scalp. Several studies of scalp or subdural LEPs have converged on the conclusion that the earliest cortical response consists of a negativity that peaks between 150 and 170 ms and is maximal in the scalp centrotemporal region contralateral to stimulation, which is compatible with a generator located in SII/insular areas (Treede et al., 1988
; Tarkka and Treede, 1993; Miyazaki et al., 1994; Xu et al., 1995; Valeriani et al., 1996; Lenz et al., 1998). This negativity was found to be associated with a mid-frontal positivity peaking around 200 ms in mapping studies (Treede et al., 1988; Tarkka and Treede, 1993; Valeriani et al., 1996), suggesting a dipolar source close to the sylvian fissure and at a tangent to the scalp surface. According to these studies, this dipolar source remains active at the latency of a later response recorded on the scalp 250 ms after the painful stimulus, which is in the range of our insular positivity latency.
Is the N180–P230 actually generated in the insular cortex?
The question of whether the insular responses might reflect the diffusion of the suprasylvian LEPs with a polarity reversal across the sylvian fissure deserved our attention.
Several arguments support the interpretation that the N140–P170 and the N180–P230 are independent responses. In most cases (eight patients) the suprasylvian P170 potential clearly peaked before the first insular N180 negativity and its latency was significantly shorter, by 27 ms (P = 0.0002) (26.8 ± 11.1 ms on average for these patients). In one patient we even recorded a polarity reversal of the suprasylvian opercular P170 peaking at 162 ms into a negativity peaking with the same latency at the deepest insular contact, where the first insular negativity peaked at 214 ms (Fig. 2, Patient D). Moreover, the insular N180 negativity often spread to the suprasylvian contacts (Fig. 2, Patients B and E), and was then superimposed on the P170 potential (see Results).
Since only a few contacts per electrode track explored the insula proper, we were not in a position to show a polarity reversal of the N180–P230 between the surface and the depth of the insular cortex. However, when at least two contacts explored the insular cortex, we always recorded from these contacts the N180–P230 responses with an amplitude gradient along the x axis (Figs 1 and 2). Thus, in spite of inter-individual variation in waveform, the suprasylvian and insular responses are unlikely to be generated by a single source in the upper bank of the suprasylvian fissure.
Location of LEP activities in the operculo-insular cortex
Our results are consistent with data from numerous imaging studies that have shown a double representation of pain in the operculo-insular cortex (Coghill et al., 1994; Casey et al., 1996; Craig et al., 1996; Andersson et al., 1997; Rainville et al., 1997; Svensson et al., 1997; Xu et al., 1997; Svensson et al., 1998; Gelnar et al., 1999). As shown in Table 4, the mean coordinates of the N140–P170 responses contralateral to stimulation are very similar to those of the maximal blood-flow responses observed during different painful stimulations, although our localization was often more anterior.
|
The restricted spatial sampling along the rostrocaudal (y) and vertical (z) axes, as determined by the number of SEEG electrodes in each patient, could explain this discrepancy. Nevertheless, the N140–P170 responses were distributed along the y axis between 14 mm rostral and 20 mm caudal to the VAC, thus including the majority of the sites with maximal blood-flow responses (Table 4). In the same way, the mean coordinates of the N180–P230 responses recorded in the insular cortex were very similar to those of the maximal blood-flow responses observed in PET and fMRI studies (Table 4). Moreover, the depth (x) coordinates of the operculum and insula reported in PET studies are often on the wrong side of the circular sulcus (Table 4), whereas in the present study great care was taken to obtain precise knowledge of which contacts were in the insula and which ones were in the operculum.
We could not define distinct functional regions in the insula along the y axis on the basis of latencies and amplitudes of pain EPs recorded in this cortex (see Results). This observation is in line with data from two PET studies, using CO2 laser stimulation, which showed a maximal blood-flow response in either the anterior (Svensson et al., 1997) or the posterior insula (Xu et al., 1997) (Table 4). This suggests that a stimulus such as a CO2 laser, which does not evoke any emotional or affective reaction, is able to activate a widely distributed functional region of the insular cortex.
Transcallosal inputs transmission
This study showed that a painful stimulation elicits responses in the contra- and ipsilateral suprasylvian and insular cortices that are separated by a delay of 11–18 ms. This delay is compatible with callosal transmission times estimated by numerous studies [e.g. 15 ms between primary visual areas (Swanson et al., 1978)]; it is in the same range as that measured between ipsi- and contralateral SII magnetic fields evoked by electrical stimulation of the median nerve (20 ms in Hari et al., 1993; 10 ms in Mauguière et al., 1997), the shortest callosal transmission time between the two SI areas being estimated at 6–7 ms (Noachtar et al., 1997).
However, we cannot conclude that there is callosal transfer from the contralateral to the ipsilateral suprasylvian and insular cortices solely on the basis of this time difference. The possibility remains that responses ipsilateral to the stimulus could be triggered via ipsilateral thalamic fibres with slower conduction velocity. Only intracortical recordings of suprasylvian or insular cortex evoked potentials to ipsilateral stimuli in patients with a lesion of the homologous areas in the opposite hemisphere could address this question directly.
Activation timing of the LEP suprasylvian and insular sources
If we consider that the N140–P170 and the N180–P230 are independent responses generated by different cortices, it is still necessary to explain the delay of 50 ms observed between the suprasylvian and insular responses. This delay could reflect the transmission time from the SII area to the insula, a hypothesis which is supported by the observation in monkeys that most of the inputs reaching the insular cortex come from the SII area (Friedman and Murray, 1986). However, this delay of 50 ms seems long for monosynaptic transmission between two close cortical areas known to be interconnected by direct projections (Friedman et al., 1986). Alternatively, knowing that both SII and the insula receive direct projections from the thalamus (Friedman et al., 1980; Friedman and Murray, 1986; for a review see Augustine 1985, 1996), the explanation for the delay between the suprasylvian and insular responses could be that the latter are triggered via thalamocortical fibres with slower conduction than that of thalamic projections to the SII area. To our knowledge, however, no electrophysiological demonstration of this hypothesis is available. A third hypothesis is that the suprasylvian cortex and the insula are activated by inputs conveyed by peripheral fibres with different conduction velocities. The CO2 laser beam used in this study is known to stimulate the endings of small-diameter fibres and mostly those of A
fibres (Bromm and Treede, 1984, 1991). Some studies have estimated the A conduction velocity to lie within the wide range of 7–20 m/s (Adriaensen et al., 1983; Naka and Kakigi, 1998), suggesting the existence of different A fibre subpopulations with different conduction velocities. One can hypothesize that these different subpopulations of A fibres have selective connections with the spinothalamic neurons in layers I, II and V of the spinal cord dorsal horn (for a review see Woolf, 1994). If such an organization were maintained along the spinothalamic and thalamocortical tracts, one could assume that these different subpopulations of peripheral fibres could project in distinct cortical regions. However, to our knowledge, no electrophysiological study has been devoted to the identification of separate subpopulations of fibres with different conduction velocities in the spinothalamic tract or thalamocortical projections. In spite of conjectures about their parallel or sequential activation by pain inputs, we are left with the conclusions that the SII and insular areas are those that show the earliest responses to pain and that both receive projections from the posterior thalamus.
|
Acknowledgements |
|---|
We wish to thank Dr Marc Guénot (Department of Functional Neurosurgery) for stereotaxic electrode implantation.
|
References |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Adriaensen H, Gybels J, Handwerker HO, Van Hees J. Response properties of thin myelinated (A-delta) fibers in human skin nerves. J Neurophysiol 1983; 49: 111–22.
Andersson JL, Lilja A, Hartvig P, Langstrom B, Gordh T, Handwerker H, et al. Somatotopic organization along the central sulcus, for pain localization in humans, as revealed by positron emission tomography. Exp Brain Res 1997; 117: 192–9.[CrossRef][ISI][Medline]
Augustine JR. The insular lobe in primates including humans. Neurol Res 1985; 7: 2–10.[Medline]
Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. [Review]. Brain Res Brain Res Rev 1996; 22: 229–44.[CrossRef][Medline]
Baron R, Baron Y, Disbrow E, Roberts TP. Brain processing of capsaicin-induced secondary hyperalgesia. A functional MRI study. Neurology 1999; 53: 548–57.
Becerra LR, Breiter HC, Stojanovic M, Fishman S, Edwards A, Comite AR, et al. Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study. Magn Reson Med 1999; 41: 1044–57.[CrossRef][ISI][Medline]
Bromm B, Chen AC. Brain electrical source analysis of laser evoked potentials in response to painful trigeminal nerve stimulation. Electroencephalogr Clin Neurophysiol 1995; 95: 14–26.[CrossRef][ISI][Medline]
Bromm B, Treede RD. Nerve fibre discharge, cerebral potentials and sensations induced by CO2 laser stimulation. Hum Neurobiol 1984; 3: 33–40.[ISI][Medline]
Bromm B, Treede RD. Laser-evoked cerebral potentials in the assessment of cutaneous pain sensitivity in normal subjects and patients. [Review]. Rev Neurol (Paris) 1991; 147: 625–43.[Medline]
Burton H. Second somatosensory cortex and related areas. In: Peters A, Jones EG, editors. Cerebral cortex, Vol. 5: sensory-motor areas and aspects of cortical connectivity. New York: Plenum Press; 1986. p. 31–98.
Burton H, Sinclair RJ. Second somatosensory cortical area in macaque monkeys. I. Neuronal responses to controlled, punctate indentations of glabrous skin on the hand. Brain Res 1990; 520: 262–71.[CrossRef][ISI][Medline]
Burton H, Sinclair RJ. Second somatosensory cortical area in macaque monkeys. II. Neuronal responses to punctate vibrotactile stimulation of glabrous skin on the hand. Brain Res 1991; 538: 127–35.[CrossRef][ISI][Medline]
Burton H, Fabri M, Alloway K. Cortical areas within the lateral sulcus connected to cutaneous representations in areas 3b and 1: a revised interpretation of the second somatosensory area in macaque monkeys. J Comp Neurol 1995; 355: 539–62.[CrossRef][ISI][Medline]
Casey KL, Minoshima S, Berger KL, Koeppe RA, Morrow TJ, Frey KA. Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J Neurophysiol 1994; 71: 802–7.
Casey KL, Minoshima S, Morrow TJ, Koeppe RA. Comparison of human cerebral activation patterns during cutaneous warmth, heat pain and deep cold pain. J Neurophysiol 1996; 76: 571–581.
Casey KL, Morrow TJ, Lorenz J, Minoshima S. Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography. J Neurophysiol 2001; 85: 951–9.
Coghill RC, Talbot JD, Evans AC, Meyer E, Gjedde A, Bushnell MC, et al. Distributed processing of pain and vibration by the human brain. J Neurosci 1994; 14: 4095–108.[Abstract]
Craig AD, Reiman EM, Evans, Bushnell MC. Functional imaging of an illusion of pain. Nature 1996; 384: 258–60.[CrossRef][Medline]
Craig AD, Chen K, Bandy D, Reiman EM. Thermosensory activation of insular cortex. Nat Neurosci 2000; 3: 184–90.[CrossRef][ISI][Medline]
Cusick CG, Wall JT, Felleman DJ, Kaas JH. Somatotopic organization of the lateral sulcus of owl monkeys: area 3b, S-II, and a ventral somatosensory area. J Comp Neurol 1989; 282: 169–90.[CrossRef][ISI][Medline]
Davis KD, Kwan CL, Crawley AP, Mikulis DJ. Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli. J Neurophysiol 1998; 80: 1533–46.
Derbyshire SWG, Jones AKP, Devani P, Friston KJ, Feinmann C, Harris M, et al. Cerebral responses to pain in patients with atypical facial pain measured by positron emission tomography. J Neurol Neurosurg Psychiatry 1994; 57: 1166–72.[Abstract]
Friedman DP, Murray EA. Thalamic connectivity of the second somatosensory area and neighboring somatosensory fields of the lateral sulcus of the macaque. J Comp Neurol 1986; 252: 348–73.[CrossRef][ISI][Medline]
Friedman DP, Jones EG, Burton H. Representation pattern in the second somatic sensory area of the monkey cerebral cortex. J Comp Neurol 1980; 192: 21–41.[CrossRef][ISI][Medline]
Friedman DP, Murray EA, O’Neill JB, Mishkin M. Cortical connections of the somatosensory fields of the lateral sulcus of macaques: evidence for a corticolimbic pathway for touch. J Comp Neurol 1986; 252: 323–47.[CrossRef][ISI][Medline]
Frot M, Mauguière F. Timing and spatial distribution of somatosensory responses recorded in the upper bank of the sylvian fissure (SII area) in humans. Cereb Cortex 1999; 9: 854–63.
Frot M, Rambaud L, Mauguière F. Intracerebral recordings of responses from the parieto-frontal opercular area S2 after electrical and CO2 laser stimuli in humans [abstract]. Electroencephalogr Clin Neurophysiol 1997; 103: 179.
Frot M, Rambaud L, Guénot M, Mauguière F. Intracortical recordings of early pain-related CO2 laser evoked potentials in the human second somatosensory (SII) area. Clin Neurophysiol 1999; 110: 133–45.[CrossRef][ISI][Medline]
Frot M, Garcia-Larrea L, Guénot M, Mauguière F. Responses of the supra-sylvian (SII) cortex in humans to painful and innocuous stimuli. A study using intra-cerebral recordings. Pain 2001; 94: 65–73.[CrossRef][ISI][Medline]
Gelnar PA, Krauss BR, Sheehe PR, Szeverenyi NM, Apkarian AV. A comparative fMRI study of cortical representations for thermal painful, vibrotactile, and motor performance tasks. Neuroimage 1999; 10: 460–82.[CrossRef][ISI][Medline]
Greenspan JD, Winfield JA. Reversible pain and tactile deficits associated with a cerebral tumor compressing the posterior insula and parietal operculum. Pain 1992; 50: 29–39.[CrossRef][ISI][Medline]
Greenspan JD, Lee RR, Lenz FA. Pain sensitivity alterations as a function of lesion location in the parasylvian cortex. Pain 1999; 81: 273–82.[CrossRef][ISI][Medline]
Hari R, Karhu J, Hämäläinen M, Knuutila J, Salonen O, Sams M, et al. Functional organization of the human first and second somatosensory cortices: a neuromagnetic study. Eur J Neurosci 1993; 5: 724–34.[CrossRef][ISI][Medline]
Iadarola MJ, Berman KF, Zeffiro TA, Byas-Smith MG, Gracely RH, Max MB, et al. Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. Brain 1998; 121: 931–47.
Isnard J, Guénot M, Ostrowsky K, Sindou M, Mauguière F. The role of the insular cortex in temporal lobe epilepsy. Ann Neurol 2000; 48: 614–23.[CrossRef][ISI][Medline]
Kakigi R, Koyama M, Hoshiyama M, Kitamura Y, Shimojo M, Watanabe S. Pain related magnetic fields following painful CO2 laser stimulation in man. Neurosci Lett 1995; 192: 45–8.[CrossRef][ISI][Medline]
Kakigi R, Koyama S, Hoshiyama M, Kitamura Y, Shimojo M, Watanabe S. Pain-related brain responses following CO2 laser stimulation: magnetoencephalographic studies. Electroencephalogr Clin Neurophysiol Suppl 1996; 47: 111–20.
Krubitzer L, Clarey J, Tweedale R, Elston G, Calford M. A redefinition of somatosensory areas in the lateral sulcus of macaque monkeys. J Neurosci 1995; 15: 3821–39.[Abstract]
Lenz FA, Rios M, Chau D, Krauss GL, Zirh TA, Lesser RP. Painful stimuli evoke potentials recorded from the parasylvian cortex in humans. J Neurophysiol 1998; 80: 2077–88.
Mauguière F, Merlet I, Forss N, Vanni S, Jousmäki V, Adeleine P, et al. Activation of a distributed somatosensory cortical network in the human brain. A dipole modelling study of magnetic fields evoked by median nerve stimulation. Part I: location and activation timing of SEF sources. Electroencephalogr Clin Neurophysiol 1997; 104: 281–9.[CrossRef][Medline]
May A, Kaube H, Buchel C, Eichten C, Rijntjes M, Juptner M et al. Experimental cranial pain elicited by capsaicin: a PET study. Pain 1998; 74: 61–66.[CrossRef][ISI][Medline]
Mesulam MM, Mufson EJ. Insula of the old world monkey. III: efferent cortical output and comments on function. J Comp Neurol 1982; 212: 38–52.[CrossRef][ISI][Medline]
Miyazaki M, Shibasaki H, Kanda M, Xu X, Shindo K, Honda M, et al. Generator mechanism of pain-related evoked potentials following CO2 laser stimulation of the hand: scalp topography and effect of predictive warning signal. J Clin Neurophysiol 1994; 11: 242–54.[ISI][Medline]
Naka D, Kakigi R. Simple and novel method for measuring conduction velocity of A delta fibers in humans. J Clin Neurophysiol 1998; 15: 150–3.[CrossRef][ISI][Medline]
Noachtar S, Lüders HO, Dinner DS, Klem G. Ipsilateral median somatosensory evoked potentials recorded from human somatosensory cortex. Electroencephalogr Clin Neurophysiol 1997; 104: 189–98.[CrossRef][Medline]
Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971; 9: 97–113.[CrossRef][ISI][Medline]
Ostrowsky K, Isnard J, Ryvlin P, Guénot M, Fischer C, Mauguière F. Functional mapping of the insular cortex: clinical implication in temporal lobe epilepsy. Epilepsia 2000; 41: 681–6.[CrossRef][ISI][Medline]
Ostrowsky K, Magnin M, Ryvlin P, Isnard J, Guénot M, Mauguière F. Representation of pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation. Cereb Cortex 2002; 12: 376–85.
Paulson PE, Minoshima S, Morrow TJ, Casey KL. Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans. Pain 1998; 76: 223–9.[CrossRef][ISI][Medline]
Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). [Review]. Neurophysiol Clin 2000; 30: 263–88.[ISI][Medline]
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.
Robinson CJ, Burton H. Somatotopographic organization in the second somatosensory area of M. fascicularis. J Comp Neurol 1980a; 192: 43–67.[CrossRef][ISI][Medline]
Robinson CJ, Burton H. Organization of somatosensory receptive fields in cortical areas 7b, retroinsula, postauditory and granular insula of M. fascicularis. J Comp Neurol 1980b; 192: 69–92.[CrossRef][ISI][Medline]
Robinson CJ, Burton H. Somatic submodality distribution within the second somatosensory (SII), 7b, retroinsular, postauditory, and granular insular cortical areas of M. fascicularis. J Comp Neurol 1980c; 192: 93–108.[CrossRef][ISI][Medline]
Sawamoto N, Honda M, Okada T, Hanakawa T, Kanda M, Fukuyama H, et al. Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study. J Neurosci 2000; 20: 7438–45.
Schneider RJ, Friedman DP, Mishkin M. A modality-specific somatosensory area within the insula of the rhesus monkey. Brain Res 1993; 621: 116–20.[CrossRef][ISI][Medline]
Schwarz S, Greffrath W, Büsselberg D, Treede R-D. Inactivation and tachyphylaxis of heat-evoked inward currents in nociceptive primary sensory neurones of rats. J Physiol (Lond) 2000; 528: 539–49.
Sindou M, Quoex C, Baleydier C. Fiber organization at the posterior spinal cord–rootlet junction in man. J Comp Neurol 1974; 153: 15–26.[CrossRef][ISI][Medline]
Svensson P, Minoshima S, Beydoun A, Morrow TJ, Casey KL. Cerebral processing of acute skin and muscle pain in humans. J Neurophysiol 1997; 78: 450–60.
Svensson P, Johannsen P, Jensen TS, Arendt-Nielsen L, Nielsen J, Stodkilde-Jorgensen H, et al. Cerebral blood-flow changes evoked by two levels of painful heat stimulation: a positron emission tomography study in humans. Eur J Pain 1998; 2: 95–107.[CrossRef][ISI][Medline]
Swanson J, Ledlow A, Kinsbourne M. Lateral asymmetries revealed by simple reaction time. In: Kinsbourne M, editor. Asymmetrical function of the brain. Cambridge: Cambridge University Press; 1978. p. 274–91.
Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain. 3-dimensional proportional system: an approach to cerebral imaging. Stuttgart: Thieme; 1988.
Talbot JD, Marrett S, Evans AC, Meyer E, Bushnell MC, Duncan GH. Multiple representations of pain in human cerebral cortex. Science 1991; 251: 1355–8.
Tarkka IM, Treede RD. Equivalent electrical source analysis of pain-related somatosensory evoked potentials elicited by a CO2 laser. J Clin Neurophysiol 1993; 10: 513–9.[CrossRef][ISI][Medline]
Treede RD, Kief S, Hölzer T, Bromm B. Late somatosensory evoked cerebral potentials in response to cutaneous heat stimuli. Electroencephalogr Clin Neurophysiol 1988; 70: 429–41.[CrossRef][ISI][Medline]
Valeriani M, Rambaud L, Mauguière F. Scalp topography and dipolar source modeling of potentials evoked by CO2 laser stimulation of the hand. Electroencephalogr Clin Neurophysiol 1996; 100: 343–53.[CrossRef][Medline]
Valeriani M, Restuccia D, Barba C, Le Pera D, Tonali P, Mauguière F. Sources of cortical responses to painful CO2 laser skin stimulation of the hand and foot in the human brain. Clin Neurophysiol 2000; 116: 1103–12.
Woolf CJ. The dorsal horn: state-dependent sensory processing and the generation of pain. In: Wall PD, Melzack R, editors. Textbook of pain. 3rd ed. Edinburgh: Churchill Livingstone; 1994. p. 101–28.
Xu X, Kanda M, Shindo K, Fujiwara N, Nagamine T, Ikeda A, et al. Pain-related somatosensory evoked potentials following CO2 laser stimulation of foot in man. Electroencephalogr Clin Neurophysiol 1995; 96: 12–23.[CrossRef][Medline]
Xu X, Fukuyama H, Yazawa S, Mima T, Hanakawa T, Magata Y, et al. Functional localization of pain perception in the human brain studied by PET. Neuroreport 1997; 8: 555–9.[ISI][Medline]
Young GB, Barr HW, Blume WT. Painful epileptic seizures involving the second sensory area. Ann Neurol 1986; 19: 412.[ISI][Medline]
Zhang ZH, Dougherty PM, Oppenheimer SM. Monkey insular cortex neurons respond to baroreceptive and somatosensory convergent inputs. Neuroscience 1999; 94: 351–60.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Weiss, W. Hesse, M. Ungureanu, H. Hecht, L. Leistritz, H. Witte, and W. H. R. Miltner How Do Brain Areas Communicate During the Processing of Noxious Stimuli? An Analysis of Laser-Evoked Event-Related Potentials Using the Granger Causality Index J Neurophysiol, May 1, 2008; 99(5): 2220 - 2231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. G. Macefield, S. Gandevia, and L. A. Henderson Discrete Changes in Cortical Activation during Experimentally Induced Referred Muscle Pain: A Single-Trial fMRI Study Cereb Cortex, September 1, 2007; 17(9): 2050 - 2059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ogino, H. Nemoto, K. Inui, S. Saito, R. Kakigi, and F. Goto Inner Experience of Pain: Imagination of Pain While Viewing Images Showing Painful Events Forms Subjective Pain Representation in Human Brain Cereb Cortex, May 1, 2007; 17(5): 1139 - 1146. [Abstract] [Full Text] [PDF]
|
|