Abstract

The SII area and the posterior insular region are both activated by thermal stimuli in functional imaging studies. However, controversy remains as to a possible differential encoding of thermal intensity by each of these 2 contiguous areas. Using CO2 laser stimulations, we analyzed the modifications induced by increasing thermal energy on evoked potentials recorded with electrodes implanted within SII and posterior insula in patients referred for presurgical evaluation of epilepsy. Although increasing stimulus intensities enhanced both SII and insular responses, the “dynamics” of their respective amplitude changes were different. SII responses were able to encode gradually the intensity of stimuli from sensory threshold up to a level next to pain threshold but tended to show a ceiling effect for higher painful intensities. In contrast, the posterior insular cortex failed to detect nonnoxious laser pulses but reliably encoded stimulus intensity variations at painful levels, without showing saturation effects for intensities above pain threshold. According to these results, one can assume that insular cortex could be more involved in the triggering of affective recognition of, and motor reaction to, noxious stimuli, whereas SII would be more dedicated to finer-grain discrimination of stimulus intensity, from nonpainful to painful levels.

Introduction

According to numerous electrophysiological and functional imaging studies carried out in humans in the recent years, pain perception is built up by the coordinated activation of multiple cortical regions. These regions are not strictly identical throughout studies, and their respective involvement in pain coding depends upon the specific stimulus parameters and the experimental conditions used. However, it appears clearly that the cortical regions located in the upper bank of the lateral sulcus, including the second somatosensory area (SII) and the insular cortex, are the sites most consistently activated by all kinds of nociceptive stimuli (reviews in Peyron and others 2000; Schnitzler and Ploner 2000; Treede and others 2000; Garcia-Larrea and others 2003; Vogel and others 2003). Single unit recordings in monkeys have demonstrated the existence of nociceptive neurons in both SII and insula (Robinson and Burton 1980a, 1980b; Dong and others 1989, 1994; Dostrovsky and Graig 1996; Zhang and others 1999), and nociceptive regions of thalamus in nonhuman primates have been shown to send axons to the parietal operculum, the mid and posterior insular cortex, as well as the retroinsular region (Burton and Jones 1976; Jones and Burton 1976; Mufson and Mesulam 1984; Mesulam and Mufson 1985; Burton and Carlson 1986; Friedman and Murray 1986; Stevens and others 1993; Craig 1995). In humans, regions containing nociresponsive neurons in and around the thalamic ventral caudal nucleus (Lenz and others 1993, 1994) project to the insular cortex and the parietal operculum (Van Buren and Borke 1972). These 2 suprasylvian pain areas are also involved in the processing of innocuous somatosensory inputs. In functional imaging studies, there is a substantial overlap in activity evoked by noxious and innocuous stimuli within SII (Coghill and others 1994; Chen and others 2002), and our previous studies have shown that both noxious CO2 laser and innocuous electrical stimulations trigger evoked potentials within the same subregions of the human SII area (Frot and others 2001). One recent study has provided functional magnetic resonance imaging (fMRI) evidence, suggesting that a posterior region within SII could be specifically involved in the processing of noxious stimuli (Ferretti and others 2004). However, these authors used electrical stimuli that activated simultaneously noxious (A-delta) and nonnoxious (A-Beta) afferents (Gracely 1994); therefore, no definite conclusion can be drawn as to whether this SII subarea participates in the encoding of inputs produced selectively by activation of nociceptors.

A major obstacle for understanding the role of the operculoinsular region in pain perception is our limited knowledge on response properties of perisylvian nociceptive neurons (Treede and others 2000). Previous studies, including ours, usually compared stimulations of different modalities (mostly electrical or tactile vs. noxious heat) and, therefore, could not assess specifically whether the SII–insular cortex is able to encode intensity “within the thermoalgesic modality.” Moreover, differentiating between the functional properties of the contiguous SII and posterior insular cortices has proven very difficult in both functional imaging and electrophysiological studies. In most of the pain imaging studies, the SII–insular region, especially in its posterior extent, is considered as a single functional entity (for reviews, see Peyron and others 2000; Garcia-Larrea and others 2003). However, Ferretti and others (2004) suggested the existence of several opercular subareas with distinct roles in somatic sensation and pain processing. Moreover, we have shown by intracortical recordings that responses of opercular and contiguous insular cortices to laser stimuli could be distinguished on the basis of their respective latencies and shapes, suggesting that their functional capacities to encode stimulus intensity might be different (Frot and Mauguière 2003).

Studies of somatosensory stimulus intensity encoding properties of the SII–insular cortex brought drastically controversial results. Timmerman and others (2001) and Bornhövd and others (2002) studied the response modes of SII and insula to progressively increasing stimulus intensities and concluded that both areas responded exclusively to painful stimuli. On the contrary, Davis and others (1998) found that innocuous thermal stimuli often activated the posterior insula but never SII. In contrast to all of them, Coghill and others (1999) found consistent SII activation at innocuous intensities (35–46 °C) and reported a significant correlation between thermal intensity and contralateral SII activity, whereas the anterior insula tended to be activated only at painful levels. Very recently, Iannetti and others (2005) described a positive correlation between the amplitude of SII–insular laser-evoked potentials (LEPs) and the subjective pain magnitude reported by the subjects. However, these authors used exclusively stimuli in the painful range and, therefore, could not investigate whether subpain sensations were also coded by SII–insular cortices.

In this study, we attempted to characterize response properties of the SII and posterior insular regions by studying local intracortical evoked potentials directly recorded within these 2 areas, and using increasing levels of thermal energy, ranging from nonnoxious to noxious levels. Stimuli were delivered by means of a laser beam, avoiding skin contact and thus coactivation of mechanoreceptors. In these experimental conditions, cortical activations could be safely ascribed to stimulation of epidermal thermonociceptors exclusively.

Materials and Methods

Patients

All the 10 patients included in this study suffered from refractory temporal lobe epilepsy and were investigated using stereotactically implanted intracerebral electrodes before functional surgery. Among other sites, these patients had electrodes chronically implanted in the SII–insular cortex for the recording of their seizures. The decision to explore this area resulted from the observation during scalp video-electroencephalography (EEG) recordings of ictal manifestations, suggesting the possibility of seizures originating in SII and/or insula (for a complete description of the rationale of electrode implantation, see Isnard and others 2000, 2004). This procedure, performed routinely before epilepsy surgery in patients implanted with depth electrodes, is completed by the functional mapping of potentially eloquent cortical areas using evoked potentials recordings and cortical electrical stimulation (for a description of the stimulation procedure, see Ostrowsky and others 2002; Mazzola and others 2005). In agreement with French regulations relative to invasive investigations with a direct individual benefit, patients were fully informed about electrode implantation, stereotactic electroencephalography (SEEG), evoked potentials recordings, and cortical stimulation procedures used to localize the epileptogenic and eloquent brain areas and gave their consent. The CO2 laser stimulation paradigm was submitted to, and approved by, the local Ethics Committee.

Two patients out of the 10 recorded were excluded from the study because paroxysmal epileptic discharges originated in the recorded SII and/or insula. For the other patients (8 cases), several spontaneous seizures could be recorded during the SEEG, all of which originated in the mesial structures of the temporal lobe. In these patients, ictal discharges propagated outside the mesiotemporal cortex and involved most frequently the temporal pole, the temporal neocortex, the cingulate gyrus, and the orbitofrontal cortex. In 3 patients, the suprasylvian operculum showed a rhythmic spike-wave activity during the spread of the discharges, and in 2 of them this type of activity was also observed in the insular cortex.

The possibility remains that, in these 3 patients, the suprasylvian opercular and insular cortices could have shown some degree of interictal hyperexcitability modifying their responsiveness to somatosensory or pain inputs. However, this possibility seems unlikely for the following reasons: 1) none of the patients included in this study showed ictal discharges onset in the operculoinsular cortex, and no low voltage fast activity was recorded in this cortex during spontaneous seizures; 2) focal bipolar electric stimulations delivered through the contacts used for LEP recordings did not show any evidence of focal hyperexcitability manifesting by the occurrence of after-discharges at stimulus intensities of 1–3 mA currently used for functional mapping (reported in Mazzola and others 2005); and 3) latency and amplitude of somatosensory and pain LEPs recorded in the operculoinsular cortex concerned by the spread of ictal mesiotemporal activities were not different from those recorded in patients whose seizures did not propagate to these cortical areas.

LEPs were thus recorded from a total of 63 opercular and 30 posterior insular sites in 8 patients (4 females, 4 males, mean age 33 years, range 22–59 years). They were obtained at the end of the SEEG monitoring period of 2 weeks, once relevant seizures had been recorded. At that time, patients were under monotherapy with one of the major antiepileptic drugs (carbamazepine, phenytoin, valproate, lamotrigine, or topiramate) with daily dosages at or slightly under the minimum of their therapeutic usual range.

Electrode Implantation

Intracerebral electrodes were implanted using the Talairach's stereotactic frame. As a first step, a cerebral angiography was performed in stereotactic conditions using an X-ray source located 4.85 m away from the patient's head. This eliminates the linear enlargement due to X-ray divergence, so that the films could be used for measurements without any correction. In the second step, the relevant targets were identified on the patient's magnetic resonance imaging (MRI), previously enlarged at scale one-to-one. As magnetic resonance and angiographic images were at the same scale, they could easily be superimposed, thus minimizing the risk of any damage to cerebral veins or arteries during implantation. The electrodes were orthogonally implanted using the Talairach's stereotactic grid; each electrode had 10–15 contacts, each of 2 mm length, separated by 1.5 mm, and could be left in place chronically up to 15 days. Because of the physical characteristics of the contacts (stainless steel), it was impossible to perform MRI with electrodes in place. Scale 1:1 skull radiographies superimposed to scale 1:1 angiographies were used to perform the implantation within the stereotactic frame of Talairach and Tournoux (1988). The electrode tracks and the contacts of each electrode could be plotted onto the appropriate MRIs slices of each patient (MRIcro® software; Rorden and Brett 2000). Each of the contacts was then localized in the Talairach space using its stereotactic coordinates: x for the lateral medial axis, with x = 0 being the coordinate of the sagittal interhemispheric plane; y for the rostrocaudal (anterior–posterior) axis, y = 0 being the coordinate of the vertical anterior commissure (VAC) plane; and z for the inferior–superior axis, z = 0 being the coordinate of the horizontal anterior commissure–posterior commissure (AC–PC) plane (see also, Frot and Mauguière 1999, 2003; Frot and others 1999, 2001).

In the SII region, electrodes were implanted caudal and rostral to the VAC plane (y = 0). The deepest contacts of the electrodes implanted in SII or the first temporal gyrus explored the insula proper. Four patients were implanted by a single opercular electrode, exploring either the prerolandic (2 cases) or the postrolandic (2 cases) SII cortex. In the 4 other patients, both the frontal and the parietal SII were each implanted by 1 electrode. Five patients had 1 electrode implanted in the first temporal gyrus, the deepest contacts of which exploring the insula proper. Thus, our data were collected using a total number of 17 electrodes, 12 of them having contacts in SII and 15 of them in the posterior insula (Fig. 4 and Table 3). Thirty contacts explored the posterior insular cortex, distributed along the rostrocaudal axis, 14 mm rostral and 19 mm caudal to the VAC plane (y coordinates). Sixty-three contacts explored the SII area, distributed along the rostrocaudal axis, 14 mm rostral and 23 mm caudal to the VAC plane (y coordinates).

Stimulation Procedure, Recording, and Signal Averaging

The LEP recordings were performed between 10 and 15 days after electrodes implantation. During the recordings, the patients laid relaxed on a bed in a quiet room. Cutaneous heat stimuli were delivered by a CO2 laser (10.6-μm wavelength, beam diameter 3 mm; Optilas®, Evry, France), thus avoiding skin contact and coactivation of mechanoreceptors. Therefore, the cortical activations linked to laser stimuli could be safely ascribed to the specific stimulation of epidermal thermonociceptors.

CO2 laser pulses were applied at 4 different intensities in each subject. The power output being fixed, the amount of thermal energy delivered depended on the duration of the pulse. Pulse duration was set up according to subjects' subjective reports, rated on a visual analog scale (VAS) with an anchor point corresponding to pain threshold. The printed scales consisted of 10-cm horizontal lines, where the left extreme was labeled “no sensation” and the right extreme “maximal pain”, and an anchored level 4 was at pain threshold (Lickert-type scale).

The different stimuli and related subjective sensation were as follows:

  1. Intensity 0 (I0): below sensory threshold (pulse duration: 5–15 ms, mean energy density: 7 mJ/mm2, no sensation);

  2. Intensity 1 (I1): above sensory threshold (pulse duration: 15–45 ms, mean energy density: 19 mJ/mm2, producing a detectable nonpainful sensation reported for more than 90% of stimulations; for one-third of patients, this sensation was a warmth sensation and for the other two-thirds, a slight nonpainful pinprick sensation; VAS 1.6 ± 1.09);

  3. Intensity 2 (I2): pain threshold (pulse duration: 25–80 ms, mean energy density: 33 mJ/mm2, producing a pricking sensation, like a hair pulling or a drop of hot boiling water on the skin; VAS 3.9 ± 1.46);

  4. Intensity 3 (I3): 20% above pain threshold (pulse duration: 35–110 ms, mean energy density: 46 mJ/mm2, producing a pricking sensation described as clearly painful; VAS 5.4 ± 1.6).

The subjects were instructed to draw a vertical mark at the appropriate position on the VAS to indicate the perceived sensation intensity. This procedure mostly aimed at differentiating between pain threshold (I2) and clearly painful sensation (I3). It was checked that VAS rates were significantly higher for the latter intensity (Student's t-test for paired data, P < 0.05).

Two separate runs of 12–16 stimulations applied to the superficial radial nerve territory on the dorsum of the hand were delivered at each intensity value, the order of intensities being randomized. The interstimulus interval varied randomly between 10 and 25 s. The laser beam was slightly moved between 2 successive stimuli to avoid habituation and especially to avoid peripheral nociceptor fatigue (Schwarz and others 2000).

Online recordings were performed using a sample frequency of 256 Hz and a band-pass filter of 0.03–400 Hz (Micromed®, St Etienne des Oullières, France) both in bipolar and reference modes. The reference electrode was chosen for each patient on an implanted contact located in the skull.

Epoching of the EEG, selective averaging, and record analysis were performed off-line using the Neuroscan® software. The continuous EEG was cut in epochs (each epoch of EEG began 100 ms before the stimulus and ended 900 ms after). A 100-ms prestimulus baseline correction was performed. Analysis was performed both on single epochs and on averages. Averaging was performed to reduce the background EEG noise so as to facilitate analysis of stimulus-locked activity (evoked potentials); epoch averaging was done after rejecting epochs with epileptic transient activities. Finally, the 2 runs for a given stimulation intensity were averaged after having checked that the averaged waveforms were reproducible.

Amplitude Measurements

Given the high signal/noise ratio obtained in intracortical recordings, the LEP amplitudes at insular and opercular sites could be measured on individual single sweeps, without the need of averaging. A total of 112 single responses were analyzed for each intensity level.

Statistical Analysis

Amplitudes and latencies of responses were submitted to repeated-measures analysis of variance (ANOVA) (Statistica 6, Tulsa, OK), with 3 within-subject factors: Intensity (I0, I1, I2, and I3), localization (Pre- vs. postcentral operculum for SII, and pre vs. post vs. ventral insula for the insular cortex), and epoch order. The Geisser–Greenhouse (G–G) procedure was applied to correct degrees of freedom (Geisser and Greenhouse 1958). The G–G correction was used whenever a significant violation of the sphericity assumption was detected in repeated-measures ANOVA (with more than 2 df) (see Vasey and Thayer 1987). Significance was accepted at P < 0.05. Post hoc comparisons t-tests were performed with a threshold significance at P < 0.05. Correlation between VAS and intensity was assessed using a linear regression model. To define the dynamics of the LEP amplitudes as a function of stimulus intensity obtained in SII and insula, data were fitted with a polynomial function [f(x) = b0 + (b1 × x) + (b2 × x2) + (b3 × x3)]. Paired t-tests were performed between the coefficients determining the increase (b1) and shape (b2 and b3) of the fitted curves (see Timmermann and others 2001).

Results

Psychophysical Responses

By definition (see Experimental Procedures), all the subjects rated 0 (no sensation) on the VAS when the intensity was under the perception threshold (I0). Subjective intensity rates to I2 corresponded well to a barely painful sensation (boiling water drop on the skin), whereas I3 (maximal intensity) was considered by all subjects as painful and quite unpleasant, albeit tolerable (mean 5.4/10). The latter stimulus intensity being at the upper limit of tolerance, higher intensities were not used for evident ethical reasons. There was a positive significant linear correlation between the subjective VAS reports and the stimulus intensities (r = 0.87, P < 0.001) (Fig. 1).

Figure 1.

Correlation between the subjective VAS reports and the stimulus intensities.

Figure 1.

Correlation between the subjective VAS reports and the stimulus intensities.

Polarity, Latency, and Voltage of SII–Insular LEPs

Two distinct LEP components contralateral to the stimulation site were recorded along all the electrode tracks implanted in SII, anterior and posterior to the rolandic fissure. They consisted of a negative wave (Nop, for “negative opercular”) followed by a positive one (Pop), the latencies of which are given in Tables 1 and 2. Similarly, a biphasic negative (Ni, for “negative insular”)–positive (Pi) components were recorded on contacts located in the posterior insular cortex. Note that absolute latency values could not be used for comparison due to latency prenormalization across patients (see Figs 3 and 5). However, latency differences among electrode plots within a single patient remained valuable despite normalization. Calculation on relative latencies showed a significant delay of the insular response relative to the opercular one (t-tests, P < 0.05, Tables 1 and 2). No earlier response peaking before these Nop–Pop and Ni–Pi were observed along the electrode tracks implanted, respectively, in SII and in the insula (Figs 2 and 3).

Figure 2.

Effects of intensity on SII–insular responses—one patient. LEPs recorded on 2 depth contacts located in SII (1) and insular (2) cortices of 1 patient, for each level of stimulus intensity (I0, I1, I2, I3). These LEPs were recorded in referential mode. Note that in SII (1), we recorded a late negative response indicated by a black star. This component did not appear to be generated in SII but rather corresponded to the diffusion of the Ni component of the insular LEPs, due to the proximity of the contacts 1 and 2. This was confirmed by recordings in bipolar mode, where this late SII negative component disappeared (see Fig. 5). A similar phenomenon is present on insular recordings, where a positive peak occurs at about 180 ms (black star on 2).

Figure 2.

Effects of intensity on SII–insular responses—one patient. LEPs recorded on 2 depth contacts located in SII (1) and insular (2) cortices of 1 patient, for each level of stimulus intensity (I0, I1, I2, I3). These LEPs were recorded in referential mode. Note that in SII (1), we recorded a late negative response indicated by a black star. This component did not appear to be generated in SII but rather corresponded to the diffusion of the Ni component of the insular LEPs, due to the proximity of the contacts 1 and 2. This was confirmed by recordings in bipolar mode, where this late SII negative component disappeared (see Fig. 5). A similar phenomenon is present on insular recordings, where a positive peak occurs at about 180 ms (black star on 2).

Figure 3.

LEPs recorded on depth contacts located in SII and insular cortices of all patients (8 subjects) for each level of stimulus intensity. All these responses have been latency normalized according to the maximal LEP peaks (Pop for SII and Ni for insular responses). A response has been recorded for all patients in SII at I1, whereas the first evoked response in the insular cortex was recorded at I2 in the majority of cases.

Figure 3.

LEPs recorded on depth contacts located in SII and insular cortices of all patients (8 subjects) for each level of stimulus intensity. All these responses have been latency normalized according to the maximal LEP peaks (Pop for SII and Ni for insular responses). A response has been recorded for all patients in SII at I1, whereas the first evoked response in the insular cortex was recorded at I2 in the majority of cases.

Table 1.

Amplitudes (μV) of responses

N_P peak amplitudes 
 I0 I1–I0 I1 I2–I1 I2 I3–I2 I3 
SII 27.6 ± 3.2 11.9 ± 4.4 39.5 ± 4 22.4 ± 4.3 61.9 ± 4.8 11.3 ± 4.5 73.2 ± 4.9 
Insula 23 ± 1.7 4.9 ± 2.4 27.9 ± 2.4 9.5 ± 3 37.4 ± 2.5 16.5 ± 3.1 53.9 ± 2.9 
N_P peak amplitudes 
 I0 I1–I0 I1 I2–I1 I2 I3–I2 I3 
SII 27.6 ± 3.2 11.9 ± 4.4 39.5 ± 4 22.4 ± 4.3 61.9 ± 4.8 11.3 ± 4.5 73.2 ± 4.9 
Insula 23 ± 1.7 4.9 ± 2.4 27.9 ± 2.4 9.5 ± 3 37.4 ± 2.5 16.5 ± 3.1 53.9 ± 2.9 

Note: All the means are given with the standard errors.

Table 2

Latencies (ms) of responses

Latencies 
 I0 I1 I2 I3 
 
SII 150.9 ± 9.7 215.9 ± 20.5 150.6 ± 12.5 211.5 ± 20.1 154.3 ± 20 215.7 ± 22.5 149.4 ± 22.3 210.03 ± 25.1 
Insula 270.6 ± 37.6 403.3 ± 44.6 273.9 ± 39.4 400.2 ± 43.3 275.7 ± 41 401.8 ± 48.8 268.7 ± 40.6 398.5 ± 53.6 
Latencies 
 I0 I1 I2 I3 
 
SII 150.9 ± 9.7 215.9 ± 20.5 150.6 ± 12.5 211.5 ± 20.1 154.3 ± 20 215.7 ± 22.5 149.4 ± 22.3 210.03 ± 25.1 
Insula 270.6 ± 37.6 403.3 ± 44.6 273.9 ± 39.4 400.2 ± 43.3 275.7 ± 41 401.8 ± 48.8 268.7 ± 40.6 398.5 ± 53.6 

Note: All the means are given with the standard errors.

Stereotactic Localization of the SII–Insular LEPs

The maximal amplitude of the N/P (Negative/Positive) deflection was taken to determine the electrode contact likely to be the closest to the source.

The SII LEPs were recorded along the trajectory of all electrodes penetrating the SII cortex within a rectangle bounded by vertical planes 14 mm anterior and 23 mm posterior (y coordinates) to the VAC plane and between horizontal planes 2 mm below and 21 mm above (z coordinates) the horizontal AC–PC plane. These responses were picked up with a maximal amplitude on contacts located between 33.25 and 52.75 mm from the midsagittal vertical plane (x coordinates) (Table 3 and Fig. 4).

Figure 4.

Location of the contacts where the maximal amplitudes of the N/P deflection in bipolar mode were recorded. Black crosses: contacts located in SII, black squares: contacts located in the insula. Contacts have been located on the 3-dimensional MRI of each patient. y: anteroposterior coordinate (in mm) of the coronal plane according to the Talairach and Tournoux atlas.

Figure 4.

Location of the contacts where the maximal amplitudes of the N/P deflection in bipolar mode were recorded. Black crosses: contacts located in SII, black squares: contacts located in the insula. Contacts have been located on the 3-dimensional MRI of each patient. y: anteroposterior coordinate (in mm) of the coronal plane according to the Talairach and Tournoux atlas.

Table 3.

Coordinates (atlas of Talairach and Tournoux) of contacts (in mm) where the maximal amplitudes of the N/P deflection in bipolar mode were recorded

Patients  SII cortex Insular cortex 
  x y z x y z 
AL PrC 33.25 14 29 14 
LS PrC 41.75 12 38.25 12 
 PoC 37.25 −16 20 32.75 −16 20 
 T1    38.25 −12 −1 
FF PrC 38.75 −2 12 31 −2 12 
 PoC 45.75 −23 21    
 T1    33 −10 −2 
CM PrC 45.75 −1 17 31 −1 17 
VE PrC 33.25 29 
 PoC 42.25 −12 31 −12 
DB PoC 35.75 −12 18 35 −12 18 
 T1    34 −9 −4 
LM PrC 52.75 −2 35.25 −2 
 PoC 36.75 −12 14    
 T1    32.75 −19 −4 
KL PoC 37.75 −13 14 30 −13 14 
 T1    32.75 −10 −1 
Mean  40.1 −5.8 12.3 32.9 −6.3 6.7 
SD  5.8 10.5 6.6 2.9 9 8.5 
Patients  SII cortex Insular cortex 
  x y z x y z 
AL PrC 33.25 14 29 14 
LS PrC 41.75 12 38.25 12 
 PoC 37.25 −16 20 32.75 −16 20 
 T1    38.25 −12 −1 
FF PrC 38.75 −2 12 31 −2 12 
 PoC 45.75 −23 21    
 T1    33 −10 −2 
CM PrC 45.75 −1 17 31 −1 17 
VE PrC 33.25 29 
 PoC 42.25 −12 31 −12 
DB PoC 35.75 −12 18 35 −12 18 
 T1    34 −9 −4 
LM PrC 52.75 −2 35.25 −2 
 PoC 36.75 −12 14    
 T1    32.75 −19 −4 
KL PoC 37.75 −13 14 30 −13 14 
 T1    32.75 −10 −1 
Mean  40.1 −5.8 12.3 32.9 −6.3 6.7 
SD  5.8 10.5 6.6 2.9 9 8.5 

Note: PrC, precentral SII cortex; PoC, postcentral SII cortex.

The insular LEPs were recorded by the 2 or 3 deepest contacts of the electrodes penetrating the opercular and temporal cortex between vertical planes 14 mm rostral and 19 mm caudal (y coordinates) to the VAC plane and between horizontal planes 4 mm below and 20 mm above (z coordinates) the AC–PC plane. The contacts recording these responses with maximal amplitude were distributed between 29 and 38.25 mm from the median line (x coordinates) (Table 3 and Fig. 4).

Statistical Analysis

Effect of Electrode Localization on SII–Insular LEPs

In the patients whose SII or posterior insular cortices were explored by 2 or 3 electrodes along the anteroposterior axis (y), repeated-measures ANOVA showed no effect of electrode location on the latency or amplitude of LEP components (Tables 4 and 5). This reflected a certain level of homogeneity of responses recorded by the different electrode tracks, at least in the subregions of SII and insular cortices we explored. In support of this, 1) there was no waveform difference in SII or insular responses recorded along different electrode tracks; 2) polarity reversals along the different electrode tracks in a given patient always occurred at the same depth; and 3) the dynamics of SII and insular responses to variations of stimulus intensity (see below) were always similar along the different electrode tracks. Therefore, we considered that when several electrodes with different anteroposterior (y) coordinates were located in SII or in the insula, they all recorded responses originating from the same source.

Table 4.

Statistical analysis (ANOVA) of the effects of intensity, electrode localization, and epoch order on amplitude of SII and insular LEPs

 SII
 
Insula
 
Amplitude Nop–Pop Ni–Pi 
Intensity F3,40 = 2.9, P < 0.05* F3,48 = 4.8, P < 0.01* 
Electrode localization F1,40 = 0.4, P = 0.5 F2,48 = 0.4, P = 0.7 
Epoch order F11,440 = 0.7, P = 0.7 F11,528 = 1.7, P = 0.07 
 SII
 
Insula
 
Amplitude Nop–Pop Ni–Pi 
Intensity F3,40 = 2.9, P < 0.05* F3,48 = 4.8, P < 0.01* 
Electrode localization F1,40 = 0.4, P = 0.5 F2,48 = 0.4, P = 0.7 
Epoch order F11,440 = 0.7, P = 0.7 F11,528 = 1.7, P = 0.07 

Note: Significant results were indicated by a * and were in bold and underlined. df: before the G–G correction.

Table 5.

Statistical analysis (ANOVA) of the effects of intensity, electrode localization, and epoch order on latency of SII and insular LEPs

 SII Insula 
Latency Nop Pop Ni Pi 
Intensity F3,40 = 0.3, P = 0.82 F3,40 = 0.3, P = 0.85 F3,48 = 0.06, P = 0.98 F3,48 = 0.05, P = 0.98 
Electrode localization F1,40 = 1.4, P = 0.2 F1,40 = 1.9, P = 0.2 F2,48 = 3.2, P = 0.06 F2,48 = 0.2, P = 0.83 
Epoch order F11,440 = 1.6, P = 0.1 F11,440 = 1.4, P = 0.2 F11,528 = 1.8, P = 0.06 F11,528 = 0.89, P = 0.54 
 SII Insula 
Latency Nop Pop Ni Pi 
Intensity F3,40 = 0.3, P = 0.82 F3,40 = 0.3, P = 0.85 F3,48 = 0.06, P = 0.98 F3,48 = 0.05, P = 0.98 
Electrode localization F1,40 = 1.4, P = 0.2 F1,40 = 1.9, P = 0.2 F2,48 = 3.2, P = 0.06 F2,48 = 0.2, P = 0.83 
Epoch order F11,440 = 1.6, P = 0.1 F11,440 = 1.4, P = 0.2 F11,528 = 1.8, P = 0.06 F11,528 = 0.89, P = 0.54 

Note: df, before the G–G correction.

Effect of Stimulus Intensity

On source localization

For each patient, the electrode contacts yielding maximal SII or insular responses were the same for all intensities. Therefore, the source location of these responses did not appear to be modified by the intensity changes. However, due to our restricted spatial sampling, especially along the anteroposterior (y) and vertical (z) axes, we cannot draw any definitive conclusion on this point.

On SII and insular LEPs latencies and amplitudes

Repeated-measures ANOVA showed no significant effect of intensity on the latencies of insular or SII LEPs (Table 5). There was no effect of epoch order on response latencies either, that is, for all intensity conditions, both insular and SII response latencies remained stable between consecutive epochs (Table 5).

Repeated-measures ANOVA showed a significant effect of stimulus intensity on SII and insular LEP amplitudes (Table 4). For a given stimulation intensity, there was no effect of the epoch order on response amplitudes, that is, both insular and SII response amplitudes remained stable between consecutive epochs (Table 4). SII and insular responses showed a highly significant increase of their amplitude between the 2 extreme intensities (I0 and I3; t-tests, P < 0.001) (Fig. 5).

Figure 5.

Effects of intensity on SII–insular responses. On the top of the columns are represented the latency normalized grand average LEPs in bipolar mode from all the patients in SII (on the left) and insula (on the right) for each level of stimulus intensity. Below are represented the amplitude of SII and insular LEPs as a function of intensities (I0, I1, I2, I3). Error bars indicate SE. *P < 0.05, **P < 0.001.

Figure 5.

Effects of intensity on SII–insular responses. On the top of the columns are represented the latency normalized grand average LEPs in bipolar mode from all the patients in SII (on the left) and insula (on the right) for each level of stimulus intensity. Below are represented the amplitude of SII and insular LEPs as a function of intensities (I0, I1, I2, I3). Error bars indicate SE. *P < 0.05, **P < 0.001.

On the dynamics of SII and insular LEPs

Although increasing stimulus intensities enhanced both SII and insular responses, the “dynamics” of their respective amplitude changes were different. In SII, a significant increase of the LEP amplitude was observed as soon as the stimulus intensity reached the sensory threshold (between I0 and I1, P < 0.001) as well as between sensory and pain thresholds (I1–I2, P < 0.001) while amplitudes rapidly reached a plateau for intensities above pain threshold (no significant amplitude difference between I2 and I3, P = 0.1). In the insula, no significant LEP amplitude increase was observed for low-stimulation intensities (P = 0.1 between I0 and I1). LEP amplitudes also increased between sensory and pain threshold intensities (P < 0.05 between I1 and I2) but, contrary to what was observed in SII, continued to increase significantly at higher intensities over pain threshold (P < 0.001 between I2 and I3). Figure 3 illustrates this point in the whole set of patient's responses. It is noteworthy that increasing slightly the stimulus intensity above perception threshold produced clear LEP within SII but no significant response above noise in the contiguous posterior insula. Thus, the stimulus-response function of posterior insula and SII appeared different and was fitted with different polynomial functions [f(x) = b0 + (b1 × x) + (b2 × x2) + (b3 × x3)], which had an exponential profile in the insula and a S-shaped profile in SII (Fig. 6). The coefficients determining the increase (b1) and shape (b2 and b3) of the fitted curves were significantly different between SII and insula (SII: b1, 56.4 ± 28.7; b2, −30.7 ± 13.3; b3, 5.09 ± 1.4; Insula: b1, −16.03 ± 19.6; b2, −0.06 ± 8.3; b3, 0.31 ± 1.11; mean ± standard error (SE); paired t-tests for b1, b2, and b3 in SII and insula: P < 0.05). Interestingly, when SII and insular data were pooled together, the linear stimulus LEP amplitude function of the coupled areas was similar to the one linking stimulus intensities and VAS reports (right part of Fig. 6).

Figure 6.

Insula and SII peak amplitudes as a function of stimulus intensity. Using the polynomial function f(x) = b0 + (b1 × x) + (b2 × x2) + (b3 × x3), curves were fitted on the stimulus-response amplitude functions. The dynamics of response were significantly different in SII and in the insula: the fitting curve had an exponential profile for the insula (r = 0.98, P = 0.02) and a S-shaped profile in SII (r = 0.98, P = 0.016). Amplitudes were those measured between N and P peaks for both SII and insula. The right part of the figure shows the correlation between the amplitudes when SII and Insula data were pooled together.

Figure 6.

Insula and SII peak amplitudes as a function of stimulus intensity. Using the polynomial function f(x) = b0 + (b1 × x) + (b2 × x2) + (b3 × x3), curves were fitted on the stimulus-response amplitude functions. The dynamics of response were significantly different in SII and in the insula: the fitting curve had an exponential profile for the insula (r = 0.98, P = 0.02) and a S-shaped profile in SII (r = 0.98, P = 0.016). Amplitudes were those measured between N and P peaks for both SII and insula. The right part of the figure shows the correlation between the amplitudes when SII and Insula data were pooled together.

Discussion

Intracranial recordings provide a unique opportunity to explore the activity of most cortical structures, with good spatiotemporal resolution, even in regions buried in the depth of sulci and hence of difficult access using scalp or subdural electrocorticographic recordings. Using this technique, we previously showed that the responses to painful stimuli in SII and insula could be distinguished on the basis of their latencies and their stereotactic source coordinates (Frot and Mauguière 2003). In the present work, we further specify that, although increasing stimulus intensities enhanced both SII and insular LEP amplitudes, the “dynamics” of SII and insular responses as a function of thermal stimulus intensity are significantly different. The SII responses were able to encode gradually the intensity of laser thermal stimuli from sensory threshold up to pain threshold level but tended to show a ceiling effect for increasing pain intensities. In contrast, the posterior insular cortex failed to detect stimulus intensity changes for very low levels of stimulation (around sensory perception threshold) but encoded stimulus intensity variations in the painful range without showing saturation effects for the highest painful intensities that we have tested.

Very recently, Iannetti and others (2005) described a positive relationship between the amplitude of SII–insular responses and the reported subjective pain magnitude to laser pulses. These authors analyzed the evolution of the scalp “N1” response, which most probably reflects lumped opercular and insular LEP subcomponents (Valeriani and others 2000; Garcia-Larrea and others 2003); therefore, the sustained increase of the response amplitude they observed within the painful stimulus range may reflect the insular, rather than the SII contribution to the scalp N1 component. In addition, because they used exclusively painful stimuli, these authors could not investigate whether sensations induced by different levels of innocuous stimuli are also coded by the amplitude of the N1 scalp response.

No evoked responses were recorded in the insular cortex for stimulus intensities at, or just above, sensory threshold (I1). Clearly recordable insular LEPs were only present at and above pain threshold (I2, I3). However, as we did not test intermediate intensities, firm conclusions cannot be drawn on the insular encoding properties for intensities between sensory and pain levels. It is noteworthy that no significant LEPs could be recorded in posterior insular cortex for the nonnoxious stimulus intensities that consistently evoked responses in the neighboring opercular (SII) cortex. This is in agreement with the results of an elegant study by Bornhövd and others (2002) on the dynamics of fMRI signals in response to laser pulses of increasing intensities. These authors showed that, in anterior or in posterior insular cortex, the activation levels were not related to stimulus intensity in the nonpainful range, although they correlated positively with stimulus intensity in the painful range as we observed for LEPs amplitudes in our insular recordings. This point deserves some comments because, contrary to Bornhövd's and our data, several previous studies reported insular cortex activation by nonnoxious stimuli (Coghill and others 1994; Craig and others 1996, 2000; Davis and others 1998; Becerra and others 1999; Maihöfner and others 2002). Differences in stimulation techniques may be at the origin of this discrepancy because Bornhövd and others (2002) used laser stimulations similar to ours (brief thermal pulses, 1–110 ms, small skin surface stimulated, about 30 mm2), whereas in other studies, stimulations of much longer durations (several hundreds of milliseconds up to minutes) that involved larger skin areas (thermode, up to several square centimeters) were used. These diverging results suggest that insular activation by nonnoxious stimuli may occur provided that thermal nonnoxious stimuli are applied long enough on sufficient extended skin areas. This could indicate that some time/surface-dependent recruitment processes are needed to obtain some responses within the posterior insular cortex. However, reports of posterior insular activation by nonnoxious stimuli (innocuous warmth) most often used mixed mechanical and thermal stimuli, making difficult to ascertain which of stimulus duration, stimulus surface, or mechanical contact was the most important contributor for eliciting the insular responses. This problematic situation could be clarified in a near future using specific stimulations of warmth (C-fiber) receptors without skin contact, a laser technique recently described (Cruccu and others 2003).

Bornhövd and others (2002) reported similar activation patterns in SII and posterior insula, whereas our intracranial data showed different dynamics of response between the insula “proper” and SII responses. According to our data, only SII is able to code for low levels of innocuous stimulus intensities (see Figs 3 and 5). Given the limited spatial resolution of fMRI as compared with that of SEEG studies, it is possible that separate activation of SII could not be disentangled from that of insular cortex in the study of Bornhövd and others (2002), and therefore, the SII–insular fMRI signal they analyzed could have reflected almost exclusively the insular response. A similar inability to detect SII response changes to small intensity levels was reported by Timmermann and others (2001) using magnetoencephalography (MEG). The stimulus-response function of SII described by these authors in SII cortex showed no significant activation change at low stimulus intensities (subthreshold and perception threshold), whereas a sharp increase in source activation was observed for stimuli above pain threshold. Surface MEG recordings are probably not precise enough to dissociate activation patterns emanating from SII and posterior insula, even when using dipolar modeling. Therefore, one can assume that the results of Timmermann and others (2001) probably reflect a mixed signal largely dominated by the insular responses. In accordance with this view, recent meta analyses of dipole-modeling studies of cortical pain responses suggest that scalp-derived, modeled dipoles reflect a “lumped” activation of several sources in the suprasylvian region, including both SII and the insula (Garcia-Larrea and others 2003; Apkarian and others 2005). Separation of SII and insular encoding properties looks beyond the reach of both blood flow functional imaging (positron emission tomography/fMRI) and scalp electrocortical recordings (EEG/MEG), at least until the signals emanating from these 2 very closely located regions can be reliably segregated by these techniques (see reviews in Derbyshire 2000; Peyron and others 2000; Jones and others 2002; Garcia-Larrea and others 2003; Apkarian and others 2005).

To our knowledge, the present work is the first demonstrating that the closely located SII and posterior insular cortices differently encode gradual thermal stimulus intensity changes and thus points out different functional roles for each of these 2 areas. The fact that insular responses continued to increase when SII potentials tampered makes it clear that posterior insula cannot receive thermal information “exclusively” from the SII regions that we explored in this study. This is consistent with anatomical and physiological data, suggesting that SII and insula belong to different, though partially overlapping, networks involved in somatosensory information processing. In monkeys, SII cortex receives its major thalamic input from the ventroposterior inferior thalamic nucleus (VPI) (Friedman and Murray 1986; Stevens and others 1993), whereas the posterior insula (granular and dysgranular parts of insular cortex) receives afferent fibers from a variety of thalamic nuclei including, in addition to VPI, the suprageniculate-limitans complex, the basal ventromedial medial pulvinar, and posterior nuclei (Burton and Jones 1976; Mufson and Mesulam 1984; Friedman and Murray 1986). In monkeys, VPI neurons are known to respond mostly to somatosensory stimuli, and most of them are nonnociceptive and wide–dynamic-range cells that could encode gradually the stimulus intensity both in the nonpainful and painful ranges (Apkarian and others 1991; Apkarian and Shi 1994). Conversely, thalamic nuclei sending projections to the insular cortex contain polymodal neurons that respond not only to somatosensory but also to auditory and visual stimuli (Berkley 1973; Hicks and others 1984; Benedek and others 1997). Given the properties of its thalamic afferent neurons, the insular cortex appears to be clearly multimodal as compared with SII. This is further supported by stimulation data showing that contrary to SII stimulations, which elicit almost exclusively somatosensory responses, insular stimulations produce nearly 40% of nonsomatosensory responses including viscerosensitive, auditory, speech, vestibular, and olfacto-gustatory responses (Isnard and others 2004; Mazzola and others 2005).

The patterns of insular and SII cortical connections also support this hypothesis. Insula receives afferents from multiple cortical areas including somatosensory SI and SII areas, auditory cortex, orbitofrontal cortex, amygdala, cingulate gyrus, and other limbic areas (Mesulam and Mufson 1982; Augustine 1985; Friedman and others 1986; Augustine 1996). In contrast, cortical projections to SII area arise exclusively from SI and 7b parietal areas, posterior insular, and retroinsular cortices (Friedman and others 1986). The massive amount of afferents coming from associative cortices to the insula suggests that this region is involved in numerous types of information processing. Such a continuous and multimodal input might create a “background activity” that could hamper the precise encoding of stimulus attributes unless they are sufficiently salient. This is in agreement with our intracortical recordings, as well as the results reported by Bornhövd and others (2002) using fMRI, suggesting that insular activity is modulated mostly by brief thermal stimuli of high intensity, whereas it remains poorly modified by stimuli at or near sensory threshold.

Efferent insular projections are massive to limbic and memory-related areas involved in the processing of emotions such as amygdala and cingulate cortex (Augustine 1985, 1996). This probably explains why the amplitude of insular responses does not saturate for stimulus intensities above painful threshold. It is not surprising that posterior insular cortex, which is directly connected with areas contributing to the emotional processing of painful events (Büchel and others 1999; Bornhövd and others 2002), and the orienting reactions toward the noxious stimulation (Büchel and others 2002) encode for stimuli well above painful threshold.

According to our results, we can assume that the complete encoding of thermal stimuli above pain threshold includes a maximal response in SII and a pain level–related response in the insula. Accordingly, pain perception should derive from this coupled activation of both areas. This assumption is supported by the fact that when amplitudes of SII and insular responses are pooled together, the stimulus-response function of the coupled areas yields a linear function similar to that of the subjective intensity perception (compare Fig. 1 and the right part of Fig. 6).

For obvious ethical reasons, we fixed the highest stimulus intensity (I3) at 20% over the pain threshold level, and thus, we did not explore subjective pain levels higher than 6–7/10 on VAS ratings. Consequently, we cannot be sure that the “ceiling effect” that we observed for painful pulses in SII persists at very high painful intensities. A similar ceiling effect was, however, suggested by Ferretti and others (2004) in a recent fMRI study. These authors showed that the anterior part of SII, largely overlapping the area explored by our SII electrodes, failed to discriminate nonpainful from painful stimulations, whereas the blood oxygen level–dependent signal in a more posterior part of SII keeps increasing between prepain and pain stimulus intensities. None of our opercular electrodes was implanted posterior enough to explore this most caudal region in SII, so that our recordings may reflect only part of the opercular pain network. However, contrary to us, these authors did not explore the SII responses to gradually increasing stimulus intensities. Thus, in the eventuality that a posterior SII subregion would be able to code for stimulus intensities above pain threshold, it would remain to determine whether this area is nociceptive specific, or made of wide-dynamic–range cells able to code for stimulus intensities both below and above pain threshold.

Grateful thanks are due to Dr M. Guénot (Department of Functional Neurosurgery) for stereotactic electrode implantation and to Dr J. Isnard for useful discussions on these data. Thanks also to Drs C. Fischer and P. Ryvlin for the opportunity to study their patients. This work has been supported by grants of UPSA Institute against Pain and European Federation of Chapters of the International Association for the Study of Pain Grünenthal. Conflict of Interest: None declared.

References

Apkarian
AV
Bushnell
MC
Treede
RD
Zubieta
JK
Human brain mechanisms of pain perception and regulation in health and disease
Eur J Pain
 , 
2005
, vol. 
9
 (pg. 
463
-
484
)
Apkarian
AV
Shi
T
Squirrel monkey lateral thalamus. I. Somatic nociresponsive neurons and their relation to spinothalamic terminals
J Neurosci
 , 
1994
, vol. 
14
 (pg. 
6779
-
6795
)
Apkarian
AV
Shi
T
Stevens
RT
Kniffki
KD
Hodge
CJ
Properties of nociceptive neurons in the lateral thalamus of the squirrel monkey
Soc Neurosci Abstr
 , 
1991
, vol. 
17
 pg. 
838
 
Augustine
JR
The insular lobe in primates including humans
Neurol Res
 , 
1985
, vol. 
7
 (pg. 
2
-
10
)
Augustine
JR
Circuitry and functional aspects of the insular lobe in primates including humans
Brain Res Rev
 , 
1996
, vol. 
22
 (pg. 
229
-
244
)
Becerra
LR
Breiter
HC
Stojanovic
M
Fishman
S
Edwards
A
Comite
AR
Gonzalez
RG
Borsook
D
Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study
Magn Reson Med
 , 
1999
, vol. 
41
 (pg. 
1044
-
1057
)
Benedek
G
Perény
J
Kovács
G
Fischer-Szátmári
L
Katoh
YY
Visual, somatosensory, auditory and nociceptive modality properties in the feline suprageniculate nucleus
Neuroscience
 , 
1997
, vol. 
78
 (pg. 
179
-
189
)
Berkley
KJ
Response properties of cells in the ventrobasal and posterior group nuclei of the cat
J Neurophysiol
 , 
1973
, vol. 
36
 (pg. 
940
-
952
)
Bornhövd
K
Quante
M
Glauche
V
Bromm
B
Weiller
C
Büchel
C
Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study
Brain
 , 
2002
, vol. 
125
 (pg. 
1326
-
1336
)
Büchel
C
Bornhovd
K
Quante
M
Glauche
V
Bromm
B
Weiller
C
Dissociable neural responses related to pain intensity, stimulus intensity, and stimulus awareness within the anterior cingulate cortex: a parametric single-trial laser functional magnetic resonance imaging study
J Neurosci
 , 
2002
, vol. 
22
 
3
(pg. 
970
-
976
)
Büchel
C
Dolan
RJ
Armony
JL
Friston
KJ
Amygdala-hippocampal involvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging
J Neurosci
 , 
1999
, vol. 
25
 (pg. 
10869
-
10876
)
Burton
H
Carlson
M
Second somatic sensory cortical area (SII) in a prosimian primate, Galago crassicaudatus
J Comp Neurol
 , 
1986
, vol. 
247
 (pg. 
200
-
220
)
Burton
H
Jones
EG
The posterior thalamic region and its cortical projection in new world and old world monkeys
J Comp Neurol
 , 
1976
, vol. 
168
 (pg. 
249
-
302
)
Chen
JI
Ha
B
Bushnell
MC
Pike
B
Duncan
GH
Differentiating noxious and innocuous related activation of human somatosensory cortices using temporal analysis of fMRI
J Neurophysiol
 , 
2002
, vol. 
88
 (pg. 
464
-
474
)
Coghill
RC
Sang
CN
Maisog
JMA
Iadarola
MJ
Pain intensity within the human brain: a bilateral distributed mechanism
J Neurophysiol
 , 
1999
, vol. 
82
 (pg. 
1934
-
1943
)
Coghill
RC
Talbot
JD
Evans
AC
Meyer
E
Gjedde
A
Bushnell
MC
Duncan
GH
Distributed processing of pain and vibration by the human brain
J Neurosci
 , 
1994
, vol. 
14
 (pg. 
4095
-
4108
)
Craig
AD
Distribution of brainstem projections form spinal lamina lneurons in the cat and the monkey
J Comp Neurol
 , 
1995
, vol. 
361
 (pg. 
225
-
248
)
Craig
AD
Chen
K
Bandy
D
Reiman
EM
Thermosensory activation of insular cortex
Nat Neurosci
 , 
2000
, vol. 
3
 
2
(pg. 
184
-
190
)
Craig
AD
Reiman
EM
Evans
A
Bushnell
MC
Functional imaging of an illusion of pain
Nature
 , 
1996
, vol. 
384
 (pg. 
258
-
260
)
Cruccu
G
Pennisi
E
Truini
A
Iannetti
GD
Romaniello
A
Le Pera
D
De Armas
L
Leandri
M
Manfredi
M
Valeriani
M
Unmyelinated trigeminal pathways as assessed by laser stimuli in humans
Brain
 , 
2003
, vol. 
126
 (pg. 
2246
-
2256
)
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
, vol. 
80
 (pg. 
1533
-
1546
)
Derbyshire
SWG
Exploring the pain “neuromatrix.”
Curr Rev Pain
 , 
2000
, vol. 
4
 
6
(pg. 
467
-
477
)
Dong
WK
Chudler
EH
Sugiyama
K
Roberts
VJ
Hayashi
T
Somatosensory, multisensory, and task-related neurons in cortical area 7b (PF) of unanesthetized monkeys
J Neurophysiol
 , 
1994
, vol. 
72
 (pg. 
542
-
564
)
Dong
WK
Salonen
LD
Kawakami
Y
Shiwaku
T
Kaukoranta
EM
Martin
RF
Nociceptive responses of trigeminal neurons in SII-7b cortex of awake monkeys
Brain Res
 , 
1989
, vol. 
484
 (pg. 
314
-
324
)
Dostrovsky
JO
Graig
AD
Cooling-specific spinothalamic neurons in the monkey
J Neurophysiol
 , 
1996
, vol. 
76
 
6
(pg. 
3656
-
3665
)
Ferretti
A
Del Gratta
C
Babiloni
C
Caulo
M
Arienzo
D
Tartaro
A
Rossini
PM
Romani
GL
Functional topography of the secondary somatosensory cortex for nonpainful and painful stimulation of median and tibial nerve: an fMRI study
Neuroimage
 , 
2004
, vol. 
23
 (pg. 
1217
-
1225
)
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
, vol. 
252
 (pg. 
348
-
373
)
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
, vol. 
252
 (pg. 
323
-
347
)
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
, vol. 
94
 
1
(pg. 
65
-
73
)
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
, vol. 
9
 (pg. 
854
-
863
)
Frot
M
Mauguière
F
Dual representation of pain in the operculo-insular cortex in humans
Brain
 , 
2003
, vol. 
126
 (pg. 
1
-
13
)
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
, vol. 
110
 
1
(pg. 
133
-
145
)
Garcia-Larrea
L
Frot
M
Valeriani
M
Brain generators of laser-evoked potentials: from dipoles to functional significance
Neurophysiol Clin
 , 
2003
, vol. 
33
 
6
(pg. 
279
-
292
)
Geisser
S
Greenhouse
SW
An extension of Box's results on the use of the F distribution in multivariate analysis
Ann Math Stat
 , 
1958
, vol. 
29
 (pg. 
885
-
891
)
Gracely
RH
Wall
PD
Melzack
R
Studies of pain in normal man
Textbook of pain
 , 
1994
New York
Churchill Livingston
(pg. 
315
-
336
)
Hicks
TP
Watanabe
S
Miyake
A
Shoumura
K
Organization and properties of visually responsive neurones in the suprageniculate nucleus of the cat
Exp Brain Res
 , 
1984
, vol. 
55
 (pg. 
359
-
367
)
Iannetti
GD
Zambreanu
L
Cruccu
G
Tracey
I
Operculoinsular cortex encodes pain intensity at the earliest stages of cortical processing as indicated by amplitude of laser-evoked potentials in humans
Neuroscience
 , 
2005
, vol. 
131
 (pg. 
199
-
208
)
Isnard
J
Guénot
M
Ostrowsky
K
Sindou
M
Mauguière
F
The role of the insular cortex in temporal lobe epilepsy
Ann Neurol
 , 
2000
, vol. 
48
 
4
(pg. 
614
-
623
)
Isnard
J
Guénot
M
Sindou
M
Mauguière
F
Clinical manifestations of insular lobe seizures: a stereo-electroencephalographic study
Epilepsia
 , 
2004
, vol. 
45
 
9
(pg. 
1079
-
1090
)
Jones
AK
Kulkarni
B
Derbyshire
SWG
Functional imaging of pain perception
Curr Rheumatol Rep
 , 
2002
, vol. 
4
 
4
(pg. 
329
-
333
)
Jones
EG
Burton
H
Areal differences in the laminar distribution of thalamic afferents in cortical fields of the insular, parietal and temporal regions of primates
J Comp Neurol
 , 
1976
, vol. 
168
 (pg. 
197
-
248
)
Lenz
FA
Gracely
RH
Rowland
LH
Dougherty
PM
A population of cells in the human thalamic principal sensory nucleus respond to painful mechanical stimuli
Neurosci Lett
 , 
1994
, vol. 
180
 (pg. 
46
-
50
)
Lenz
FA
Seike
M
Lin
YC
Baker
FH
Rowland
LH
Gracely
RH
Richardson
RT
Neurons in the area of human thalamic nucleus ventralis caudalis respond to painful heat stimuli
Brain Res
 , 
1993
, vol. 
623
 (pg. 
235
-
240
)
Maihöfner
C
Kaltenhauser
M
Neundörfer
B
Lang
E
Temporo-spatial analysis of cortical activation by phasic innocuous and noxious cold stimuli—a magnetoencephalographic study
Pain
 , 
2002
, vol. 
100
 (pg. 
281
-
290
)
Mazzola
L
Isnard
J
Mauguière
F
Somatosensory and pain responses to stimulation of the second somatosensory area (SII) in humans. A comparison with SI and insular responses
Cereb Cortex
 , 
2005
September
21
 
10.1093/cercor/bhj038
Mesulam
MM
Mufson
EJ
Insula of the old world monkey: III efferent cortical output and comments on function
J Comp Neurol
 , 
1982
, vol. 
212
 (pg. 
38
-
52
)
Mesulam
MM
Mufson
EJ
Peters
A
Jones
EG
The insula of Reil in man and monkey
Cerebral cortex
 , 
1985
, vol. 
Volume 4
 
New York
Plenum Press
(pg. 
179
-
226
)
Mufson
EJ
Mesulam
MM
Thalamic connections of the insula in the rhesus monkey and comments on the paralimbic connectivity of the medial pulvinar nucleus
J Comp Neurol
 , 
1984
, vol. 
227
 (pg. 
109
-
120
)
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
, vol. 
12
 (pg. 
376
-
385
)
Peyron
R
Laurent
B
Garcia-Larrea
L
Functional imaging of brain responses to pain. A review and meta-analysis
Neurophysiol Clin
 , 
2000
, vol. 
30
 (pg. 
263
-
288
)
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
 , 
1980
, vol. 
192
 (pg. 
93
-
108
)
Robinson
CJ
Burton
H
Organization of somatosensory receptive fields in cortical areas 7b, retroinsula, postauditory and granular insula of M. fascicularis
J Comp Neurol
 , 
1980
, vol. 
192
 (pg. 
69
-
92
)
Rorden
C
Brett
M
Stereotaxic display of brain lesions
Behav Neurol
 , 
2000
, vol. 
12
 (pg. 
191
-
200
)
Schnitzler
A
Ploner
M
Neurophysiology and functional neuroanatomy of pain perception
J Clin Neurophysiol
 , 
2000
, vol. 
17
 (pg. 
592
-
603
)
Schwarz
S
Greffrath
W
Büsselberg
D
Treede
RD
Inactivation and tachyphylaxis of heat-evoked inward currents in nociceptive primary sensory neurones of rats
J Physiol
 , 
2000
, vol. 
528
 
3
(pg. 
539
-
549
)
Stevens
RT
London
SM
Apkarian
AV
Spinothalamocortical projections to the secondary somatosensory cortex (SII) in squirrel monkey
Brain Res
 , 
1993
, vol. 
631
 (pg. 
241
-
246
)
Talairach
J
Tournoux
P
Co-planar stereotaxic atlas of the human brain. 3-dimensional proportional system: an approach to cerebral imaging
1988
Stuttgart, Germany
Georg Thieme Verlag
Timmermann
L
Ploner
M
Haucke
K
Schmitz
F
Baltissen
R
Schnitzler
A
Differential coding of pain intensity in the human primary and secondary somatosensory cortex
J Neurophysiol
 , 
2001
, vol. 
86
 (pg. 
1499
-
1503
)
Treede
RD
Apkarian
AV
Bromm
B
Greenspan
JD
Lenz
FA
Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus
Pain
 , 
2000
, vol. 
87
 (pg. 
113
-
119
)
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
, vol. 
111
 (pg. 
1103
-
1112
)
Van Buren
JM
Borke
RC
Variation and connections of the human thalamus
 , 
1972
Berlin, Germany
Springer-Verlag
Vasey
MW
Thayer
JF
The continuous problem of false positives in repeated measures ANOVA in psychophysiology: a multivariate solution
Psychophysiology
 , 
1987
, vol. 
24
 (pg. 
479
-
486
)
Vogel
H
Port
JD
Lenz
FA
Solaiyappan
M
Krauss
G
Treede
RD
Dipole source analysis of laser-evoked subdural potentials recorded from parasylvian cortex in humans
J Neurophysiol
 , 
2003
, vol. 
89
 (pg. 
3051
-
3060
)
Zhang
ZH
Dougherty
PM
Oppenheimer
SM
Monkey insular cortex neurons respond to baroreceptive and somatosensory convergent inputs
Neuroscience
 , 
1999
, vol. 
94
 (pg. 
351
-
360
)