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1Institute of Physiology and Pathophysiology, Johannes Gutenberg University, D-55099 Mainz, Germany; Departments of 2 Neurosurgery, 3Neurology, and 4Radiology, The Johns Hopkins Hospital, Baltimore, Maryland 21218; and 5Department of Radiology, Mayo Clinic, Rochester, Minnesota 55905
Submitted 6 September 2002; accepted in final form 26 January 2003
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ABSTRACT |
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INTRODUCTION |
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; Talbot et al. 1991). In addition to techniques that measure changes of blood flow in active brain areas [PET or functional magnetic resonance imaging (MRI)], the electrical activity of the brain itself is accessible via dipole source analysis of evoked potentials that are recorded outside the skull by electro- or magnetoencephalographic (EEG or MEG) techniques. For these noninvasive electrophysiological techniques, the recording of laser-evoked potentials (LEPs) has proven a powerful method because brief laser radiant heat pulses applied to hairy skin elicit a purely nociceptive input and are readily adapted for stimulus-locked averaging of evoked potentials (Bromm and Treede 1984).
The discovery of an early negativity N1 at 170 ms latency with a scalp maximum over the Sylvian fissure (Treede et al. 1988) and of a preceding positivity eP at 83 ms (Valeriani et al. 2000b) led to the use of LEPs to study the functions of nociceptive areas in parasylvian cortex. Using brain electrical source analysis techniques, the possible generators of laser evoked potentials were identified in bilateral secondary somatosensory cortex (SII) and in the anterior cingulate cortex (Bromm and Chen 1995; Opsommer et al. 2001; Tarkka and Treede 1993; Valeriani et al. 1996). Subdural recording has confirmed the anterior cingulate generator (Lenz et al. 1998b). Source analysis of laser-evoked magnetic fields has also shown activity near SII (Bromm et al. 1996; Kakigi et al. 1995; Ploner et al. 1999). The source near contralateral SII had the shortest onset latency, suggesting that this area receives direct spinothalamo-cortical nociceptive input.
The SII is situated within the parietal operculum in the upper bank of the Sylvian fissure (Burton 1986). SII and the adjacent parietal ventral area (PV) contain multiple somatotopic representations of the body surface and are surrounded by several other somatosensory areas within the frontoparietal operculum and the adjacent insula (Burton et al. 1993; Craig and Dostrovsky 1997; Disbrow et al. 2000; Krubitzer et al. 1995). Therefore it has been difficult to assign specific functions to any of the somatosensory areas in parasylvian cortex. There is some evidence that nociceptive areas may be situated outside the classical SII region (for review, see Treede et al. 2000). The number of neurons responding to noxious stimuli (nociceptive neurons) in SII of Old World monkeys appear to be small (Robinson and Burton 1980). The majority of recordings from nociceptive neurons in this region have been made in parietal area 7b (Dong et al. 1994), which is posteriorly adjacent to SII in the monkey but not in humans. Medially adjacent areas in the insula have been suggested to be the projection targets of a nociceptive pathway from lamina I of the spinal cord via the thalamic nucleus posterior part of the ventromedial nucleus (VMpo) (Blomqvist et al. 2000; Casey et al. 2001; Craig et al. 1996).
LEP recordings from subdural grids implanted for seizure monitoring have raised doubts that SII is the parasylvian nociceptive area (Lenz et al. 1998a). SII proper, as defined by vibrotactile stimuli, is situated in the upper bank of the Sylvian fissure, opposite to the primary auditory cortex AI (Burton et al. 1993). If SII is the generator of the LEP, then both the auditory-evoked potential (AEP) and the LEP should exhibit polarity reversal across the Sylvian fissure. This prediction is based on the fact that specific thalamic input to pyramidal cells in a cortical area generates a current sink in layer 4 and a corresponding current source at the apical dendrites (box 46–1 in Kandel et al. 2000). The resulting electrical dipole is perpendicular to the cortical surface and positive at its surface. Appropriate polarity reversal was demonstrated for AEPs but not for LEP, which had the same polarity when recorded on either side of the Sylvian fissure (Lenz et al. 2000).
Depth recordings of LEPs by stereotactically placed multicontact electrodes showed amplitude maxima both within the frontoparietal operculum and near the insula (Frot et al. 1999). Polarity reversals along an electrode track were rare in that study, and thus most tracks did not pass through the LEP generators. As outlined in the preceding text, the orientation of an equivalent electrical dipole is perpendicular to the surface of the cortical generator. Therefore knowing its orientation would predict which cortical area near the amplitude maximum in the electrode track was the most likely generator. The orientation of the equivalent electrical dipole, however, is not determined in these depth recordings. Therefore the location of the cortical area that is activated most rapidly by noxious heat stimuli is still not known.
In the present study, we chose a different approach by performing a dipole source analysis on subdural recordings of LEPs to estimate both the location and orientation of the equivalent electrical dipoles. Subdural LEPs from parasylvian cortex are particularly useful for this exercise because likely generators are in deep structures (SII or insula) rather than superficial gyri. Use of subdural recordings diminished the distortion of the signal produced by recording the generator through layers of brain, cerebrospinal fluid, bone, and scalp. To verify the accuracy of our approach, we compared the dipole locations for the LEP N1 with those of the AEP N1, which is generated in the superior temporal cortex (Celesia and Puletti 1969). Both sources were also projected back into the MRI of the brain.
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METHODS |
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These patients were tested with AEP and LEP. For LEPs, a CO2 laser with a wavelength of 10,600 nm (in the infrared range) was used to stimulate left and right face and left and right hand (20-ms duration, 6-mm diam, 10–13 W/mm2). The auditory stimulus consisted of 500- and 1,000-Hz tones (70 dB, 50-ms duration) presented binaurally via headphones in an oddball paradigm (frequent tone 80%, infrequent tone 20%, counterbalanced across tone frequency). The EEG was recorded from the left frontotemporal grid with 256-Hz sampling rate in a time window from -102 ms (prestimulation) to +996 ms (poststimulation). The EEG recording for AEPs was done with 200-Hz sampling rate in a time window of -100 to +796 ms. LEPs were averaged across 30–50 trials, AEPs across 300 trials including both frequent and infrequent tones. Individual trials were reviewed for artifacts before averaging and root mean square cutoffs were adjusted to reject 10% of the trials (Lenz et al. 2000). Each average was repeated at least once to establish reproducibility of the potentials.
Modeling of LEP generators was carried out with the Brain Electromagnetic Source Analysis software (BESA; MEGIS Software, Munich, Germany), which allows calculation of source models of evoked potential generators in the brain by fitting a mathematical model of one or more equivalent dipoles to the data recorded from the brain surface or the scalp. To enhance the signal-to-noise ratio, the data were filtered with a low-pass filter (3 dB down at 50 Hz), and baseline was corrected in the prestimulus window. The time window for source analysis was set to cover the first peak in the global field power (GFP). GFP is the spatial SD of amplitudes across all recorded EEG channels as a function of time (Lehmann and Skrandies 1984); larger values of the GFP indicate a larger number of simultaneously active dipoles and/or an increase in dipole moment. As a first approximation, a single moving dipole (SMD) analysis was performed so that one equivalent dipole was calculated for each time point. The time range of stable periods, when SMD locations remained constant within a small region of the brain, was used to further delineate the time window for source analysis.
In the final analysis, we used a source with fixed location and orientation throughout the analysis window because this way the resulting source waveform represents the time course of activity in the modeled brain region. Location and orientation were fitted separately by using a regional source (Waberski et al. 2000). A regional source is a set of three orthogonal dipoles with the same dipole location. This set of dipoles can represent the electrical activity of a small brain volume independent of changes of the net orientation of the equivalent dipole over time and is a robust estimator for source location, because it has only 3 df for the fitting procedure. To obtain the orientation of the equivalent dipole for N1, the regional source was rotated in such a way that one of the three dipoles represented the net dipole orientation at the time of the GFP peak.
All dipole models were calculated in a spherical volume conductor with homogenous conductivity of 0.33 m/
by using the "epicortical recording" switch in BESA. Due to the subdural placement of recording electrodes, additional shells for scalp, skull, dura, CSF were not necessary. Although the shape of the brain in the parasylvian region differs substantially from a sphere, realistically shaped head models and spherical head models had the same mean localization error of 10 ± 5 mm for dipoles generated by implanted electrode pairs (Cuffin et al. 2001a,b). For each patient, the positions of the grid electrodes were determined in the postoperative CT scan using the Analysis of Functional Neuroimages software (AFNI; Robert W. Cox, Medical College of Wisconsin, Milwaukee, WI 53226). These positions were measured relative to the standard fiducial points of the 10–20 system of EEG electrode placement (nasion, inion, preauricular points, and vertex) that were determined from the same CT images. The individual head models were verified by projection of electrodes into an MRI image of the brain, and identifying their position relative to the Sylvian fissure and central sulcus on both the MRI and the intraoperative sketch and photos (see Fig. 1).
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RESULTS |
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; Treede et al. 1988). The first GFP peak of the AEP corresponded to the scalp recorded N1 (i.e., the negativity of the vertex potential), which was preceded by a small positivity that only showed up as a shoulder in the GFP. The GFP peaks corresponding to the respective N1 components were selected for source analysis of both LEP and AEP.
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The first step in the source analysis was calculation of a single dipole for each time point within the analysis window ("single moving dipole": SMD). As shown in Fig. 3 for one patient, the location of the SMD remained within a small area of the brain for 
50 ms for the LEP and 100 ms for the AEP (horizontal lines in the figure). These stable periods were used to constrain the analysis time window for the regional source beyond that suggested by the GFP peaks in Fig. 2. Applying these criteria, we found an optimized analysis window for LEP from 129 to 195 ms and from 95 to 210 ms for AEP (Table 1).
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Figure 4 illustrates the results of the analysis using a regional source within the constraints described in the preceding text. The regional source was initially placed at the center of the head model, and its location was then optimized to represent the recorded data throughout the specified analysis window. In contrast to the SMD analysis, the location of the regional source was fixed throughout the analysis window. The resulting location was in the frontoparietal operculum above the Sylvian fissure for the LEP and in the temporal lobe below the Sylvian fissure for the AEP. Table 1 shows the resulting locations for the three patients in Talairach coordinates (Talairach and Tournoux 1988). The LEP source was located 13 mm anterior, 6 mm superior, and slightly medial (2 mm) of the AEP source.
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To estimate the time course of electrical activity at the regional source locations, we studied the time course of dipole strength along the net source vector. For this purpose, we rotated the coordinate system spanned by the regional source such that one of the orthogonal dipoles (dipole 1) was parallel to the net source vector at the time of the first GFP peak (orthogonal rotation). The resulting dipole orientations and source waveforms in Fig. 4 indicate that the N1 dipole of the LEP was pointing inward and that of the AEP N1 was pointing upward. These dipole orientations correspond to a positivity at the inner vertical surface of the frontoparietal operculum for the LEP N1. The AEP dipole started with a small positivity at the upper surface of the temporal lobe, but according to its latency, the auditory N1 measured at the vertex corresponded to the subsequent negativity. Dipoles 2 and 3 were inactive during the first peak of each source waveform, but they contributed to later components.
The time courses of the amplitude of the net source vectors for all three patients are summarized in Fig. 5. The LEP source waveform was biphasic with first peak latencies of 140–160 ms. In two patients (H and C), but not the third (P), the latency was shorter for stimulation of the contralateral face than for stimulation of the ipsilateral face (Table 2). The AEP source waveform was dominated by the negativity at 100 ms (N1) in both patients. The preceding positivity had identical latencies and amplitudes for both frequent and rare stimuli.
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The projection of the Talairach coordinates resulting from the brain electrical source analysis into a standardized brain MRI is shown in Fig. 6, with 
for AEP and 
for LEP. In one patient (C), the LEP dipole was located on the Sylvian fissure; in the other two patients (H and P), it was located above the fissure (the light gray symbols in Fig. 6 indicate that the LEP dipole was above the plane of the slice). All dipoles were located within the frontoparietal operculum overlying the insula. The AEP dipoles were located in the superior temporal lobe, near Heschl's gyrus. In one patient (H), signal-to-noise ratio was sufficient to analyze LEP data for hand and for face stimulation (Fig. 7). The equivalent dipole for hand stimulation was lateral, posterior, and inferior to that for face stimulation (10 mm distance between equivalent dipole locations). This somatotopy is consistent with that of the projection area of the presumed nociceptive thalamic nucleus VMpo (see also Table 3).
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DISCUSSION |
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150-ms latency, corresponding to the peak latency of the scalp recorded N1 (Kazarians et al. 1995; Kunde and Treede 1993; Miyazaki et al. 1994; Treede et al. 1988). Source analysis of laser-evoked magnetic fields has also shown an initial component with onset latencies of 100 ms for face stimulation, 150 ms for hand stimulation, and 200 ms for foot stimulation (Bromm et al. 1996; Kakigi et al. 1995; Ploner et al. 1999). In contrast to scalp recordings and MEG recordings, however, the amplitude of the first GFP peak of the subdural recordings was enhanced relative to the second peak. This finding suggested that the generator of N1, but not that of later LEP components, was close to the subdural grids. The differential location of the generators of N1 and later LEP components was not evident from visual inspection of the subdural LEP waveform, which in general appeared similar to the wave-form recorded from the scalp (Lenz et al. 1998a).
To estimate the location of the N1 generator, a regional source was fitted to the latency range of the first GFP peak, when the location of the equivalent dipole stayed approximately constant. Its location was found to be within the frontoparietal operculum in all patients, similar to the position described in previous EEG and MEG source analysis studies (Table 3). According to the brain atlas of Talairach and Tournoux, our mean N1 source location was 6 mm lateral of the circular sulcus of the insula (Talairach and Tournoux 1988). For comparison, the mean location of sources in the foot area of the primary somatosensory cortex was 8 mm lateral of the interhemispheric fissure (Baumgärtner et al. 1998). In the mediolateral direction, our N1 source location was 1.4 mm medial of the one found in LEP recordings with depth electrodes stereotactically implanted into the frontoparietal operculum (Frot et al. 1999), but 18 mm lateral of the mean location in the insula, where electrical stimulation induced pain (Ostrowsky et al. 2002). These data indicate that equivalent dipole source analysis yielded an accurate estimate of the location of the LEP generator in the direction perpendicular to the plane of the subdural grid.
As a functional marker with a well-known cortical generator (Celesia and Puletti 1969), AEPs were recorded from the same subdural electrodes as LEPs. Compared with probability contour maps of the primary auditory cortex in humans (Penhune et al. 1996), the mean AEP source coordinates in Talairach space were slightly displaced in an anterior direction, but in the mediolateral direction, they were right in the center of Heschl's gyrus in the superior temporal lobe. On average, the LEP source was 13 mm anterior, 6 mm superior, and 2 mm medial of the AEP source. This relative position also suggests a generator within the frontoparietal operculum overlying the insula.
Within the frontoparietal operculum, the N1 generator might be located in the upper bank of the Sylvian fissure that is facing the auditory cortex, at the outer surface of the operculum or at its inner vertical surface facing the insula. Source location alone was not precise enough to decide between these possibilities because the mean localization error of dipole source analysis in this region is 10 ± 5 mm (Cuffin et al. 2001a,b). Therefore we followed the approach used in source localization of epileptic foci (Scherg and Ebersole 1994) and evaluated the orientation of the equivalent dipole. Assuming that the recorded signal is generated by intracortical postsynaptic potentials elicited by specific thalamocortical input, the equivalent dipole should be perpendicular to the surface of that brain area that contains the generator (box 46–1 in Kandel et al. 2000). Its polarity should be positive at the cortical surface and negative inside the cortex. At the latency of the first GFP peak, the equivalent dipole of the LEP pointed inward, suggesting a generator within the inner vertical surface of the frontoparietal operculum.
A similar equivalent dipole orientation was also found in previous EEG source analysis studies, whereas MEG studies had suggested an orientation tangential to the scalp. This orientation was perpendicular to the Sylvian fissure and was hence interpreted as evidence for a source location in SII in the upper bank of the Sylvian fissure. The positivity of the equivalent MEG dipole, however, pointed upward (Kakigi et al. 1995; Ploner et al. 1999). This orientation is nearly identical to the one that we found for the AEP, and it would suggest a generator in the lower bank of the Sylvian fissure, i.e., within the temporal lobe. This discrepancy is due to the fact that the MEG is intrinsically incapable of recording dipoles with a radial orientation, perpendicular to the scalp, and only detected the small tangential component of the oblique equivalent dipole orientation (Hari et al. 1991). Thus the equivalent dipole orientations described by MEG recordings from human parasylvian cortex may be misleading for LEPs, although this method was successful in describing dipole locations and source potential waveforms in that area.
Previous LEP scalp mapping studies are fully consistent with the equivalent dipole source location and orientation reported here. Those studies had reported a maximal scalp negativity N1 at temporal electrode locations and a simultaneous positivity in the midline (García-Larrea et al. 1997; Kunde and Treede 1993; Miyazaki et al. 1994; Treede et al. 1988). According to the present source analysis, the midline positivity is the projection of the positivity at the cortical surface of the inner vertical surface of the frontoparietal operculum. The negativity at temporal electrodes is the projection of the negativity of deep cortical layers to the scalp.
Source analysis of subdural recordings provides information that is complementary to that from invasive recordings with depth electrodes. Depth recordings in parasylvian cortex are carried out through multi-contact wire electrodes stereotactically placed at nearly right angles to the convexity. They provide the third dimension that is missing in subdural grid recordings but have poor resolution in the other two dimensions as they are limited in the volume that can be explored (usually either to a few points reached by the electrode tip or to a few tracks when using multi-contact electrodes). Moreover, the orientation of the equivalent dipole cannot be determined from these depth recordings. In our study, source analysis of subdural LEPs accurately provided the missing third dimension (see comparison with depth recordings in Table 3). Thus source analysis of subdural LEPs may replace invasive recordings with depth electrodes because this technique provides three-dimensional information on both the location and orientation of the equivalent electrical dipoles. Compared with source analysis of scalp recordings, subdural recordings provide more precise information on the neural generators of evoked potentials because of the better signal-to-noise ratio and the simplified head model, since the intervening structures scalp, skull, dura, and CSF are absent.
Within the tactile areas of both SII and adjacent parietal ventral area PV, the face is represented superficially and the foot is represented deep along the Sylvian fissure (Disbrow et al. 2000; Krubitzer et al. 1995). Somatotopy in our study was assessed in one patient and showed that the hand representation was lateral, posterior, and inferior to that for face stimulation with an overall distance of 10 mm. When the results of previous LEP source analysis studies were transformed into Talairach coordinates, they also revealed a somatotopy, where the face area is anterior of the hand and foot areas (Table 3). This somatotopy suggests that the nociceptive area in human parasylvian cortex may be separate from the tactile areas SII and PV. This suggestion would be consistent with the small number of nociceptive neurons found in SII of old world monkeys (Robinson and Burton 1980) and the larger numbers in adjacent areas (Dong et al. 1994). In PET and fMRI studies, direct comparison of activation by heat pain and by tactile stimuli revealed partly overlapping but not identical foci in the SII region (Coghill et al. 1994; Gelnar et al. 1999; Chen et al. 2002).
A somatotopy, where the face is represented anteriorly and the foot is represented posteriorly along the circular sulcus of the insula has been reported for a presumed nociceptive area in the dorsal insula (Craig 1995). This region was suggested to be an interoceptive cortical area and was found to be activated in PET studies of heat pain, visceral pain, innocuous temperature stimuli, sensual touch, and itch (for review see Craig 2002). The same author suggested that the dorsal insula receives nociceptive specific input from lamina I of the spinal cord dorsal horn via the posterior part of the ventromedial nucleus (VMpo) of the thalamus (Craig et al. 1994). Other authors have proposed a nociceptive specific pathway from lamina I to the inner vertical surface of the frontoparietal operculum via the ventral posterior inferior (VPI) and posterior nucleus (POa) of the thalamus (Apkarian and Shi 1994; Stevens et al. 1993). The precise organization of spinothalamocortical pathways for pain sensation is a matter of ongoing debate (Craig and Blomqvist 2002; Jones 2002; Willis et al. 2002). It may be that this debate will turn out to be on nomenclature instead of topography (Treede 2002) because the locations of nociceptive neurons reported in the various studies were in a similar region, inferior and posterior of the principal somatosensory nucleus, where nociceptive neurons have also been found in the human thalamus (Lenz et al. 1993).
The roles of the cortical projection targets of these thalamic nuclei are the topic of a similar debate. The anterior insula (VMpo projection target) was the only area that was significantly more active during heat pain than during vibration in a PET study (Coghill et al. 1994), but lesions that led to a loss of pain sensitivity in patients had to encompass the operculum (VPI projection target) rather than the insula (Greenspan et al. 1999). When the locations of maximal cortical activation by heat pain are compared in PET or fMRI studies, there is a remarkable similarity in coordinates (given in Talairach space) although this location may be designated as "insula" in some and "SII" in other studies (e.g., Brooks et al. 2002; Chen et al. 2002). Again, this debate may be a matter of nomenclature instead of location because the projection target of VMpo extends from the dorsal insula into the adjacent frontoparietal operculum (Craig 1995) and SII extends from the inner vertical surface of the operculum onto the insula, particularly its anterior dysgranular part that receives input from VPI (Jones and Burton 1976).
An intriguing possibility emerging from these considerations suggests that the nociceptive area in human parasylvian cortex may encompass the dorsal insula and adjacent parts of the frontoparietal operculum (cf. Craig 2002), separate from the tactile SII area. Our findings are fully consistent with this concept. In addition, our data suggest that the opercular part of this cortical region receives the most rapid input from nociceptive pathways. This suggestion is supported by recent invasive recordings that found a latency difference of 50 ms between the operculum and the insula (Frot and Mauguière 2003).
In summary, multiple lines of evidence from electrophysiological and imaging studies in humans indicate that parasylvian cortex is prominently involved in the processing of nociceptive stimuli. Our data suggest that the inner vertical surface of the operculum is activated most rapidly, but evidence from other studies indicates that the nociceptive area in this region extends into the adjacent dorsal insula. The functions of this operculoinsular region are still a matter of debate and may involve sensory integration of tactile, nociceptive, and visual input, as well as spatially directed attention (Treede et al. 2000). The insula is also considered a visceral sensory and visceral motor area (Augustine 1996) and may thus serve a sensory integrative function for pain, taste, and other visceral sensations as well as tactile and vestibular input. Because of its projection to the amygdala, the insula may also be involved in affective and emotional processes and in sensory memory—particularly memory of previously experienced pain (Lenz et al. 1995). Detailed analysis of the interconnections of this nociceptive cortical network and particularly of its functional significance for human pain sensation remains a challenging task for the future.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests: R.-D. Treede, Institute of Physiology and Pathophysiology, Johannes Gutenberg-University, Saarstr. 21, D-55099 Mainz, Germany (E-mail: treede{at}uni-mainz.de).
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ABSTRACT
INTRODUCTION
) was 5 mm lateral, 7 mm posterior, and 5 mm inferior to that for face stimulation (