Evidence that the anterior cingulate and supplementary somatosensory cortices generate the pain-related negative difference potential

Clinical Neurophysiology 110 (1999) 2117±2126 www.elsevier.com/locate/clinph

Evidence that the anterior cingulate and supplementary somatosensory cortices generate the pain-related negative difference potential Robert Dowman*, Stephanie Schell Department of Psychology, Clarkson University, Potsdam, NY 13699-5825, USA Received 10 December 1998; received in revised form 29 March 1999; accepted 18 July 1999

Abstract Objective: The pain-related negative difference potential (NDP) is derived by subtracting sural nerve-evoked somatosensory evoked potentials elicited at the pain threshold level from those elicited at supra-pain threshold levels. This experiment evaluated a hypothesis derived from our earlier work, namely that the NDP is generated by pain-related activity in the primary somatosensory (SI) cortex. Methods: The dipole source localization method was applied to NDPs evoked by electrical stimulation of the ®nger and of the sural nerve in 20 subjects. Results: Comparison of several one-, two- and three-source con®gurations demonstrated that both the ®nger-evoked NDP and the sural nerve-evoked NDP are best-®t by two sources, with one located in or near the anterior cingulate cortex and the other in or near the supplementary somatosensory area. Conclusions: Both the anterior cingulate cortex and the supplementary somatosensory area receive afferent projections from medial thalamic nuclei that receive nociceptive inputs, and both have been shown to respond to noxious stimulation. Hence, although the results of this experiment did not con®rm our hypothesis that the NDP is generated in SI, they are consistent with the hypothesis that the NDP is generated in the supraspinal pain pathways. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Somatosensory evoked potentials; Pain; Anterior cingulate cortex; Supplementary somatosensory area

1. Introduction We have been exploring the possibility of using the sural nerve-evoked somatosensory evoked potential (SEP) to measure pain-related cortical activity in humans. One of the advantages of the sural nerve evoking stimulus is that it elicits a spinal nociceptive withdrawal re¯ex that has proven very useful in the study of the spinal pain pathways (e.g., Kiernan et al., 1995; Garcia-Larrea and Mauguiere, 1990; Willer, 1985; Willer et al., 1979, 1989). If our work is successful, it could lead to a non-invasive strategy for simultaneously measuring the excitability and integrity of both the spinal and supraspinal pain pathways. The disadvantage of the painful sural nerve evoking stimulus is that it also elicits a signi®cant amount of activity in the innocuous somatosensory pathways, which makes it dif®cult to distinguish the innocuous-related SEP components from the painrelated components (Dowman, 1996b). We have attempted to circumvent this problem by employing a subtraction procedure that has been used with some success in regional * Corresponding author. Tel.: 11-315-268-3836. E-mail address: [email protected] (R. Dowman)

cerebral blood ¯ow studies of pain (see Jones and Derbyshire, 1995). The electrical properties of the sural nerve peripheral afferents are such that activity in the innocuous Ab peripheral afferents, and presumably the central innocuous somatosensory pathways to which they project, should saturate at about the subjective pain threshold. That is, the peripheral afferents' electrical thresholds are inversely proportional to axon diameter (Raymond and Gissen, 1987), the innocuous Ab afferents are for the most part larger than the nociceptive Ad afferents (Martin and Jessel, 1991; Perl, 1984), and subjective pain threshold tends to be somewhat higher than the threshold of the nociceptive Ad afferents (Greenspan and McGillis, 1991). Therefore, subtracting SEPs evoked at the pain threshold level from those evoked at supra-pain threshold levels should, at least in theory, largely eliminate scalp potentials generated by activity in the innocuous somatosensory pathways. Evidence to date suggests that the initial negative peak in the difference SEP (approximately 75±240 ms post-stimulus), which we have labeled the negative difference potential (NDP), does in fact re¯ect activity in the supraspinal pain pathways. That is, NDP amplitude increases with increasing noxious stimulus intensity, and changes in NDP peak

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CLINPH 98175

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latency produced by stimulation at different points along the sural nerve demonstrate that the peripheral afferents giving rise to the NDP have conduction velocities in the Ad range (Dowman, 1996b). We have also shown that, like subjective pain ratings, NDP amplitude is unaffected by changes in inter-stimulus interval (ISI) (Dowman, 1996b). This is not the case with the late pain-related positive peak the unsubtracted SEP that has been the focus of most pain-related SEP work, where it has been shown that the amplitude of this peak but not pain ratings decrease with decreasing ISI (Dowman, 1996a; Chapman et al., 1981). The subtraction procedure assumes that there are no interactions between the innocuous-related and pain-related cortical activities. These possible interactions are important, as they could lead to erroneous conclusions about whether or not the NDP is generated by activity in the pain pathways. Indeed, our initial analysis of the NDP and studies by others examining the effect of heat pain on vibrotactile sensitivity suggested that the NDP might represent a pain-related inhibition of neurons that are involved in the innocuous aspects of somatosensation (Dowman, 1996b). We have recently completed several studies that strongly suggest that this is not the case (Dowman, 1999; Dowman and Schell, 1999a; Dowman and Zimmer, 1996]. Hence, our current working hypothesis is that the NDP is generated by activity in the supraspinal pain pathways. Our dipole source localization analysis of the NDP (Dowman, 1996b) has shown that it can be ®t very well by a single source located in the same general location as that for the P40 peak of the unsubtracted sural nerve-evoked SEP. Since the P40 peak is generated in the primary somatosensory cortex (SI) foot area (Allison et al., 1996; Emerson 1988), it is reasonable to hypothesize that the NDP is likewise generated in or near the SI foot area. If this is the case, the NDP could become a valuable tool for studying the role of SI in pain in humans, and could provide a relatively simple non-invasive means of assessing the integrity of the cortical pain pathways. The objective of the present experiment, therefore, was to verify that the NDP is generated in SI and not some other somatosensory-receptive area located near the SI foot area, such as the supplementary motor area (Coghill et al., 1994; Wiesendanger, 1986). If this is the case, then the NDP topographic pattern evoked by electrical stimulation of the ®ngers should be best-®t by a single source located in the SI hand area. 2. Methods The NDP reported here was recorded during the same experiment described in the companion paper (Dowman and Schell, 1999b), where the neural generators of two innocuous-related components of the unsubtracted ®ngerevoked and sural nerve-evoked SEPs were determined. Descriptions of the 20 subjects, the ®nger and sural nerve evoking stimuli locations and parameters, the recording

electrode locations and parameters, and the procedure can be found in the companion paper. The description here will focus on the methods used to derive and analyze the difference SEP. 2.1. Data analysis The difference potential was derived by subtracting SEPs evoked at the pain threshold level (stimulus level 2) from SEPs evoked at supra-pain threshold levels (levels 3 and 4). (Stimulus level 1 was non-painful, and will not, therefore, be considered here.) Prior to subtraction, individual subject SEPs were digitally ®ltered (¯at between 2 and 30 Hz and down 12 dB per octave), and the DC offsets were corrected by subtracting the mean amplitude of the time points that followed the stimulus artifact and preceded the initial SEP peak from every time point in the waveform. The analysis in this report focuses on stable periods in the NDP scalp topography, where a stable period refers to consecutive time points having the same topographic pattern. Stable periods were determined from the grand average normalized difference SEPs, as described in the companion paper (Dowman and Schell, 1999b). The NDP topographies were separated into stable periods using the visual and statistical criteria we have established in our earlier work (Dowman 1994, 1996a; Dowman and Schell, 1999b). NDP amplitudes were measured from the minimum location in the topography (Cz 0 ) and were averaged across the stable period epoch that encompassed the NDP peak. Changes in NDP amplitude were evaluated by a Greenhouse±Geisser-corrected repeated measures ANOVA. In reporting signi®cance levels the uncorrected degrees of freedom are given along with the epsilon (e ) values used to adjust the degrees of freedom in determining the signi®cance level. The dipole source localization analysis involved a 3-shell sphere, spatiotemporal model applied throughout the stable period corresponding to the NDP peak (see Dowman and Schell, 1999b). The ®rst step in this analysis involved testing the single source hypotheses described in Section 1, namely that the NDP evoked by a 5-pulse stimulus train applied to the ®ngers would be best-®t by a single source located in the SI hand area, and that the 5-pulse sural nerveevoked NDP would be best-®t by a single source located in the SI foot area. The location coordinates for the SI hand and foot areas were determined from SEPs evoked by 500 innocuous single-pulse stimulations of the ®nger and sural nerve recorded in separate counterbalanced blocks at the end of the recording session. Coordinates for the SI hand area were de®ned as the location of the best-®t single source for the P30±N30 peaks in the single-pulse ®nger SEP, and the coordinates for the SI foot area were de®ned as the location of the best-®t single source for the P40 peak in the single-pulse sural nerve SEP (see (Dowman and Schell, 1999b) for a justi®cation of this approach). The source analysis was performed on the grand average normalized

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Fig. 1. Upper panel: Grand average sural nerve-evoked difference potentials recorded from Cz 0 (2-cm posterior to the Cz position of the International 10-20 System (Sharbrough et al., 1991)) and elicited at the two supra-pain threshold stimulus levels. Bottom panels: Grand average normalized sural nerve-evoked NDP stable period topographies obtained at the supra-pain threshold stimulus levels. The onset and offset latencies of each stable period are given above its topography. The amplitude and dipole source localization analysis focused on the stable period encompassing the ®rst negative peak in the NDP (i.e. the 85± 121 ms and the 85±117 ms epochs in the levels 3 and 4 topographies, respectively). The small solid circles identify recording electrode locations. Cz 0 is the third electrode from the bottom along the sagittal midline. The inter-electrode distance along the sagittal and coronal axes is 5 cm.

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Table 1 Best-®t single source solutions for the sural nerve NDP, the ®nger NDP, and the single-pulse sural nerve-evoked P40 peak (i.e. SI foot area) a Magnitude (a±m £ 10 26)

Location (cm)

Sural nerve P40 (SI foot area) Sural nerve NDP Finger NDP

Fit

X

Y

Z

X

Y

Z

r2

2.1 2.6 3.8

1.0 1.0 1.7

10.7 10.8 11.4

20.005 0.004 0.001

20.005 0.002 20.001

0.011 20.004 20.006

0.99 0.90 0.57

a

The X and Y axes of the location and magnitude (moment) coordinate systems run through the nasion (1X) and left (1Y) and right (2Y) preauricular points. The Z axis runs through the top of the head (1Z). The NDP source solutions were obtained at stimulus level 4.

difference topographies rather than individual subject topographies, given the critical importance of the signal-to-noise ratio on the accuracy of the source solutions (Fender, 1987). 3. Results The sural nerve difference SEP is shown in Fig. 1. The initial negative potential, that is, the NDP, is characterized by two peaks, as we have noted earlier (Dowman, 1996b). As in Dowman (1996b), the analysis here will focus on the ®rst peak. The sural nerve NDP is characterized by a central negativity (the 85±121 ms and 85±117 ms epochs in the stimulus levels 3 and 4 topographies, respectively, shown in Fig. 1) whose best-®t single source is located near the SI foot area (Table 1). The sural nerve NDP amplitude (as measured across the 85±117 ms interval across all levels and subjects) increased with increasing painful stimulus intensity (Fig. 1 and Table 2), as we have shown in previous work (Dowman, 1996b). The ®nger difference SEP recorded from Cz 0 is very similar to the sural nerve difference SEP waveform (c.f. Figs. 1 and 2). Note that the offset of the ®nger NDP (about 150 ms) was considerably earlier than that for the sural nerve NDP (about 240 ms). This likely re¯ects less dispersion of activity in the nociceptive Ad peripheral afferents and central pain pathways over the shorter distance between the ®nger and cortex. The earlier peak latency of the ®nger NDP (77 ms at level 4) as compared to the sural nerve NDP (101 ms at level 4) likewise re¯ects the shorter ®nger to cortex conduction distance. The topographic patterns present throughout the ®nger NDP epoch are shown in Fig. 3. The initial segment of the ®nger NDP (the 61±73 ms and 57±65 ms epochs in the stimulus levels 3 and 4 topographies, respectively, shown in Fig. 3) is characterized by a negativity over the contralateral frontal region and a positivity over the contralateral

temporal region. Unfortunately, the signal-to-noise ratios for these topographies were too low to permit a meaningful dipole source localization analysis. This topographic pattern evolved into the central negativity and the parietal and ipsilateral frontal positivities characteristic of the stable period surrounding the ®nger NDP peak (the 89±109 ms and 85± 113 ms epochs for the stimulus levels 3 and 4 topographies, respectively, shown in Fig. 3). This pattern then gradually (the 113±133 ms and 117±133 ms epochs for the levels 3 and 4 topographies, respectively, shown in Fig. 3) evolved

Table 2 Finger and sural nerve NDP amplitudes

Sural NDP Finger NDP

Level 3 (xÅ)

Level 4 (xÅ)

t(19)

P

21.27 21.63

23.89 22.17

3.96 0.56

,0.001 .0.10

Fig. 2. Grand average ®nger-evoked somatosensory evoked potentials recorded from Cz 0 (2-cm posterior to the Cz position of the International 10-20 System (Sharbrough et al., 1991) and an electrode 10 cm ipsilateral and 10 cm anterior to Cz 0 (IFP, i.e. the site of the ipsilateral frontal positivity shown in Fig. 3) at the supra-pain threshold levels.

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Fig. 3. Grand average normalized ®nger-evoked NDP stable period topographies obtained at the two supra-pain threshold stimulus levels. The onset and offset latencies of each stable period are given above its topography. The amplitude and source localization analysis focused on the stable period encompassing the negative peak in the NDP (i.e. the 89±109 ms epoch and the 85±113 ms epoch in the levels 3 and 4 topographies, respectively). The small solid circles identify recording electrode locations. Cz 0 (i.e. 2-cm posterior to the Cz position of the International 10-20 System (Sharbrough et al., 1991) is the third electrode from the bottom along the sagittal midline. The inter-electrode distance along the sagittal and coronal axes is 5 cm.

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Table 3 Start

Result Magnitude (a±m £ 10 26)

Location (cm) X

Y

Z

Fit

X

Y

Z

r2

(A) Best-®t two-source solutions for the ®nger NDP a SI HAND 20.7 0.9 ACC 5.7 1.0

9.3 4.7

20.12 0.015

0.001 20.003

20.009 0.004

0.95

SI HAND SMA

20.3 3.9

0.6 0.3

9.1 6.2

20.017 0.018

0.001 20.002

20.011 0.006

0.95

SMA ACC

20.3 4.6

0.6 0.2

9.1 6.0

20.015 0.016

0.001 20.002

20.010 0.006

0.95

SII (CLT) SII (IPL)

20.6 6.5

0.8 0.5

9.1 3.3

20.012 0.016

0.000 20.002

20.010 0.007

0.95

IPC (CLT) IPC (IPL)

21.6 4.6

0.7 20.2

9.6 5.6

20.012 0.014

0.000 20.002

20.007 0.001

0.94

0.6 0.2

11.7 5.0

0.001 0.004

0.001 0.002

20.004 0.000

0.95

(B) Result of a two-source hypothesis b AMP 1.6 ACC 5.0

a Start refers to the approximate starting location of the sources, and Result refers to the best-®t solution resulting from those starting locations. The X and Y axes of the location and magnitude (moment) coordinate systems run through the nasion (1X) and left (1Y) and right (2Y) preauricular points. The Z axis runs through the top of the head (1Z). Abbreviations: ACC, anterior cingulate cortex; IPC, inferior parietal cortex; SI hand, SI hand area; SII, second somatosensory/insular cortical areas; SMA, supplementary motor area; CLT, contralateral; IPL, ipsilateral. The source solutions were derived from the NDP topographies evoked at stimulus level 4. b With starting locations in anterior mesial parietal cortex (AMP, X ˆ 20:3 Y ˆ 0:6 Z ˆ 9:1) and anterior cingulate cortex (ACC: X ˆ 5:0 Y ˆ 0:2 Z ˆ 5:0), applied to the sural nerve NDP topography evoked at stimulus level 4.

into a pattern consisting of bilateral fronto-temporal negativities (the 137 ms and 137±145 ms epochs for the levels 3 and 4 topographies, respectively, shown in Fig. 3). Although there was a trend for the ®nger NDP amplitude (as measured over the 89±109 ms interval across levels and subjects) to increase with increasing painful stimulus intensity, it was not statistically signi®cant (Table 2). This was likely due to there not having been a large enough difference between the levels 3 and 4 evoking stimulus currents. Computing a 95% con®dence interval for the level 4 ®nger NDP amplitude demonstrated that it was signi®cantly different from zero. Hence, the ®nger NDP amplitude does appear to increase with increasing painful stimulus intensity. Unlike the sural nerve NDP, the ®nger NDP could not be adequately ®t by a single source (see Table 1). This led to an evaluation of multiple source hypotheses for the ®nger NDP. The procedure used in this analysis was similar to that outlined in Dowman and Darcey (1994). That is, the source starting locations approximated brain areas that are known to be activated by noxious stimuli (see Derbyshire et al., 1997; Dong and Chudler, 1995; Kenshalo and Willis, 1991 for reviews). The areas of interest included the SI hand area, the second somatosensory/insular areas (i.e. the region

of the fronto-parietal operculum), the inferior parietal cortex, and the anterior cingulate cortex. We also included the supplementary motor area given it has been shown to be activated by painful stimuli in at least one regional cerebral blood ¯ow study (Coghill et al., 1994), and because of its close proximity to the SI foot area. The location and moment parameters of the sources were then allowed to change in directions that minimized the difference between the modeled and measured topographies. If a given hypothesis is correct, then the sources should remain at or near their starting locations. If one hypothesis is clearly better than the others, then all of the starting hypotheses should converge upon the same source con®guration. If a number of different hypotheses ®t the measured topography equally well, then there will not be any convergence towards a single solution. All of the two-source hypotheses converged onto a similar solution (see Table 3A), with one source located in the anterior mesial parietal cortex approximately 2.5 cm posterior to the SI foot area (see Table 1) and the other located deep in the mesial frontal cortex, about 3.0 cm anterior and 5.6 cm inferior to the SI foot area (see Fig. 4). Note that this two-source solution provided a much better ®t for the ®nger

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Fig. 4. Best-®t two-source solutions for the ®nger-evoked (upper panel) and sural nerve-evoked NDP (lower panel). Superimposed on the two-source solution is the best-®t single source for the P40 peak of the single pulse SEP (i.e. the SI foot area). The location and moment parameters for the ®nger-evoked NDP sources were the average the four two-source solutions shown in Table 3A that resulted in ®ts of 0.95. The location and moment parameters for the SI foot area source can be found in Table 1, and those for the best-®t two-source solution for the sural nerve NDP can be found in Table 3B. The circles identify the source location and the lines identify the source orientation, where the line is pointing towards the positive end of the dipole.

NDP topography (r 2 ˆ 0:95) than the one-source solution (r 2 ˆ 0:57; see Table 1). We also examined a number of 3source hypotheses that involved combinations of the same starting locations used in the two-source analysis (Table 4). These resulted in either poorer ®ts than the anterior mesial parietal ± deep mesial frontal hypothesis (r 2 ranging between 0.90 and 0.94), or, as in four cases (the SI/ACC/ SMA; ACC/IPC(CLT)/IPC(IPL); SMA/IPC(CLT)/ IPC(IPL); and SI/IPC(CLT)/IPC(IPL) starting locations shown in Table 4), the solution essentially resolved into that derived from the two-source analysis. That is, two of the sources ended up in or near the anterior mesial parietal and deep mesial frontal cortices and the third source ended up with a negligible magnitude (i.e. approximately onetenth that of the other two). The ®nger NDP source analysis raises the possibility that two midline sources will provide a better ®t for the sural nerve NDP than the one-source hypothesis. As Table 3B demonstrates, this is indeed the case. Hence, two midline sources, one located in the anterior parietal cortex just

posterior to the SI foot area and another located in the deep frontal cortex provides an excellent ®t for both the sural nerve and ®nger NDP scalp topographies (see Fig. 4). Note, however, that the anterior mesial parietal source for the sural nerve NDP is about 2 cm more anterior than that for the ®nger NDP. 4. Discussion The ®nger-evoked and sural nerve-evoked difference SEPs exhibited similar waveforms at the Cz 0 recording site, and the initial negative peak in these difference SEPs, i.e. the NDP, both increased with increasing painful stimulus intensity. There were, however, some important differences in the ®nger-evoked and sural nerve-evoked NDP topographic patterns. As we have shown elsewhere (Dowman 1996b), the sural nerve NDP was characterized by a central negativity that persisted throughout most of its epoch. The early time points in the ®nger NDP topography,

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Table 4 Best-®t three-source solutions for the ®nger NDP a Start

Result Location (cm) X

Magnitude (a±m £ 10 26)

Fit

Y

Z

X

Y

Z

r2

SI HAND SII (CLT) SII (IPL)

0.2 3.6 3.2

0.8 3.3 20.2

9.3 5.0 5.5

20.012 0.008 0.007

0.002 20.009 0.006

20.013 0.000 0.006

0.94

SMA SII (CLT) SII (IPL)

0.7 2.0 2.0

0.2 3.6 23.0

9.0 5.0 5.0

20.009 0.004 0.006

0.002 20.013 0.010

20.017 0.001 0.006

0.90

ACC SII (CLT) SII (IPL)

0.5 20.7 2.0

0.0 1.2 25.0

6.0 5.5 4.0

0.026 20.019 20.003

0.001 0.002 20.003

20.012 0.002 0.005

0.90

SI HAND ACC SMA

2.8 4.9 20.2

3.4 0.0 0.6

9.3 4.0 8.5

0.002 0.017 20.017

20.002 20.002 0.003

0.000 0.011 20.013

0.96

ACC IPC (CLT) IPC (IPL)

5.0 20.7

0.3 6.3

3.8 8.2

0.017 20.002

20.001 20.001

0.010 0.000

0.96

20.4

0.3

8.9

20.012

0.001

20.012

5.4 20.5

0.2 6.8

3.6 8.0

0.016 20.002

20.001 20.001

0.008 0.000

20.7

0.3

9.2

20.011

0.000

20.010

4.3 21.9

0.1 4.6

5.5 6.8

0.017 20.003

20.002 0.000

0.006 0.000

20.4

20.1

9.0

20.013

0.000

20.009

SMA IPC (CLT) IPC (IPL) SI HAND IPC (CLT) IPC (IPL)

0.96

0.95

a

Start refers to the approximate starting location of the sources, and Result refers to the best-®t solution resulting from those starting locations. The X and Y axes of the location and magnitude (moment) coordinate systems run through the nasion (1X) and left (1Y) and right (2Y) preauricular points. The Z axis runs through the top of the head (1Z). Abbreviations: ACC, anterior cingulate cortex; IPC, inferior parietal cortex; SI hand, SI hand area; SII, second somatosensory/insular cortical areas; SMA, supplementary motor area; CLT, contralateral; IPL, ipsilateral. The source solutions were derived from the NDP topographies evoked at stimulus level 4.

on the other hand, exhibited a relatively small contralateral frontal negativity and a contralateral temporal positivity. This topographic pattern suggests the possible involvement of SI in the generation of the NDP. Unfortunately, the poor signal-to-noise ratio of this topography precluded the use of the source analysis to quantitatively evaluate this hypothesis. It is interesting, however, that the relatively small contribution of SI to the pain-related NDP suggested by the topographic analysis is consistent with animal studies showing that only a small percentage of cells in SI respond to nociceptive stimulation (Kenshalo and Willis, 1991). Like the sural nerve-evoked NDP, the topographic pattern encompassing the ®nger-evoked NDP peak was character-

ized by a central negativity. However, unlike the sural nerve NDP, this topographic pattern could not be ®t by a single source. Evaluation of several two- and three-source hypotheses revealed a two-source con®guration that clearly resulted in a best-®t for the ®nger NDP. This con®guration consisted of one source located deep in the mesial frontal cortex and another in the anterior mesial parietal cortex just posterior to the SI foot area. This two-source hypothesis also resulted in a better ®t for the sural nerve NDP than a single source located in SI (r2 ˆ 0:95 vs. r 2 ˆ 0:90, respectively). The anterior mesial parietal source for the sural nerve NDP was about 2 cm more anterior than that for the ®nger NDP. The closer spacing between the anterior mesial parietal and deep mesial frontal sources in the sural nerve NDP explains, at least in part, why a single source can account for the sural nerve NDP but not the ®nger NDP. We have been reluctant to add more sources to the model when a single-source hypothesis accounts for a substantial amount of variability in the measured topography (r 2 $ 0:90; see Dowman, 1996a; Dowman and Darcey, 1994), as adding a source will often improve the ®t regardless of its physiological validity (Fender, 1987). In this study, however, applying the source analysis to NDP topographies evoked by stimulation of the ®nger and sural nerve clearly demonstrated the inadequacy of the single-source hypothesis. A possible candidate for the deep mesial frontal cortex NDP source is the anterior cingulate cortex. Several lines of evidence make it reasonable to expect that the anterior cingulate would be activated by painful sural nerve and ®nger stimulation. The anterior cingulate has been shown to receive nociceptive inputs via the medial and intralaminar thalamic nuclei (Vogt et al., 1993). Neurophysiological studies in animals have revealed neurons located in the anterior cingulate that respond to nociceptive stimulation (Sikes and Vogt, 1992), and regional cerebral blood ¯ow studies in humans have consistently shown activation of the anterior cingulate during painful stimulation (e.g. Davis et al., 1997; Vogt et al., 1996; Casey et al., 1994; Coghill et al., 1994]. Interestingly, the region within the anterior cingulate that is activated by painful stimuli differs from that which is activated during non-pain-related cognitive tasks (Derbyshire et al., 1998; Davis et al., 1997), which argues against the idea that the pain-evoked anterior cingulate response merely re¯ects the anterior cingulate's involvement in non-speci®c cognitive (e.g. attending to important stimuli in the environment) and/or motivational processes. Finally, surgical resection of the anterior cingulate has been shown to have a profound impact on the pain experience (see Vogt et al., 1993 for review). That is, although the patients can readily localize and detect pain, it no longer bothers them. It is unlikely that the motor areas lying within the cingulate sulcus contribute to the NDP. The topographic organization of the cingulate motor areas is such that the leg areas are located roughly inferior to the leg area representation of the supplementary motor area (Dum and Strick, 1993), which is

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considerably more posterior than the frontal NDP source obtained here. The second putative source generating the NDP is located in the anterior mesial parietal cortex. There is one area within the mesial parietal cortex, the supplementary somatosensory area, whose physiological properties appear to be similar to the pain-related NDP's mesial parietal source. The supplementary somatosensory area lies within Brodmann's areas 5 and/or 7 (Murray and Coulter, 1981), and appears to correspond to the PE area in the monkey (Schmahmann and Pandya, 1990). This region receives inputs from medial thalamic nuclei that respond to nociceptive stimulation (Schmahmann and Pandya, 1990) and some of the cells in the supplementary somatosensory area have been shown to respond to noxious stimulation (Murray and Coulter, 1981). Woolsey et al. (1979) reported an interesting case of a patient with phantom foot pain that was exacerbated by stimulation of the supplementary somatosensory area and that was alleviated by its surgical resection. The supplementary somatosensory area is somatotopically organized, where the forelimb representation is caudal to that for the hindlimb (Murray and Coulter, 1981; Woolsey et al., 1979). This organization could account for the more posterior location of the mesial parietal source for the ®nger NDP as compared to the sural nerve NDP. Thus, the supplementary somatosensory area appears to be a reasonable candidate for one of the NDP sources. In sum, the brain areas that produced the best-®t for the ®nger-evoked and the sural nerve-evoked NDP topographies have pain-related properties, and hence are consistent with our hypothesis that the NDP is generated by activity in the supraspinal pain pathways. The anterior cingulate, which has received considerable attention in recent years, appears to play a role in the affective/motivational aspect of pain (see Vogt et al. (1993) for review). Relatively little is known, however, about the role of the supplementary somatosensory area in pain. Although our NDP studies and the small number of physiological, anatomical, and clinical studies reviewed above suggest that the supplementary somatosensory area is involved in pain, more work is needed to clarify exactly what, if any, its role might be. One of the issues that needs resolution is the apparent failure of regional cerebral blood ¯ow studies to detect any painrelated activation of the mesial parietal cortex (see Derbyshire et al. (1997) for a recent review). Rather, the only painrelated change in blood ¯ow reported in this area was a decrease observed by Vogt et al. (1996). At this point we can only speculate as to the reasons for the discrepancy between the regional cerebral blood ¯ow studies and our source analysis of the NDP. Clearly, our source analysis could be incorrect. As noted earlier, the source analysis is very useful in comparing different source con®guration hypotheses, however, it does not guarantee that the best-®t con®guration is the true source con®guration. Alternatively, the activation of the supplementary somatosensory area may have been below the level of resolution of the PET and

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