Differential Coding of Pain Intensity in the Human Primary and Secondary Somatosensory Cortex

Lars Timmermann,1 Markus Ploner,1 Katrin Haucke,2 Frank Schmitz,1 Rüdiger Baltissen,2 and Alfons Schnitzler1

 1Department of Neurology, Heinrich-Heine-University, 40225 Dusseldorf; and  2Department of Psychology, University of Wuppertal, 42119 Wuppertal, Germany


    ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Timmermann, Lars, Markus Ploner, Katrin Haucke, Frank Schmitz, Rüdiger Baltissen, and Alfons Schnitzler. Differential Coding of Pain Intensity in the Human Primary and Secondary Somatosensory Cortex. J. Neurophysiol. 86: 1499-1503, 2001. The primary (SI) and secondary (SII) somatosensory cortices have been shown to participate in human pain processing. However, in humans it is unclear how SI and SII contribute to the encoding of nociceptive stimulus intensity. Using magnetoencephalography (MEG) we recorded responses in SI and SII in eight healthy humans to four different intensities of selectively nociceptive laser stimuli delivered to the dorsum of the right hand. Subjects' pain ratings correlated highly with the applied stimulus intensity. Activation of contralateral SI and bilateral SII showed a significant positive correlation with stimulus intensity. However, the type of dependence on stimulus intensity was different for SI and SII. The relation between SI activity and stimulus intensity resembled an exponential function and matched closely the subjects' pain ratings. In contrast, SII activity showed an S-shaped function with a sharp increase in amplitude only at a stimulus intensity well above pain threshold. The activation pattern of SI suggests participation of SI in the discriminative perception of pain intensity. In contrast, the all-or-none-like activation pattern of SII points against a significant contribution of SII to the sensory-discriminative aspects of pain perception. Instead, SII may subserve recognition of the noxious nature and attention toward painful stimuli.


    INTRODUCTION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The ability to differentiate intensities of painful stimuli is one of the major properties of the nociceptive system to be classified as a separate sensory modality. In primates, different intensities of nociceptive stimuli are encoded from peripheral nociceptors up to cortical nociceptive neurons (Doubell et al. 1999; Kenshalo and Willis 1991; Raja et al. 1999). In the monkey primary somatosensory cortex (SI) nociceptive neurons respond to both tactile and nociceptive stimuli and faithfully encode the perception of stimulus intensity (Kenshalo et al. 1989, 2000). Therefore SI is attributed to play a role in the sensory-discriminative aspects of pain processing (Kenshalo and Willis 1991; Schnitzler and Ploner 2000). In contrast, in primate area 7b, as a functionally and anatomically related part of the secondary somatosensory cortex (SII) (Whitsel et al. 1969), nociceptive neurons show complex response characteristics (Robinson and Burton 1980). Activity of these neurons reflects poorly if at all the intensity of nociceptive stimuli (Dong et al. 1989, 1994) and points toward an involvement of SII in recognition, learning, and memory of painful events (Dong et al. 1994; Lenz et al. 1997; Schnitzler and Ploner 2000).

In humans, functional brain imaging (Casey et al. 1996; Coghill et al. 1994; Craig et al. 1996; Talbot et al. 1991) and magnetoencephalography (MEG) studies (Kakigi et al. 1999; Ploner et al. 1999b, 2000) demonstrated that peripheral nociceptive stimuli activate SI and SII. Functional imaging studies, focusing on the intensity coding of nociceptive stimuli in humans, found high correlation between pain ratings/stimulus intensity and activity in contralateral SI (Coghill et al. 1999; Derbyshire et al. 1997; Porro et al. 1998) and bilateral SII (Coghill et al. 1999). However, probably due to the indirect measurement of neuronal activation and the limited time resolution of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), these studies did not support the different neurophysiological properties of nociceptive neurons in SI and SII as revealed from nonhuman primates. Thus it remains currently in dispute whether human SI and SII subserve specific and different functions in the processing of nociceptive stimuli.

We therefore used whole-head MEG to record cortical responses within the human SI and SII to different intensities of selectively nociceptive laser stimuli (Bromm and Treede 1984). Our findings provide evidence for a differential coding of nociceptive stimuli in human SI and SII.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Experiments were performed on eight healthy male volunteers (age: mean 28.3 yr, range 26-33 yr) who were experienced in pain experiments. All subjects gave written informed consent prior to the experiments. The study was approved by the local ethics committee and is in accordance with the Declaration of Helsinki.

Stimulation

One hundred sixty selectively nociceptive laser stimuli (Bromm and Treede 1984) of four different intensities (150, 300, 450, and 600 mJ) were pseudorandomly applied to the dorsum of the right hand using a Thulium:YAG laser (Baasel Lasertech) with a wavelength of 2000 nm. Pulse duration was 1 ms, stimuli were spots of 6-mm diameter, and the interstimulus interval was randomly varied between 10 and 14 s. After each stimulus the stimulation site was slightly changed within an area of 40 × 40 mm to avoid tissue damage. In all subjects, pain threshold determined by the method of limits ranged between 200 and 300 mJ.

Rating

Before the measurement started a standardized instruction was given for the rating of the applied nociceptive stimuli: the phenomena of first and second pain were described to the subjects. Subjects were instructed to rate the initial, "pin-prick" like, first pain on a rating scale from 0-100. Zero was defined as "no pain" and 100 was defined as the "worst imaginable pain." Subjects were instructed to rate each nociceptive stimulus after a tone signal that followed 3 s after each laser stimulus. To familiarize volunteers with the experimental setup and the rating procedure, a set of 20 stimuli was applied before MEG recordings started.

Data acquisition and analysis

Cortical activity was recorded with a Neuromag-122 whole-head neuromagnetometer (Ahonen et al. 1993) in a magnetically shielded room. The helmet-shaped sensor array contains 122 planar SQUID gradiometers that detect the largest signals just above the local cortical current sources. The sample rate was 483 Hz, and signals were band-pass filtered between 0.03 and 160 Hz. The vertical electrooculogram was recorded, and epochs contaminated with blink artifacts were excluded. The MEG data were averaged time-locked to the laser stimuli separately for each of the four stimulus intensities. Data analysis focused on a period comprising 100 ms prestimulus baseline and 300 ms after stimulation. During this time period, cortical responses are adequately explained by sources in contralateral SI and bilateral SII (Ploner et al. 1999b, 2000). Sources of responses were modeled as equivalent current dipoles identified during clearly dipolar field patterns. Only sources accounting for more than 85% of the local field variance (goodness-of-fit) and with at least 95% confidence limits of source localization were accepted. Dipole location and orientation were calculated within a spherical conductor model of each subject's head, determined from the individual high-resolution MRIs acquired on a 1.5 T Siemens Magnetom. The MRI and MEG coordinate systems were aligned based on fiducial point markers, and sources were superposed on individual MRI scans.

Dipoles were introduced into a spatiotemporal source model where locations and orientations were fixed and source strengths were allowed to vary over time (for further details see Hämäläinen et al. 1993). The dipole model determined from responses to highest stimulus intensity was applied to evoked responses of all four stimulation intensities. Peak amplitudes of SI and SII sources were determined at all intensities. When no obvious responses were discernible in the low stimulus intensity condition, maximum amplitudes were accepted in a time window of ±60 ms with respect to the peak amplitude of the highest stimulus intensity.


    RESULTS
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INTRODUCTION
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DISCUSSION
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Laser stimuli above 250 mJ consistently evoked "pin-prick-like" painful sensations. In all subjects, increased intensities of laser stimulation were rated with higher mean pain scores. This resulted in a significant correlation between stimulus intensity and pain rating (r = 0.84, P < 0.001, Spearman-rho).

As described previously (Ploner et al. 1999b), nociceptive laser stimuli evoked almost simultaneous activation of contralateral SI and SII (Fig. 1). In general, source strengths in both areas were higher with higher stimulation intensities (Figs. 1 and 2). Consistently, in contralateral SI (r = 0.76), contralateral SII (r = 0.79), and ipsilateral SII (r = 0.64) this resulted in a highly significant correlation between stimulus intensity and source amplitudes (P < 0.001). The previously described parallel activation pattern of SI and SII was not grossly altered at lower stimulus intensities.



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Fig. 1. A: source activations in contralateral primary somatosensory cortex (SI) and bilateral secondary somatosensory cortex (SII) at different stimulus intensities in a single subject. Note that SI activity increases monotonically with stimulus intensity. In contrast, subthreshold (150 mJ) and threshold (300 mJ) intensities did not evoke clear contra- or ipsilateral SII activations, whereas stimulation at 450 mJ elicits strong activation that increased very little at 600 mJ (SI contra, contralateral SI; SII contra, contralateral SII; SII ipsi, ipsilateral SII). B: localization of the contralateral SI source and bilateral SII sources on high-resolution magnetic resonance imaging (MRI) scans (left: axial slice at the level of SI; middle: axial slice at the level of SII; right: coronal slice at the level of SII).



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Fig. 2. Source peak amplitudes and pain rating as a function of stimulus intensity. Shown are group means (n = 8); error bars indicate standard error (SE). Using the polynomal function f(x) = b0 + (b1 * x) + (b2 * x2) + (b3 * x3) curves were fitted on the stimulus response functions. A: amplitudes of contralateral SI activity (black line, left scale) match precisely the subjects' pain ratings (gray line, right scale). Both stimulus response functions are fitted by an exponential curve. B: the amplitude of contralateral SII activity (black line, left scale) and pain ratings of the subjects (gray, scale on the right) dissociate at 450 mJ: the increase in contralateral SII activity is stronger than the increase in pain ratings, and the curve fitted on the stimulus response function of SII is S-shaped. C: amplitudes of ipsilateral SII sources show a similar behavior with a pronounced increase in source activation between 300 and 450 mJ (black line, left scale). Again the increase in source activation is stronger than in pain ratings (gray, scale on the right), and the curve fitted on the SII activation is S-shaped.

The relation between stimulus intensity and response amplitude revealed fundamental differences between SI and SII (Figs. 1 and 2). In contralateral SI, increasing stimulus intensities showed continuously increasing source activation closely resembling the exponential stimulus intensity/pain rating function [fit on exponential function f(x) = b0<IT>e</IT><SUP>(<IT>b</IT><SUB>1</SUB>∗<IT>x</IT>)</SUP>: pain ratings: R2 = 0.95 ± 0.02, mean ± SE; contralateral SI: R2 = 0.95 ± 0.015]. This exponential function fitted significantly better to the individual stimulus response functions in contralateral SI than to the stimulus response functions in contralateral SII (R2 = 0.83 ± 0.056, P < 0.05) and in ipsilateral SII (R2 = 0.67 ± 0.08, P < 0.05, paired t-test). In contrast, an S-shaped stimulus-response function was observed in bilateral SII with small activations at the two low-intensity, subthreshold and threshold, stimuli and a sharp increase in source activation at stimuli well above pain threshold. A polynomial function that can either have an S-shaped or exponential appearance [f(x) = b0 + (b1x) + (b2x2) + (b3x3); x corresponds to stimulus intensity] was fitted to the stimulus response functions to describe the differences between SI and SII (Fig. 2). The coefficients determining the increase (b1) and shape (b2 and b3) of the fitted curves were significantly different between the S-shaped functions in contralateral SII and the exponential functions in contralateral SI (contralateral SI: b1, -0.05 ± 0.09; b2, 0.0002 ± 0.0003; b3, -1e - 7 ± 3.1e - 7; contralateral SII: b1, -0.78 ± 0.19; b2, 0.0026 ± 0.0006; b3, -2e - 6 ± 5.4e - 7; ipsilateral SII: b1, -0.31 ± 0.098; b2, 0.0099 ± 0.0003, b3, -7, 5e - 4 ± 7e - 4; mean ± SE; paired t-tests for b1, b2, and b3 in SI and contralateral SII: P < 0.02, Bonferroni corrected). Comparison between bilateral SII and pain ratings revealed clear differences in the step from 300 to 450 mJ in the laser stimuli. The quotient of source activation at 450 and 300 mJ ("activation-ratio") was significantly larger in bilateral SII than in contralateral SI, indicating a significantly steeper increase in source activation between 300 and 450 mJ in SII than in SI (P < 0.05, t-test, Fig. 3). The absolute amplitudes in contralateral SII compared with contralateral SI and ipsilateral SII were not significantly different.



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Fig. 3. "Activation-ratio" (quotient of source amplitudes at 450 and 300 mJ) in contralateral SI and bilateral SII. The activation-ratio in bilateral SII is significantly larger than in contralateral SI (* P < 0.05, t-test; n = 8, error bars indicate SE).


    DISCUSSION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The present study demonstrates a high correlation of nociceptive stimulus intensity with activity in contralateral SI and bilateral SII. However, the pattern of source activation reveals significant differences between SI and SII. The SI activation closely matches the pain intensity. In contrast, SII activation shows a sharp increase above pain threshold not corresponding to the pain intensity.

In monkeys, the applied physical intensity and perception of painful heat stimuli is highly correlated with the firing rate of wide-dynamic-range (WDR) neurons in SI (Chudler et al. 1990; Kenshalo et al. 1988, 2000). Moreover, after ablation of SI, monkeys show a severe deficit in the detection and discrimination of noxious thermal stimuli (Kenshalo and Willis 1991). These results in nonhuman primates support the view that SI is primarily involved in the encoding of sensory-discriminative aspects of pain (Kenshalo and Willis 1991; Schnitzler and Ploner 2000). Our data demonstrate a high correlation between stimulus intensity, pain ratings, and contralateral SI activation in humans. Thus our results provide evidence that the encoding of stimulus intensity within human SI closely corresponds to the electrophysiological findings in monkeys. This result is corroborated by indirect evidence from clinical lesion studies, suggesting that SI ablation or injury produced impairment of pain sensation (Marshall 1951; Russell 1945). In the light of complementary findings from imaging studies showing spatial discrimination (Andersson et al. 1997; Tarkka and Treede 1993), temporal discrimination (Porro et al. 1998), stimulus size discrimination (Apkarian et al. 2000), and lack of correlation of SI activity with selective modulation of pain unpleasantness (Rainville et al. 1997), SI may serve as a sensory-discriminative evaluator of nociceptive stimuli without necessarily detecting its noxious, "painful" nature.

In nonhuman primates, investigations of the SII territory, including the functionally and anatomically related area 7b (Whitsel et al. 1969), revealed a small population of nociceptive neurons with large receptive fields responding to noxious stimuli (Dong et al. 1989, 1994; Robinson and Burton 1980). These SII neurons receive their major projections from the ventral posterior inferior nucleus (VPI) (Friedman and Murray 1986; Stevens et al. 1993), which consists of a large proportion of nociceptive-specific (NS) neurons poorly encoding the intensity of painful stimuli (Apkarian and Shi 1994). In contrast, nociceptive SI neurons receive primarily projections from thalamic WDR neurons in the ventral posterior lateral nucleus (VPL) (Gingold et al. 1991; Kenshalo et al. 1980), which faithfully represent the stimulus intensity by their firing rate (Apkarian and Shi 1994; Kenshalo et al. 1980). A majority of nociceptive neurons in SII showed complex response characteristics to fearful and threatening visual stimuli but were barely able to encode the intensity of nociceptive stimuli (Dong et al. 1989, 1994) similar to the NS neurons in VPI. These findings indicate a role of SII in spatially directed attention toward and detection/aversion of potentially harmful stimuli (Robinson and Burton 1980), but also in learning and memory of painful stimuli (Dong et al. 1994; Lenz et al. 1997). Our present study shows the capacity of human SII to encode, to a certain extent, the intensity of nociceptive stimuli. Interestingly, mildly painful stimuli around the pain threshold resulted in relatively small SII activations, whereas stronger, clearly painful stimuli were followed by strong activations of SII sources. Within SII, this activation pattern could be well explained by a large proportion of nociceptive neurons lacking the property to faithfully represent the intensity of nociceptive stimuli. It is likely that these neurons subserve, as suggested in monkeys, more complex tasks in pain processing like the detection of, aversion of, and spatially directed attention toward painful stimuli (Robinson and Burton 1980). In summary, the activation of human SII by nociceptive stimuli seems to be similar to the findings in nonhuman primates.

Interestingly, in a number of imaging studies focusing on human cortical pain processing, SII activity dominated over SI activity (Casey et al. 1994; Coghill et al. 1994, 1999; Craig et al. 1996; Davis et al. 1998; Derbyshire et al. 1997; Gelnar et al. 1999; Iadarola et al. 1998; Talbot et al. 1991). The differences in the stimulus-response function of SII and SI in our study could well explain that at moderate pain SII activity exceeds the detection level of PET and fMRI, whereas SI activity barely reaches it.

Recently, a patient with an ischemic lesion including the area of the primary and secondary somatosensory cortex was reported (Ploner et al. 1999a). This patient was able to describe a vague unpleasantness but not the intensity and location of the applied stimulus most probably due to the lesion of SI. Remarkably, he also failed to recognize the noxious nature of the painful stimuli. This deficit in the recognition of the nociceptive character of the stimulus could likely be attributed to the ischemic lesion of SII. Interestingly, these deficits can be differentiated from the "asymbolia for pain" described in patients with insular lesions. These patients demonstrate a lack of withdrawal and show absent or markedly attenuated emotional responses to painful stimuli but recognize well the "painful" nature of the stimulus (Berthier et al. 1988). Taken together, we hypothesize that the insula is involved in emotional recognition and motor reaction on noxious stimuli in close connection with the limbic system, in contrast to a possible role of SII in the cognitive detection of the noxious, "painful" nature of nociceptive stimuli.

In conclusion, we state that intensity of nociceptive stimuli is differentially represented in the primary and secondary somatosensory cortex. The activation pattern is indicative for a representation of perceived stimulus intensity in contralateral SI and detection and recognition of the noxious nature of painful stimuli in bilateral SII.


    ACKNOWLEDGMENTS

The authors thank volunteers for excellent cooperation during the measurements and E. Rädisch for technical support with the MRI scans. The assistance of Dr. Joachim Gross in the statistical analyses and fitting procedures of the data is gratefully acknowledged.

This work was supported by the Volkswagen Stiftung (I/73240), the Deutsche Schmerzstiftung, the Ute-Huneke-Stiftung, and the Deutsche Forschungsgemeinschaft (SFB 194, Z2).


    FOOTNOTES

Address for reprint requests: A. Schnitzler, Dept. of Neurology, MEG-Laboratory, Heinrich-Heine-University, Moorenstr. 5, 40225 Dusseldorf, Germany (E-mail: schnitz{at}neurologie.uni-duesseldorf.de).


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INTRODUCTION
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