1Department of Neurology, Heinrich-Heine-University, 40225 Dusseldorf; and 2Department of Psychology, University of Wuppertal, 42119 Wuppertal, Germany
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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.
|
|
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
* 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.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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).
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|