Department of Neurology, Heinrich-Heine University, D-40225 Dusseldorf, Germany
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ABSTRACT |
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Ploner, Markus, Frank Schmitz, Hans-Joachim Freund, and Alfons Schnitzler. Parallel activation of primary and secondary somatosensory cortices in human pain processing. Cerebral processing of pain has been shown to involve primary (SI) and secondary (SII) somatosensory cortices. However, the temporal activation pattern of these cortices in nociceptive processing has not been demonstrated so far. We therefore used whole-head magnetoencephalography to record cortical responses to cutaneous laser stimuli in six healthy human subjects. By using selective nociceptive stimuli our results confirm involvement of contralateral SI and bilateral SII in human pain processing. Beyond they show for the first time simultaneous activation onset of contralateral SI and SII after ~130 ms, indicating parallel thalamocortical distribution of nociceptive information. This contrasts to the serial cortical organization of tactile processing in higher primates and instead corresponds to the parallel cortical organization in lower primates and nonprimates. Thus our finding suggests preservation of the basic mammalian parallel organizational scheme in human pain processing, whereas in the tactile modality parallel organization appears to be abandoned in favor of a serial processing scheme. Functionally, preservation of direct access to SII underscores the relevance of this area in human pain processing, probably reflecting an important role of SII in nociceptive learning and memory.
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INTRODUCTION |
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From Head's statement that "pure cortical
lesions cause no increase or decrease of sensibility to measured
painful stimuli" (Head and Holmes 1911) it was
inferred for decades that the cerebral cortex is not involved in human
pain processing. Converging clinical and experimental evidence has
substantially modified this view over the past years. In particular,
participation of primary (SI) and secondary (SII) somatosensory
cortices has been confirmed by data from experimental animal, human
lesion (for reviews see Kenshalo and Willis 1991
;
Sweet 1982
), and functional imaging studies
(Casey et al. 1996
; Coghill et al. 1994
;
Craig et al. 1996
; Talbot et al. 1991
).
However, the temporal characteristics of nociceptive processing in
these cortices have remained largely unknown. Especially it is unknown
whether SI and SII are activated in a serial or a parallel mode. Serial
processing of tactile information in higher primates (Garraghty
et al. 1990
; Pons et al. 1987
, 1992
), including
humans (Allison et al. 1989a
,b
; Hari et al.
1993
; Mima et al. 1998
), may suggest a
corresponding sequential activation of SI and SII to nociceptive
stimuli, although no direct evidence for this has been presented so far.
We therefore used whole-head magnetoencephalography (MEG) to investigate the time course of cortical responses in SI and SII to selective nociceptive cutaneous laser stimuli.
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METHODS |
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Six healthy right-handed male volunteers aged 28-38 yr (mean 33 yr) paricipated in the study. All subjects gave informed consent before the experiment. The procedure was approved by the local ethical committee.
Stimulation procedure
In 2 subsequent runs, 40 selective nociceptive cutaneous laser
stimuli (Bromm and Treede 1984) were applied to the
dorsum of each hand with a Tm:YAG laser (Baasel Lasertech) with a
wavelength of 2,000 nm, a pulse duration of 1 ms, and a spot diameter
of 6 mm. Interstimulus intervals were randomly varied between 10 and
14 s, and stimulation site was slightly changed within an area of
4 × 3 cm after each stimulus. Before the recordings individual pain thresholds were determined with increasing and decreasing stimulus
intensities at 50-mJ steps. Threshold was defined as intensity that
elicited painful sensations in at least three of five applications.
Stimulation intensity was adjusted to twofold pain threshold intensity,
i.e., between 600- and 700-mJ pulse energy. After the recordings,
subjects were asked to rate mean stimulus intensity on a category
scale, including "mild," "mild to moderate," "moderate,"
"moderate to severe," and "severe" pain. No tactile sensation
was evoked at any intensity.
Data acquisition and analysis
Cortical responses were recorded with a Neuromag-122 whole-head
neuromagnetometer (Ahonen et al. 1993) in a magnetically
shielded room. The laser beam was led through an optical fiber from
outside into the recording room. Signals were digitized at 483 Hz,
band-pass filtered between 0.03 and 40 Hz, and averaged with respect to laser stimuli. Simultaneous recordings of vertical and horizontal electrooculogram were used to reject epochs contaminated by blink artifacts and eye movements. Analysis was focused on an epoch comprising 100 ms prestimulus baseline and 300 ms after stimulation. Sources of evoked responses were modeled as equivalent current dipoles
identified during clearly dipolar field patterns. Only sources
accounting for >85% of the local field variance (goodness of fit)
were accepted. Dipole location, orientation, and strength were
estimated within a spherical conductor model of each subject's head
determined from the individual magnetic resonance images (MRI) acquired
on a 1.5 T Siemens-Magnetom. The final spatiotemporal source model
consisted of two or three dipoles with fixed locations and
orientations. Dipole strength was allowed to vary over time to provide
the best fit for the recorded data (for further details concerning data
acquisition and analysis see Hämäläinen et al.
1993
). The resulting source strength waveforms as a function of
time were used for determination of peak and onset latencies. On the
basis of fiducial point markers MRI and MEG coordinate systems were
aligned, and source locations were superposed on the individual MRI
scans. To quantify location of sources MRI scans were adjusted to the
Talairach coordinate system (Talairach and Tournoux
1988
). In each individual, distances of SII sources were
determined along the medial-lateral x-axis to the circular insular sulcus and along the anterior-posterior y-axis to
the verticofrontal plane passing through the anterior commissure (VCA). Source locations were also calculated in standardized Talairach coordinates.
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RESULTS |
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In all subjects, stimuli elicited at least moderately painful,
"pinprick-like" sensations. Field patterns of pain-evoked
neuromagnetic responses indicated temporally overlapping activity of
two almost orthogonally oriented cortical sources in the contralateral
and one source in the ipsilateral hemisphere (Fig.
1a). Precise determination of activation
sites and subsequent superposition on individual MRI scans revealed a
contralateral source with an anterior-posterior current direction in
the postcentral hand area and bilateral sources with inferior-superior
orientations in the upper banks of the Sylvian fissures thus
corresponding to contralateral SI and bilateral SII cortices,
respectively (Fig. 1b); 95% confidence limits for localization of SI sources in each direction were 4 ± 2 mm
(mean ± SD) in both hemispheres and of SII sources 5 ± 2 mm
in the left and 5 ± 3 mm in the right hemisphere. Absolute
medial-lateral distances between SII sources and circular insular
sulcus were 13 ± 5 mm in the left hemisphere and 14 ± 4 mm
in the right hemisphere. Distances of SII sources to the VCA were
15 ± 8 mm and
6 ± 3 mm, respectively. Mean standardized
Talaraich coordinates (x, y, z) were
21,
33, 59 (left SI); 24,
30, 58 (right SI);
51,
15, 18 (left
SII); 52,
6, 17 (right SII). Figure 1c shows the time
course of source activations in a single subject, and Fig. 2 illustrates the group mean (±SE)
activities across left- and right-hand stimulations of all subjects.
Onset latencies of contralateral SI (131 ± 7 ms) and
contralateral SII (126 ± 4 ms) were not statistically different
(two-tailed Wilcoxon signed rank test, P = 0.33).
Slightly steeper slopes most likely reflecting a higher degree of
neuronal synchronization caused shorter peak latencies in contralateral SII (163 ± 4 ms) than in SI (174 ± 3 ms) (P = 0.013). Onsets and peaks of contralateral SII preceded ipsilateral
SII by 12 ms (P = 0.008) and 18 ms (P = 0.005), respectively. Table 1 gives
individual and mean onset and peak latencies of all stimulation
conditions.
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DISCUSSION |
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By using selective nociceptive stimuli our results confirm
previous observations of SI and SII involvement in human pain
processing (Casey et al. 1996; Coghill et al.
1994
; Craig et al. 1996
; Greenspan and
Winfield 1992
; Kenshalo and Willis 1991
;
Lenz et al. 1998
; Sweet 1982
;
Talbot et al. 1991
). In addition, we show for the first
time the temporal aspects of nociceptive processing in human somatosensory cortices.
Previous neurophysiological recordings of cortical responses to
selective nociceptive stimuli either could not demonstrate SI
activation (Bromm and Chen 1995; Hari et al.
1983
, 1997
; Huttunen et al. 1986
; Kakigi
et al. 1995
; Valeriani et al. 1996
;
Watanabe et al. 1998
) or did not provide sufficient
spatial resolution to localize sources (Spiegel et al.
1996
; Tarkka and Treede 1993
). The failure to
detect SI activation in some studies might have been due to the paucity
of nociceptive neurons in SI as revealed in experimental animal studies
(Kenshalo and Willis 1991
) and to different stimulus
characteristics possibly activating different fiber populations. In our
study, very short laser pulses of relatively high energies probably
yielded a higher degree of neuronal synchronization and therefore could
well account for larger responses. The latency of the SI response is
inconsistent with conduction via A-
fibers but agrees well with
activation of A-
fibers. Selectivity of cutaneous laser stimulation
is further corroborated by the absence of any tactile sensations in our
study and by results of microneurographic recordings (Bromm and
Treede 1984
).
The locations and orientations of our SII sources are in accordance
with previous MEG and functional imaging studies on tactile (Coghill et al. 1994; Hari et al. 1993
;
Ledberg et al. 1995
; Mima et al. 1998
;
Schnitzler et al. 1999
) and nociceptive (Casey et al.1996
; Coghill et al. 1994
; Craig et
al. 1996
; Hari et al. 1983
, 1997
; Kakigi
et al. 1995
; Talbot et al. 1991
; Watanabe
et al. 1998
) processing. The inferior-superior current flow
and the distances of SII sources to the insula and the VCA rule out a
significant contribution of insular activity to the identified sources.
Failure to detect activation of insular cortex, which was also shown to participate in nociceptive processing (Casey et al.
1996
; Coghill et al. 1994
; Craig et al.
1996
), may be due to possible cancellation of currents in the
opposite walls of the insula and to mainly radially oriented insular
source currents not detected by MEG.
Our finding of simultaneous activation of SI and SII to selective
nociceptive stimuli contrasts to the temporal activation pattern of
tactile processing. Intracranial and magnetoencephalographic recordings
in humans revealed sequential activation of SI peaking at 20-50 ms and
SII peaking at ~100-130 ms (Allison et al. 1989a,b
; Hari et al. 1993
; Mima et al. 1998
;
Schnitzler et al. 1999
). Accordingly, ablation
experiments in higher primates showed a dependence of SII responses on
the integrity of SI, indicating serial processing of tactile
information (Garraghty et al. 1990
; Pons et al.
1987
, 1992
). Results of a single study (Zhang et al.
1996
) with cortical cooling of SI were interpreted as
indication for a possible parallel activation of tactile pathways to SI
and SII in higher primates. However, incomplete deactivation of SI
cannot be ruled out in this study, and virtually all of the anatomic
and electrophysiological work in macaques clearly supports a
predominantly serial relay of tactile information from SI to SII
(Pons 1996
). By contrast, ablation experiments in lower
primates and nonprimates revealed independent activation of SI and SII
via parallel thalamocortical pathways (Garraghty et al.
1991
; Turman et al. 1992
). Thus for tactile
processing in higher primates an evolutionary shift from the basic
mammalian parallel cortical organization to serial organization of
somatosensory cortices has been proposed. Our results strongly suggest
that the parallel mode of cortical organization also applies to human
pain processing, whereas in the tactile modality parallel organization
appears to be abandoned in favor of a serial processing scheme.
Anatomically, parallel nociceptive processing is likely to be subserved
by distinct spinothalamocortical pathways via the ventroposterior
inferior thalamic nucleus (VPI) to SII (Friedman and Murray
1986
; Stevens et al. 1993
) and via the
ventroposterior lateral thalamic nucleus (VPL) to SI (Gingold et
al. 1991
). Differences in spinal input, response properties,
and receptive field sizes of nociceptive neurons along VPL-SI and
VPI-SII projections (Apkarian and Hodge 1989
;
Apkarian and Shi 1994
; Dong et al. 1989
;
Kenshalo and Willis 1991
) indicate an anatomic and
functional segregation of both pathways from the spinal cord to cortex.
Functionally, serial processing implies greater synaptic distance
between SII and the periphery and some loss of processing speed in
exchange for preferential use of SI (Garraghty et al. 1991). Given restricted receptive field sizes, somatotopical
arrangement, and accuracy of intensity coding of both SI and VPL
neurons (Apkarian and Shi 1994
; Kenshalo and
Willis 1991
), we conclude that discriminative capabilities
mediated by SI are less important in pain than in tactile perception.
Instead preserved direct access of nociceptive information to SII
indicates crucial importance of this area in human pain processing.
Direct corticolimbic projections from SII to the temporal lobe limbic
structures have been proposed to subserve tactile learning and memory
(Friedman et al. 1986
; Mishkin 1979
). Similarly, SII may play a key role in relaying nociceptive information to the temporal lobe limbic structures (Dong et al.
1989
; Lenz et al. 1997
). Thus direct
thalamocortical projection to SII provides fast and effective access of
nociceptive signals to the anatomic substrates of pain-related learning
and memory. For obvious reasons, physical integrity and survival of the
individual are heavily dependent on efficient and successful reaction
to and avoidance of harmful events. Therefore we hypothesize that the
fundamental relevance of pain-associated learning and memory accounts
for the evolutionary preservation of the direct thalamic input to SII.
Conversely, the involvement of learning and memory mechanisms in
chronification of pain (Fordyce 1986
) opens novel
approaches for exploring the role of SII in chronic pain syndromes.
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ACKNOWLEDGMENTS |
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We thank J. Gross for expert technical advice and Dr. C. J. Ploner for helpful comments on the manuscript.
This study was supported by the Huneke-Stiftung, the Deutsche Forschungsgemeinschaft (SFB 194), and the Volkswagen-Stiftung.
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FOOTNOTES |
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Address for reprint requests: A. Schnitzler, Dept. of Neurology, Heinrich-Heine University, Moorenstr. 5, D-40225 Dusseldorf, Germany.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 18 December 1998; accepted in final form 22 February 1999.
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REFERENCES |
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