Parallel Activation of Primary and Secondary Somatosensory Cortices in Human Pain Processing

Markus Ploner, Frank Schmitz, Hans-Joachim Freund, and Alfons Schnitzler

Department of Neurology, Heinrich-Heine University, D-40225 Dusseldorf, Germany


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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.


    INTRODUCTION
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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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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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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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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Fig. 1. Cortical responses to cutaneous laser stimuli applied to right hand in a representative subject. A: magnetic field patterns at 176 ms after stimulus application displayed over the helmet-shaped sensor array viewed from the left, top, and the right. Squares show locations of 61 sensor pairs. Shaded areas indicate fields directed into the head; isocontours are seperated by 45 fT. Arrows represent location and direction of cortical sources. B: location of cortical sources superposed on magnetic resonance imaging scans. Left: axial slice through SI hand area; middle and right: coronal and axial slice through SII. C: source strengths as a function of time. SI, primary somatosensory cortex; SII, secondary somatosensory cortex; L, left; R, right.



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Fig. 2. Mean source strengths as a function of time across left and right hand stimulation of all subjects. Shaded areas depict ±SE. contra, contralateral; ipsi, ipsilateral.


                              
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Table 1. Latencies of cortical responses to cutaneous laser stimuli


    DISCUSSION
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INTRODUCTION
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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-beta fibers but agrees well with activation of A-delta 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.


    ACKNOWLEDGMENTS

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.


    FOOTNOTES

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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