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Long-lasting effect evoked by tonic muscle pain on parietal EEG activity in humans
Clinical Neurophysiology 111 (2000) 2130±2137
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Long-lasting effect evoked by tonic muscle pain on parietal EEG activity in humans Domenica Le Pera a,b,*, Peter Svensson a, Massimiliano Valeriani b,c, Ippei Watanabe a, Lars Arendt-Nielsen a, Andrew C.N. Chen a a
Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark b Department of Neurology, UniversitaÁ Cattolica del S. Cuore, Roma, Italy c Casa di cura San Raffaele Pisana, Tosinvest SanitaÁ, Roma, Italy Accepted 15 September 2000
Abstract Objective: To explore EEG changes evoked by tonic experimental muscle pain compared to a non-painful vibratory stimulus. Methods: Thirty-one EEG channels were recorded before, during and after painful and non-painful stimulation. Pain was induced in the left brachioradialis muscle by injection of hypertonic (5%) saline. The vibratory stimulus was applied to the skin area overlying the brachioradialis muscle. The power of the major frequency components of the EEG activity (FFT, fast Fourier transform) was quanti®ed and t-maps between the different experimental conditions were evaluated in frequency domain. Results: The main effect of muscle pain, compared to non-painful stimulation, was a signi®cant and long-lasting increase of delta (1±3 Hz) power and an alpha-1 (9±11 Hz) power increase over the contralateral parietal locus. This ®nding could suggest a decreased excitability of the primary somatosensory cortex during muscle pain. The main effect of vibration, compared to its unstimulated baseline, consisted in an increase of beta-1 (14±20 Hz) power in the right frontal region. Conclusions: Our data demonstrate signi®cant and speci®c topographic EEG changes during tonic muscle pain. Since these modi®cations differ from those produced by an unstimulated baseline and during non-painful tonic stimulation, they might re¯ect mechanisms involved in the processing of nociceptive and adverse tonic stimuli. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Muscle pain; Electroencephalography; Event-related synchronization; Somatosensory cortex inhibition
1. Introduction In the past decades, many attempts have been made to apply neurophysiological methods for the evaluation of human pain (for a review see Bromm and Lorenz, 1998). However, an understanding of the electrophysiological nociceptive processing in the human brain has remained elusive, probably because of the complexity and multiplicity of mechanisms supporting this sensorial experience. In particular, neurophysiological studies, which aimed to identify tonic pain-relevant information in the electroencephalogram (EEG), have not led to clear conclusions (Chen, 1993; Bromm and Lorenz, 1998). Analyses of EEG power spectra have suggested that EEG amplitude and frequency components may be in¯uenced by the experience of pain. During tonic painful stimulation, a * Corresponding author. Istituto di Neurologia, Policlinico A. Gemelli, L.go A. Gemelli 8, 00168 Roma, Italy. Fax: 139-06-3550-1909. E-mail address: [email protected] (D. Le Pera).
bilateral and diffuse increase in slow activity (Chen et al., 1989; Gotliebsen and Arendt-Nielsen, 1990; Ferracuti et al., 1994), as well as increases in alpha power (Backonja et al., 1991) and beta power (Chen et al., 1989; Veerasarn and Stohler, 1992) have been shown. However, the functional meaning of these EEG changes has not unequivocally been interpreted. Indeed, because of their inconsistency and the relative poor spatial resolution, the EEG modi®cations induced by pain have been thought to be related to nonspeci®c muscle tension, motor withdrawal responses or a stress-induced activation (Veerasarn and Stohler, 1992; Chen, 1993; Bromm and Lorenz, 1998). In contrast, the signi®cant difference between the EEG changes during painful and non-painful stimulation has suggested that pain itself may speci®cally affect the spontaneous electrical brain activity in frontal and parietal regions (Backonja et al., 1991). The involvement of these cortical areas in pain processing has also been con®rmed by neurophysiological studies using pain-related evoked potentials (Tarkka and Treede, 1993; Bromm and Chen, 1995; Valeriani et al.,
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CLINPH 2000549
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1996, 2000a) and magnetoencephalography (Kitamura et al., 1995; Kakigi et al., 1995; Watanabe et al., 1998; Ploner et al., 1999; Kanda et al., 2000) as well as by the neuroimaging techniques (Talbot et al., 1991; Coghill et al., 1994; Casey et al., 1996; Svensson et al., 1997; Xu et al., 1997; Peyron et al., 1999). The aims of the present study were ®rst to explore EEG changes in relation to saline-induced experimental tonic muscle pain and second to examine whether these effects are speci®c for processing nociceptive input by comparing them with EEG modi®cations evoked by tonic non-painful vibratory stimulus.
rating during the recording of EEG in a time interval of 60 s was calculated.
2. Methods
2.5. Experimental protocol
2.1. Subjects
On two occasions, separated by one week, the subjects repeated the procedure for the muscle pain condition and the non-painful vibratory condition in a randomised order. Each experimental condition consisted of 3 stages: baseline, task and recovery. At the baseline stage (baseline 1: pain; baseline 2: vibration), 1 min of EEG recordings were obtained from the subjects with both eyes closed. During the task stage, 1 min of EEG was recorded while the subjects were exposed to the painful stimulation (after a stable level of pain intensity was reached) or the vibratory stimuli. The recovery stage (recovery 1: pain; recovery 2: vibration) consisted of 1 min of EEG recordings under conditions identical to the baseline stage and it was performed after 10 min from the pain/vibration disappeared.
Twelve young healthy male volunteers (age: 26.6 ^ 5.8 years), with no previously reported neurological illness, were included in the study. Written informed consents were obtained from all volunteers in accordance with the Declaration of Helsinki. The study was approved by the local Ethics Committee. 2.2. EEG recordings EEG recordings were obtained from subjects sitting quietly in a reclined chair with both eyes closed during the experiment. Surface recording electrodes (impedance below 5 KV) were placed at thirty-one locations on the scalp according to an enriched International 10±20 System with the use of an electrode cap (Electro-Cap international, Inc USA). The common reference was at linked ears. The ®lter bandpass 0.1±100 Hz and the recording were made by a sampling rate of 256 Hz using a Neuroscan EEG system (Herndon, Virginia, USA). EEG was recorded continuously for 1 min during the baseline, task and recovery stages. 2.3. Experimental muscle pain Pain was induced in the left brachioradialis muscle by infusion of hypertonic (5%) saline. The infusion was carried out by a computer-controlled syringe pump (IVAC, model 770, USA; Graven-Nielsen et al., 1997) with a 10-ml plastic syringe. A tube (IVAC G30303, extension set with polyethylene inner line) was connected from the syringe to the disposable stainless needle (27G, 40 mm). A standardised infusion paradigm was applied: a bolus of 0.5 ml saline was infused over 20 s followed by a steady infusion rate of 18 ml/hour for the next 440 s, and ®nally 36 ml/hour for the next 440 s (Graven-Nielsen et al., 1997). The subjects on a 0±10 electronic visual analogue scale (VAS) continuously scored the pain intensity where 0 cm indicated `no pain' and 10 cm `intolerable pain'. The VAS score was sampled every 5 s by the computer. The pain
2.4. Vibration Vibratory stimuli consisted of 120 Hz non-painful stimulation above the left brachioradialis muscle. The vibratory stimuli were controlled by a vibrator (Vibrameter type 4, Somedic AB, Sweden). The stimulator (650 g; probe diameter: 12 mm) was held perpendicularly to the surface at the stimulus location, and the amplitude was adjusted to a displacement of 200 microns. This sensation of the stimuli was always reported as non-painful.
2.6. Data analysis For frequency analysis of background EEG, 1 min of artefact-free EEG was examined according to the IFCN guidelines for topographic and frequency analysis of EEGs (Nuwer et al., 1994). The major components of EEG power change were isolated using fast Fourier transformation (FFT). T-maps comparing stages (task vs. baseline and recovery vs. baseline) and conditions (baseline 1 vs. baseline 2, pain vs. vibration, recovery 1 vs. recovery 2) were evaluated for the following frequency bands: delta (1±3 Hz), theta (4±8 Hz), alpha-1 (9±11 Hz), alpha-2 (11± 13 Hz), beta-1 (14±20 Hz) and beta-2 (20±32 Hz). The calculation of the t-maps was performed by interpolation between t-values at the 31 electrodes. Only frequency bands showing signi®cant differences in the t-maps (P , 0:05) were chosen for further statistical analysis. Absolute band power was converted into percentage power (relative power) by de®ning the total power in the frequency interval 1±32 Hz as 100%. The calculated relative power data were submitted to analysis of variance (two-way ANOVA) by considering scalp location and experimental stage as sources of variation. When a signi®cant level (P , 0:05) was reached, one-way ANOVA was
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Hz) and beta-2 bands (20±26 Hz) over the right posterior parietal locus (P4) and an increase of power within the alpha-1 band (9±11 Hz) over both parietal regions (P3, P4) (Fig. 2). It is remarkable that the relative power increase in the alpha-1 band was more signi®cant over the right parietal area, contralateral to the injection site (P4, P , 0:01) than over the left parietal area, ipsilateral to the injection site (P3, P , 0:04). (b) The delta and beta-2 activity modi®cation over the right parietal region persisted during the recovery stage (Fig. 2). 3.2.2. Vibration (a) The t-map comparing vibration with baseline 2 showed a signi®cant increase of power within the beta-1 band (14±20 Hz) over the right frontal region (F4) (Fig. 2). (b) This effect did not persist during the recovery stage.
Fig. 1. Mean VAS-time curve (n 12) during 15 min infusion of hypertonic saline in the left brachioradialis muscle. The duration of saline infusion and the start of EEG recording are indicated.
performed for each scalp location. If the one-way ANOVA was signi®cant (P , 0:05), a post-hoc analysis by Student's t test was used to compare the different stages.
3.2.3. Comparison between muscle pain and vibration (a) No signi®cant difference was observed in the comparison between baseline 1 and 2 (Fig. 3). (b) Compared to vibration, the main effect of muscle pain was an increase of delta and alpha-1 powers over the parietal loci bilaterally (P3, P4) (Fig. 3). When the relative power data were considered, the statistical signi®cance was reached only over the right parietal region, contralateral to the injection site (P4, P , 0:05; P3, P 0:3), for delta frequency and over both the parietal loci (P4, P , 0:01; P3, P , 0:04) for alpha-1 band. (c) The comparison between recovery 1 and 2 showed an increase of delta and beta-2 (20±26 Hz) power over the parietal region (Pz) (Fig. 3).
3. Results 3.1. Experimental muscle pain EEG recordings (1 min) were performed 5.8 ^ 1.4 min (mean ^ SD; n 12) after the onset of hypertonic saline infusion, when the pain intensity rating became stable (Fig. 1). The mean pain rating during EEG recordings was 5.0 ^ 1.8 and was signi®cantly different from the mean pain rating during the ®rst min after infusion (0.3 ^ 0.2, Student's t test: P , 0:01). 3.2. EEG changes topography
4. Discussion
All the signi®cant topographic EEG changes observed in the t-map comparisons were con®rmed when the relative power values were also analysed (Table 1).
This study demonstrated that tonic muscle pain induces speci®c and long-lasting EEG changes, compared with nonpainful vibration. In particular, increments of both delta and alpha-1 powers were observed bilaterally over the parietal area, more pronounced over the region contralateral to the painful stimulation.
3.2.1. Experimental muscle pain (a) The t-map comparing muscle pain with baseline 1 showed a signi®cant increase of power within delta (1±3
Table 1 Locations of signi®cant relative power comparisons (t test) between stages and conditions a Frequency Muscle pain
delta alpha-1 beta-1 beta-2 a
Vibration
Muscle pain vs. Vibration
Pain±baseline 1 Baseline 1±recovery 1 Vibration±baseline 2 Baseline 2± recovery 2
Baseline 1± baseline 2
Pain±vibration Recovery 1±recovery 2
P4 (P , 0.02) P4 (P , 0.01) P3 (P , 0.04) ± P4 (P , 0.02)
± ± ± ± ±
P4 (P , 0.03) P4 (P , 0.01) P3 (P , 0.04) ± ±
(±) Non signi®cant values.
P4 (P , 0.03) ± ± ± P4 (P , 0.04)
± ± ± F4 (P , 0.007) ±
± ± ± ± ±
Pz (P , 0.04) ± ± ± Pz (P , 0.01)
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Fig. 2. T-maps (cut-off: 22.5 to 12.5, P , 0:05) comparing the different stages (task vs. baseline and recovery vs. baseline) of each experimental condition (muscle pain and vibration). All the analysed frequency bands are displayed. The positions of the electrodes are marked in each map with black dots. Red colour indicates an increase of the EEG power.
4.1. Contralateral parietal delta and alpha-1 power increase during muscle pain The injection of hypertonic saline in the left arm led to an increase of delta and alpha-1 powers over the contralateral posterior parietal locus. This ®nding of delta power increase is in accordance with previous EEG studies, which have used tonic painful stimulation (Chen et al., 1989; Ferracuti et al., 1994). Although the mechanism responsible for the pain-related increase in delta activity has not yet been clari®ed, enhanced slow waves are usually considered to be an expression of cortical inhibition (Kogan, 1960). An increase in amplitude of the slow frequencies in the parietal area was found during control of painful stimulation in fakirs (Pelletier, 1977; Larbig et al., 1982) and a signi®cantly increased delta activity during experimental tonic pain was interpreted
as an attempt to inhibit sensorial perception of the nociceptive input (Ferracuti et al., 1994). The changes in alpha-1 power, which have been reported in our study, are not likely to represent traditional alpha-1 desynchronization (ERD: event-related desynchronization). This phenomenon is characterized by phasic decreases of alpha-1 power and has been associated with neural activation in human visual, auditory, somatosensory and motor system in response to different stimulation paradigms (Grillon and Buchsbaum, 1986; Pfurtscheller, 1989; Pfurtscheller and Berghold, 1989). Instead, our ®ndings are characterized by an augmentation of alpha-1 band activity (ERS: event-related synchronization) evoked by tonic stimulation. Studies on alpha-1 enhancement have demonstrated that when patches of neurones display synchronization in the alpha-1 band, an active processing of information
Fig. 3. T-maps (cut-off: 22.5 to 12.5, P , 0:05) between the experimental conditions (muscle pain vs. vibration) comparing correspondent stages (baseline 1 vs. baseline 2, muscle pain vs. vibration, recovery 1 vs. recovery 2). All the analysed frequency bands are displayed. The positions of the electrodes are marked in each map with black dots. Red colour indicates an increase of the EEG power. Notice that an increment of both delta and alpha-1 powers was observed bilaterally in the parietal area during muscle pain compared to vibration.
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is very unlikely and it may be assumed that the corresponding networks are in state of decreased neural excitability (Pfurtscheller, 1992), or even in a state of cortical inhibition (Klimesch, 1996; Klimesch et al., 1999). Examples of such `idling' area (Pfurtscheller et al., 1996b), which display locally enhanced alpha-1 band power, are represented by the primary sensorimotor hand area during foot movement or visual processing, the visual areas during execution of a motor task or the primary motor area after termination of movement (Pfurtscheller, 1992; Pfurtscheller and Neuper, 1994; Pfurtscheller et al., 1996a,b, 1998a). In this respect, it is of interest that some authors have suggested a good correlation between `idling' cortical areas, EEG patterns of synchronized activity and decreased regional blood ¯ow as a correlate of synaptic inhibition (Apkarian et al., 1992; Pfurtscheller et al., 1998b). Based of these previous reports, our ®ndings of delta and alpha-1 synchronization in the somatosensory cortical areas contralateral to tonic muscle pain might suggest a decreased cellular excitability and a process of cortical inhibition in this region during pain sensation. This could explain why the intramuscular infusion of hypertonic saline in some conditions entails hyposensitivity to pin-prick and touch (Graven-Nielsen et al., 1997) and, more generally, why the presence of pain reduces tactile perception (Feinstein et al., 1954; Apkarian et al., 1994; Tommerdahl et al., 1996). A recent EEG study also indicated decreased cerebral activity during sustained pain. Backonja et al. (1991) compared the effect of cool water and cold water tests on the EEG activity in 14 normal healthy subjects. The results showed that tonic painful stimulation in humans produces sustained bilateral augmentation of alpha-1 power in frontal and posterior regions after an initial decrease. The authors suggested that initial somatosensory activation in response to pain (decreased alpha-1 power) progress to somatosensory inhibition (alpha-1 augmentation) after the ®rst min of stimulation. Our results contrast with ®ndings of another EEG study using injection of hypertonic saline to induce pain in jaw muscles (Veerasarn and Stohler, 1992). That study did not ®nd signi®cant changes in alpha-1 power spectrum, although an increase of beta frequency was observed. One possible reason for this discrepancy is that theta and alpha-1 bands were averaged together in the data analysis. However, EEG frequency bands (and in particular alpha-1 and alpha-2 bands) are likely to provide complementary and different information (Backonja et al., 1991; Pfurtsceller and Lopes da Silva, 1999). Another possible explanation for the difference between our results and those of Veerasarn and Stohler comes from the evidence that nociceptive inputs from jaw and arm muscles are processed in different thalamic nuclei, i.e. ventro postero-medial (VPM) and ventro postero-lateral (VPL), respectively (Sessle, 1990; Mense, 1993; Jones and Derbyshire, 1996; Bromm and Lorenz, 1998). In our subjects the main EEG changes induced by pain (increase of delta and alpha-1 power in the parietal region)
were bilaterally distributed, even if more pronounced on the side contralateral to the stimulation (P4 vs. P3, paired t test P , 0:05). These ®ndings are in agreement with the common knowledge that pain has bilateral cortical representation (Carreras and Andersson, 1963) and the paininduced activity in the contralateral hemisphere is higher than in the ipsilateral one (Woolsey and Fairman, 1946). 4.2. Somatosensory parietal cortex and pain: contribution of electrophysiological and imaging studies The cortical representation of pain and, in particular the role of the primary somatosensory cortex (SI) in pain perception, has become an important matter of current investigation by imaging techniques. Whereas studies from a number of laboratories show that the parietal area is activated during presentation of noxious stimuli as well as in association with some pathological pain states, others do not report such activation (Derbyshire and Jones, 1998; Bushnell et al., 1999). This controversy has not been solved even by neurophysiologic studies which either failed (Kakigi et al., 1995; Bromm and Chen, 1995; Watanabe et al., 1998; Valeriani et al., 2000b) or succeeded (Tarkka and Treede, 1993; Ploner et al., 1999; Kanda et al., 2000) in showing an SI activation due to nociceptive inputs. In addition, in the previous literature there are data supporting an inhibition of the SI area during experimental tonic pain. Apkarian et al. (1992) reported decreased SI activity using SPECT during immersion of the right hand in a noxious hot water bath and suggested that the activity in SI area is inhibited to facilitate localization of painful stimuli (Stea and Apkarian, 1992). The hypothesis that tonic pain processes produce enhanced cross-modality suppression on ongoing competing sensory or cognitive processes has also been suggested in a recent positron emission tomography (PET) study by Rainville et al. (1999). Tonic pain experience during clinical disorders also appears to result in decreased activity in the somatosensory thalamus and cortex (Di Piero et al., 1991; Canavero et al., 1993; Hsieh et al., 1995; Iadarola et al., 1995). On the contrary, in a PET study no change was detected in SI region during experimental tonic heat stimulation (Derbyshire and Jones, 1998) and in a fMRI study an activation of the SI area after subcutaneous injection of ascorbic acid solution was found (Porro et al., 1998). However, tonic pain does not have the same characteristic when induced in muscle and subcutis (Inman and Saunders, 1944; Vecchiet et al., 1990; Graven-Nielsen et al., 1997), as also demonstrated by the lack of hypoesthesia to touch and hypoalgesia after infusion of hypertonic saline in the subcutis (Graven-Nielsen et al., 1997). It should also be mentioned that, during phasic painful stimulation, some metabolic studies found either a reduced (Drevets et al., 1995; Derbyshire et al., 1997; Peyron et al., 1999) or an increased (Talbot et al., 1991; Coghill et al., 1994; Svensson et al., 1997) cerebral blood ¯ow in SI cortex. However, any comparison with our ®ndings is made dif®cult by the
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evidence that tonic and phasic noxious stimuli activate different populations of C and A-delta ®ber nociceptors and are transmitted to different thalamic nuclear areas (Fields, 1987; Apkarian et al., 1991; Apkarian et al., 1992). This ®nding may also explain the apparent discrepancy between our results and those of other neurophysiological studies, where phasic painful stimuli produced an activation of the primary somatosensory region (Ploner et al., 1999; Kanda et al., 2000). In our recordings, no EEG changes were detected over scalp regions corresponding to the secondary somatosensory (SII)/insular cortex (lower temporal region) or cingulate cortex (centro-frontal midline), which have been shown to participate in the central processing of nociceptive stimuli by neurophysiological (Tarkka and Treede, 1993; Kitamura et al., 1995; Kakigi et al., 1995; Bromm and Chen, 1995; Valeriani et al., 1996; Watanabe et al., 1998; Valeriani et al., 2000a) and imaging (Talbot et al., 1991; Coghill et al., 1994; Casey et al., 1994; Xu et al., 1997; Peyron et al., 1998) techniques. However, our results agree with previous studies on-going EEG, which did not show activity changes in the SII/insular and cingular cortices during tonic pain (Backonja et al., 1991; Ferracuti et al., 1994). Since a tonic painful stimulus is likely to produce a low degree of neuronal synchronous activity and a small response, a transient and short-lasting modi®cation of EEG activity over SII/insula or cingulate cortex could remain undetected by the on-going EEG recordings or masked by the larger and longer-lasting EEG changes occurring over other regions. Moreover, it should also be considered that the responses generated in SII/insular area may be dif®cult to identify by EEG recordings (Kitamura et al., 1995) because of their vertical and tangential orientation to the surface scalp electrodes. 4.3. Other speci®c EEG changes In our subjects, the comparison between muscle pain and vibration with their respective baselines showed an increased beta power which persisted in the recovery stage after muscle pain, but not after vibration. Moreover, the comparison of the EEG recordings during the recovery stages of both pain and vibration conditions demonstrated an increase not only in beta, but also in delta power after muscle pain. The increase of both delta and beta powers might be related to the emotional/attentional component of human pain responsiveness. Acute stress and discomfort is known to produce slow EEG frequency increase (Berkout et al., 1969; Chen et al., 1989) and the increased beta power in the temporo-parietal loci has been attributed to the vigilance scanning of pain processes (Giannitrapani, 1971; Chen et al., 1989; Veerasarn and Stohler, 1992). Assuming that increase of beta power re¯ects an attentional demand, as discussed above, it is not surprising that synchronization in the beta frequency can be found also during the vibratory stimulation. Indeed, our ®nding of increased beta activity in
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the right frontal area during vibration agrees with previous EEG studies, where the same ®nding had been observed during presentation of stimuli, which require attention (Giannitrapani, 1966; Giannitrapani, 1971). The different EEG pattern after the end of the painful or non-painful stimuli suggests that the requirement of attentional resources is signi®cantly longer after pain. Further investigations are needed to clarify the mechanism responsible for the persistence of the EEG changes also after the end of the painful stimulation, but our results concur with previous reports of long-lasting effect of pain on EEG activity (Gotliebsen and Arendt-Nielsen, 1990). Enduring central changes after noxious stimulation, lasting even many hours after the recovery from pain, have been also described (Wall and Woolf, 1984; Vecchiet et al., 1988; Hoheisel and Mense, 1989; Hoheisel and Mense, 1990; Gracely et al., 1992). According to traditional views, pain experience results from a multidimensional integration of sensorydiscriminative, affective-motivational (unpleasantness) and cognitive-evaluative axes (Melzack and Casey, 1968; Melzack and Katz, 1994). The affective-motivational components are thought to be present to varying degrees depending on the type of pain stimulus and, speci®cally, tonic pain is considered more unpleasant or bothersome than phasic pain stimuli (Chen and Treede, 1985; Rainville et al., 1992). Recently, Fields (1999) has suggested that, while some aspects of pain (algosity and unpleasantness) are tightly coupled to stimulus intensity, there is a component of unpleasantness (secondary unpleasantness), which is not strictly related to the somatic sensory discrimination, but re¯ects cognitive-evaluative factors (e.g. memories, context cues). In this respect, our ®ndings suggest that the emotional-attentional and cognitive components of pain might be an important part in the long-lasting electrophysiological processing of tonic nociceptive input. 5. Conclusions To our knowledge, this is the ®rst study which reports signi®cant well-localised EEG changes in delta and alpha-1 power during tonic muscle pain stimulation, compared with a non-painful sensory input (vibration). Since these EEG modi®cations did not occur during control non-painful stimulation, they are likely related to some aspects of the multidimensional sensory experience of pain. Compared to previous results, the present study indicates that the most important EEG effect of painful stimulation can be detected over the contralateral parietal lobe. These EEG changes could be related to inhibitory process occurring in the somatosensory area. Acknowledgements The present study was supported by the Danish National Research Foundation.
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Long-lasting effect evoked by tonic muscle pain on parietal EEG activity in humans Domenica Le Pera a,b,*, Peter Svensson a, Massimiliano Valeriani b,c, Ippei Watanabe a, Lars Arendt-Nielsen a, Andrew C.N. Chen a a
Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark b Department of Neurology, UniversitaÁ Cattolica del S. Cuore, Roma, Italy c Casa di cura San Raffaele Pisana, Tosinvest SanitaÁ, Roma, Italy Accepted 15 September 2000
Abstract Objective: To explore EEG changes evoked by tonic experimental muscle pain compared to a non-painful vibratory stimulus. Methods: Thirty-one EEG channels were recorded before, during and after painful and non-painful stimulation. Pain was induced in the left brachioradialis muscle by injection of hypertonic (5%) saline. The vibratory stimulus was applied to the skin area overlying the brachioradialis muscle. The power of the major frequency components of the EEG activity (FFT, fast Fourier transform) was quanti®ed and t-maps between the different experimental conditions were evaluated in frequency domain. Results: The main effect of muscle pain, compared to non-painful stimulation, was a signi®cant and long-lasting increase of delta (1±3 Hz) power and an alpha-1 (9±11 Hz) power increase over the contralateral parietal locus. This ®nding could suggest a decreased excitability of the primary somatosensory cortex during muscle pain. The main effect of vibration, compared to its unstimulated baseline, consisted in an increase of beta-1 (14±20 Hz) power in the right frontal region. Conclusions: Our data demonstrate signi®cant and speci®c topographic EEG changes during tonic muscle pain. Since these modi®cations differ from those produced by an unstimulated baseline and during non-painful tonic stimulation, they might re¯ect mechanisms involved in the processing of nociceptive and adverse tonic stimuli. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Muscle pain; Electroencephalography; Event-related synchronization; Somatosensory cortex inhibition
1. Introduction In the past decades, many attempts have been made to apply neurophysiological methods for the evaluation of human pain (for a review see Bromm and Lorenz, 1998). However, an understanding of the electrophysiological nociceptive processing in the human brain has remained elusive, probably because of the complexity and multiplicity of mechanisms supporting this sensorial experience. In particular, neurophysiological studies, which aimed to identify tonic pain-relevant information in the electroencephalogram (EEG), have not led to clear conclusions (Chen, 1993; Bromm and Lorenz, 1998). Analyses of EEG power spectra have suggested that EEG amplitude and frequency components may be in¯uenced by the experience of pain. During tonic painful stimulation, a * Corresponding author. Istituto di Neurologia, Policlinico A. Gemelli, L.go A. Gemelli 8, 00168 Roma, Italy. Fax: 139-06-3550-1909. E-mail address: [email protected] (D. Le Pera).
bilateral and diffuse increase in slow activity (Chen et al., 1989; Gotliebsen and Arendt-Nielsen, 1990; Ferracuti et al., 1994), as well as increases in alpha power (Backonja et al., 1991) and beta power (Chen et al., 1989; Veerasarn and Stohler, 1992) have been shown. However, the functional meaning of these EEG changes has not unequivocally been interpreted. Indeed, because of their inconsistency and the relative poor spatial resolution, the EEG modi®cations induced by pain have been thought to be related to nonspeci®c muscle tension, motor withdrawal responses or a stress-induced activation (Veerasarn and Stohler, 1992; Chen, 1993; Bromm and Lorenz, 1998). In contrast, the signi®cant difference between the EEG changes during painful and non-painful stimulation has suggested that pain itself may speci®cally affect the spontaneous electrical brain activity in frontal and parietal regions (Backonja et al., 1991). The involvement of these cortical areas in pain processing has also been con®rmed by neurophysiological studies using pain-related evoked potentials (Tarkka and Treede, 1993; Bromm and Chen, 1995; Valeriani et al.,
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S13 88-2457(00)0047 4-0
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1996, 2000a) and magnetoencephalography (Kitamura et al., 1995; Kakigi et al., 1995; Watanabe et al., 1998; Ploner et al., 1999; Kanda et al., 2000) as well as by the neuroimaging techniques (Talbot et al., 1991; Coghill et al., 1994; Casey et al., 1996; Svensson et al., 1997; Xu et al., 1997; Peyron et al., 1999). The aims of the present study were ®rst to explore EEG changes in relation to saline-induced experimental tonic muscle pain and second to examine whether these effects are speci®c for processing nociceptive input by comparing them with EEG modi®cations evoked by tonic non-painful vibratory stimulus.
rating during the recording of EEG in a time interval of 60 s was calculated.
2. Methods
2.5. Experimental protocol
2.1. Subjects
On two occasions, separated by one week, the subjects repeated the procedure for the muscle pain condition and the non-painful vibratory condition in a randomised order. Each experimental condition consisted of 3 stages: baseline, task and recovery. At the baseline stage (baseline 1: pain; baseline 2: vibration), 1 min of EEG recordings were obtained from the subjects with both eyes closed. During the task stage, 1 min of EEG was recorded while the subjects were exposed to the painful stimulation (after a stable level of pain intensity was reached) or the vibratory stimuli. The recovery stage (recovery 1: pain; recovery 2: vibration) consisted of 1 min of EEG recordings under conditions identical to the baseline stage and it was performed after 10 min from the pain/vibration disappeared.
Twelve young healthy male volunteers (age: 26.6 ^ 5.8 years), with no previously reported neurological illness, were included in the study. Written informed consents were obtained from all volunteers in accordance with the Declaration of Helsinki. The study was approved by the local Ethics Committee. 2.2. EEG recordings EEG recordings were obtained from subjects sitting quietly in a reclined chair with both eyes closed during the experiment. Surface recording electrodes (impedance below 5 KV) were placed at thirty-one locations on the scalp according to an enriched International 10±20 System with the use of an electrode cap (Electro-Cap international, Inc USA). The common reference was at linked ears. The ®lter bandpass 0.1±100 Hz and the recording were made by a sampling rate of 256 Hz using a Neuroscan EEG system (Herndon, Virginia, USA). EEG was recorded continuously for 1 min during the baseline, task and recovery stages. 2.3. Experimental muscle pain Pain was induced in the left brachioradialis muscle by infusion of hypertonic (5%) saline. The infusion was carried out by a computer-controlled syringe pump (IVAC, model 770, USA; Graven-Nielsen et al., 1997) with a 10-ml plastic syringe. A tube (IVAC G30303, extension set with polyethylene inner line) was connected from the syringe to the disposable stainless needle (27G, 40 mm). A standardised infusion paradigm was applied: a bolus of 0.5 ml saline was infused over 20 s followed by a steady infusion rate of 18 ml/hour for the next 440 s, and ®nally 36 ml/hour for the next 440 s (Graven-Nielsen et al., 1997). The subjects on a 0±10 electronic visual analogue scale (VAS) continuously scored the pain intensity where 0 cm indicated `no pain' and 10 cm `intolerable pain'. The VAS score was sampled every 5 s by the computer. The pain
2.4. Vibration Vibratory stimuli consisted of 120 Hz non-painful stimulation above the left brachioradialis muscle. The vibratory stimuli were controlled by a vibrator (Vibrameter type 4, Somedic AB, Sweden). The stimulator (650 g; probe diameter: 12 mm) was held perpendicularly to the surface at the stimulus location, and the amplitude was adjusted to a displacement of 200 microns. This sensation of the stimuli was always reported as non-painful.
2.6. Data analysis For frequency analysis of background EEG, 1 min of artefact-free EEG was examined according to the IFCN guidelines for topographic and frequency analysis of EEGs (Nuwer et al., 1994). The major components of EEG power change were isolated using fast Fourier transformation (FFT). T-maps comparing stages (task vs. baseline and recovery vs. baseline) and conditions (baseline 1 vs. baseline 2, pain vs. vibration, recovery 1 vs. recovery 2) were evaluated for the following frequency bands: delta (1±3 Hz), theta (4±8 Hz), alpha-1 (9±11 Hz), alpha-2 (11± 13 Hz), beta-1 (14±20 Hz) and beta-2 (20±32 Hz). The calculation of the t-maps was performed by interpolation between t-values at the 31 electrodes. Only frequency bands showing signi®cant differences in the t-maps (P , 0:05) were chosen for further statistical analysis. Absolute band power was converted into percentage power (relative power) by de®ning the total power in the frequency interval 1±32 Hz as 100%. The calculated relative power data were submitted to analysis of variance (two-way ANOVA) by considering scalp location and experimental stage as sources of variation. When a signi®cant level (P , 0:05) was reached, one-way ANOVA was
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Hz) and beta-2 bands (20±26 Hz) over the right posterior parietal locus (P4) and an increase of power within the alpha-1 band (9±11 Hz) over both parietal regions (P3, P4) (Fig. 2). It is remarkable that the relative power increase in the alpha-1 band was more signi®cant over the right parietal area, contralateral to the injection site (P4, P , 0:01) than over the left parietal area, ipsilateral to the injection site (P3, P , 0:04). (b) The delta and beta-2 activity modi®cation over the right parietal region persisted during the recovery stage (Fig. 2). 3.2.2. Vibration (a) The t-map comparing vibration with baseline 2 showed a signi®cant increase of power within the beta-1 band (14±20 Hz) over the right frontal region (F4) (Fig. 2). (b) This effect did not persist during the recovery stage.
Fig. 1. Mean VAS-time curve (n 12) during 15 min infusion of hypertonic saline in the left brachioradialis muscle. The duration of saline infusion and the start of EEG recording are indicated.
performed for each scalp location. If the one-way ANOVA was signi®cant (P , 0:05), a post-hoc analysis by Student's t test was used to compare the different stages.
3.2.3. Comparison between muscle pain and vibration (a) No signi®cant difference was observed in the comparison between baseline 1 and 2 (Fig. 3). (b) Compared to vibration, the main effect of muscle pain was an increase of delta and alpha-1 powers over the parietal loci bilaterally (P3, P4) (Fig. 3). When the relative power data were considered, the statistical signi®cance was reached only over the right parietal region, contralateral to the injection site (P4, P , 0:05; P3, P 0:3), for delta frequency and over both the parietal loci (P4, P , 0:01; P3, P , 0:04) for alpha-1 band. (c) The comparison between recovery 1 and 2 showed an increase of delta and beta-2 (20±26 Hz) power over the parietal region (Pz) (Fig. 3).
3. Results 3.1. Experimental muscle pain EEG recordings (1 min) were performed 5.8 ^ 1.4 min (mean ^ SD; n 12) after the onset of hypertonic saline infusion, when the pain intensity rating became stable (Fig. 1). The mean pain rating during EEG recordings was 5.0 ^ 1.8 and was signi®cantly different from the mean pain rating during the ®rst min after infusion (0.3 ^ 0.2, Student's t test: P , 0:01). 3.2. EEG changes topography
4. Discussion
All the signi®cant topographic EEG changes observed in the t-map comparisons were con®rmed when the relative power values were also analysed (Table 1).
This study demonstrated that tonic muscle pain induces speci®c and long-lasting EEG changes, compared with nonpainful vibration. In particular, increments of both delta and alpha-1 powers were observed bilaterally over the parietal area, more pronounced over the region contralateral to the painful stimulation.
3.2.1. Experimental muscle pain (a) The t-map comparing muscle pain with baseline 1 showed a signi®cant increase of power within delta (1±3
Table 1 Locations of signi®cant relative power comparisons (t test) between stages and conditions a Frequency Muscle pain
delta alpha-1 beta-1 beta-2 a
Vibration
Muscle pain vs. Vibration
Pain±baseline 1 Baseline 1±recovery 1 Vibration±baseline 2 Baseline 2± recovery 2
Baseline 1± baseline 2
Pain±vibration Recovery 1±recovery 2
P4 (P , 0.02) P4 (P , 0.01) P3 (P , 0.04) ± P4 (P , 0.02)
± ± ± ± ±
P4 (P , 0.03) P4 (P , 0.01) P3 (P , 0.04) ± ±
(±) Non signi®cant values.
P4 (P , 0.03) ± ± ± P4 (P , 0.04)
± ± ± F4 (P , 0.007) ±
± ± ± ± ±
Pz (P , 0.04) ± ± ± Pz (P , 0.01)
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Fig. 2. T-maps (cut-off: 22.5 to 12.5, P , 0:05) comparing the different stages (task vs. baseline and recovery vs. baseline) of each experimental condition (muscle pain and vibration). All the analysed frequency bands are displayed. The positions of the electrodes are marked in each map with black dots. Red colour indicates an increase of the EEG power.
4.1. Contralateral parietal delta and alpha-1 power increase during muscle pain The injection of hypertonic saline in the left arm led to an increase of delta and alpha-1 powers over the contralateral posterior parietal locus. This ®nding of delta power increase is in accordance with previous EEG studies, which have used tonic painful stimulation (Chen et al., 1989; Ferracuti et al., 1994). Although the mechanism responsible for the pain-related increase in delta activity has not yet been clari®ed, enhanced slow waves are usually considered to be an expression of cortical inhibition (Kogan, 1960). An increase in amplitude of the slow frequencies in the parietal area was found during control of painful stimulation in fakirs (Pelletier, 1977; Larbig et al., 1982) and a signi®cantly increased delta activity during experimental tonic pain was interpreted
as an attempt to inhibit sensorial perception of the nociceptive input (Ferracuti et al., 1994). The changes in alpha-1 power, which have been reported in our study, are not likely to represent traditional alpha-1 desynchronization (ERD: event-related desynchronization). This phenomenon is characterized by phasic decreases of alpha-1 power and has been associated with neural activation in human visual, auditory, somatosensory and motor system in response to different stimulation paradigms (Grillon and Buchsbaum, 1986; Pfurtscheller, 1989; Pfurtscheller and Berghold, 1989). Instead, our ®ndings are characterized by an augmentation of alpha-1 band activity (ERS: event-related synchronization) evoked by tonic stimulation. Studies on alpha-1 enhancement have demonstrated that when patches of neurones display synchronization in the alpha-1 band, an active processing of information
Fig. 3. T-maps (cut-off: 22.5 to 12.5, P , 0:05) between the experimental conditions (muscle pain vs. vibration) comparing correspondent stages (baseline 1 vs. baseline 2, muscle pain vs. vibration, recovery 1 vs. recovery 2). All the analysed frequency bands are displayed. The positions of the electrodes are marked in each map with black dots. Red colour indicates an increase of the EEG power. Notice that an increment of both delta and alpha-1 powers was observed bilaterally in the parietal area during muscle pain compared to vibration.
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is very unlikely and it may be assumed that the corresponding networks are in state of decreased neural excitability (Pfurtscheller, 1992), or even in a state of cortical inhibition (Klimesch, 1996; Klimesch et al., 1999). Examples of such `idling' area (Pfurtscheller et al., 1996b), which display locally enhanced alpha-1 band power, are represented by the primary sensorimotor hand area during foot movement or visual processing, the visual areas during execution of a motor task or the primary motor area after termination of movement (Pfurtscheller, 1992; Pfurtscheller and Neuper, 1994; Pfurtscheller et al., 1996a,b, 1998a). In this respect, it is of interest that some authors have suggested a good correlation between `idling' cortical areas, EEG patterns of synchronized activity and decreased regional blood ¯ow as a correlate of synaptic inhibition (Apkarian et al., 1992; Pfurtscheller et al., 1998b). Based of these previous reports, our ®ndings of delta and alpha-1 synchronization in the somatosensory cortical areas contralateral to tonic muscle pain might suggest a decreased cellular excitability and a process of cortical inhibition in this region during pain sensation. This could explain why the intramuscular infusion of hypertonic saline in some conditions entails hyposensitivity to pin-prick and touch (Graven-Nielsen et al., 1997) and, more generally, why the presence of pain reduces tactile perception (Feinstein et al., 1954; Apkarian et al., 1994; Tommerdahl et al., 1996). A recent EEG study also indicated decreased cerebral activity during sustained pain. Backonja et al. (1991) compared the effect of cool water and cold water tests on the EEG activity in 14 normal healthy subjects. The results showed that tonic painful stimulation in humans produces sustained bilateral augmentation of alpha-1 power in frontal and posterior regions after an initial decrease. The authors suggested that initial somatosensory activation in response to pain (decreased alpha-1 power) progress to somatosensory inhibition (alpha-1 augmentation) after the ®rst min of stimulation. Our results contrast with ®ndings of another EEG study using injection of hypertonic saline to induce pain in jaw muscles (Veerasarn and Stohler, 1992). That study did not ®nd signi®cant changes in alpha-1 power spectrum, although an increase of beta frequency was observed. One possible reason for this discrepancy is that theta and alpha-1 bands were averaged together in the data analysis. However, EEG frequency bands (and in particular alpha-1 and alpha-2 bands) are likely to provide complementary and different information (Backonja et al., 1991; Pfurtsceller and Lopes da Silva, 1999). Another possible explanation for the difference between our results and those of Veerasarn and Stohler comes from the evidence that nociceptive inputs from jaw and arm muscles are processed in different thalamic nuclei, i.e. ventro postero-medial (VPM) and ventro postero-lateral (VPL), respectively (Sessle, 1990; Mense, 1993; Jones and Derbyshire, 1996; Bromm and Lorenz, 1998). In our subjects the main EEG changes induced by pain (increase of delta and alpha-1 power in the parietal region)
were bilaterally distributed, even if more pronounced on the side contralateral to the stimulation (P4 vs. P3, paired t test P , 0:05). These ®ndings are in agreement with the common knowledge that pain has bilateral cortical representation (Carreras and Andersson, 1963) and the paininduced activity in the contralateral hemisphere is higher than in the ipsilateral one (Woolsey and Fairman, 1946). 4.2. Somatosensory parietal cortex and pain: contribution of electrophysiological and imaging studies The cortical representation of pain and, in particular the role of the primary somatosensory cortex (SI) in pain perception, has become an important matter of current investigation by imaging techniques. Whereas studies from a number of laboratories show that the parietal area is activated during presentation of noxious stimuli as well as in association with some pathological pain states, others do not report such activation (Derbyshire and Jones, 1998; Bushnell et al., 1999). This controversy has not been solved even by neurophysiologic studies which either failed (Kakigi et al., 1995; Bromm and Chen, 1995; Watanabe et al., 1998; Valeriani et al., 2000b) or succeeded (Tarkka and Treede, 1993; Ploner et al., 1999; Kanda et al., 2000) in showing an SI activation due to nociceptive inputs. In addition, in the previous literature there are data supporting an inhibition of the SI area during experimental tonic pain. Apkarian et al. (1992) reported decreased SI activity using SPECT during immersion of the right hand in a noxious hot water bath and suggested that the activity in SI area is inhibited to facilitate localization of painful stimuli (Stea and Apkarian, 1992). The hypothesis that tonic pain processes produce enhanced cross-modality suppression on ongoing competing sensory or cognitive processes has also been suggested in a recent positron emission tomography (PET) study by Rainville et al. (1999). Tonic pain experience during clinical disorders also appears to result in decreased activity in the somatosensory thalamus and cortex (Di Piero et al., 1991; Canavero et al., 1993; Hsieh et al., 1995; Iadarola et al., 1995). On the contrary, in a PET study no change was detected in SI region during experimental tonic heat stimulation (Derbyshire and Jones, 1998) and in a fMRI study an activation of the SI area after subcutaneous injection of ascorbic acid solution was found (Porro et al., 1998). However, tonic pain does not have the same characteristic when induced in muscle and subcutis (Inman and Saunders, 1944; Vecchiet et al., 1990; Graven-Nielsen et al., 1997), as also demonstrated by the lack of hypoesthesia to touch and hypoalgesia after infusion of hypertonic saline in the subcutis (Graven-Nielsen et al., 1997). It should also be mentioned that, during phasic painful stimulation, some metabolic studies found either a reduced (Drevets et al., 1995; Derbyshire et al., 1997; Peyron et al., 1999) or an increased (Talbot et al., 1991; Coghill et al., 1994; Svensson et al., 1997) cerebral blood ¯ow in SI cortex. However, any comparison with our ®ndings is made dif®cult by the
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evidence that tonic and phasic noxious stimuli activate different populations of C and A-delta ®ber nociceptors and are transmitted to different thalamic nuclear areas (Fields, 1987; Apkarian et al., 1991; Apkarian et al., 1992). This ®nding may also explain the apparent discrepancy between our results and those of other neurophysiological studies, where phasic painful stimuli produced an activation of the primary somatosensory region (Ploner et al., 1999; Kanda et al., 2000). In our recordings, no EEG changes were detected over scalp regions corresponding to the secondary somatosensory (SII)/insular cortex (lower temporal region) or cingulate cortex (centro-frontal midline), which have been shown to participate in the central processing of nociceptive stimuli by neurophysiological (Tarkka and Treede, 1993; Kitamura et al., 1995; Kakigi et al., 1995; Bromm and Chen, 1995; Valeriani et al., 1996; Watanabe et al., 1998; Valeriani et al., 2000a) and imaging (Talbot et al., 1991; Coghill et al., 1994; Casey et al., 1994; Xu et al., 1997; Peyron et al., 1998) techniques. However, our results agree with previous studies on-going EEG, which did not show activity changes in the SII/insular and cingular cortices during tonic pain (Backonja et al., 1991; Ferracuti et al., 1994). Since a tonic painful stimulus is likely to produce a low degree of neuronal synchronous activity and a small response, a transient and short-lasting modi®cation of EEG activity over SII/insula or cingulate cortex could remain undetected by the on-going EEG recordings or masked by the larger and longer-lasting EEG changes occurring over other regions. Moreover, it should also be considered that the responses generated in SII/insular area may be dif®cult to identify by EEG recordings (Kitamura et al., 1995) because of their vertical and tangential orientation to the surface scalp electrodes. 4.3. Other speci®c EEG changes In our subjects, the comparison between muscle pain and vibration with their respective baselines showed an increased beta power which persisted in the recovery stage after muscle pain, but not after vibration. Moreover, the comparison of the EEG recordings during the recovery stages of both pain and vibration conditions demonstrated an increase not only in beta, but also in delta power after muscle pain. The increase of both delta and beta powers might be related to the emotional/attentional component of human pain responsiveness. Acute stress and discomfort is known to produce slow EEG frequency increase (Berkout et al., 1969; Chen et al., 1989) and the increased beta power in the temporo-parietal loci has been attributed to the vigilance scanning of pain processes (Giannitrapani, 1971; Chen et al., 1989; Veerasarn and Stohler, 1992). Assuming that increase of beta power re¯ects an attentional demand, as discussed above, it is not surprising that synchronization in the beta frequency can be found also during the vibratory stimulation. Indeed, our ®nding of increased beta activity in
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the right frontal area during vibration agrees with previous EEG studies, where the same ®nding had been observed during presentation of stimuli, which require attention (Giannitrapani, 1966; Giannitrapani, 1971). The different EEG pattern after the end of the painful or non-painful stimuli suggests that the requirement of attentional resources is signi®cantly longer after pain. Further investigations are needed to clarify the mechanism responsible for the persistence of the EEG changes also after the end of the painful stimulation, but our results concur with previous reports of long-lasting effect of pain on EEG activity (Gotliebsen and Arendt-Nielsen, 1990). Enduring central changes after noxious stimulation, lasting even many hours after the recovery from pain, have been also described (Wall and Woolf, 1984; Vecchiet et al., 1988; Hoheisel and Mense, 1989; Hoheisel and Mense, 1990; Gracely et al., 1992). According to traditional views, pain experience results from a multidimensional integration of sensorydiscriminative, affective-motivational (unpleasantness) and cognitive-evaluative axes (Melzack and Casey, 1968; Melzack and Katz, 1994). The affective-motivational components are thought to be present to varying degrees depending on the type of pain stimulus and, speci®cally, tonic pain is considered more unpleasant or bothersome than phasic pain stimuli (Chen and Treede, 1985; Rainville et al., 1992). Recently, Fields (1999) has suggested that, while some aspects of pain (algosity and unpleasantness) are tightly coupled to stimulus intensity, there is a component of unpleasantness (secondary unpleasantness), which is not strictly related to the somatic sensory discrimination, but re¯ects cognitive-evaluative factors (e.g. memories, context cues). In this respect, our ®ndings suggest that the emotional-attentional and cognitive components of pain might be an important part in the long-lasting electrophysiological processing of tonic nociceptive input. 5. Conclusions To our knowledge, this is the ®rst study which reports signi®cant well-localised EEG changes in delta and alpha-1 power during tonic muscle pain stimulation, compared with a non-painful sensory input (vibration). Since these EEG modi®cations did not occur during control non-painful stimulation, they are likely related to some aspects of the multidimensional sensory experience of pain. Compared to previous results, the present study indicates that the most important EEG effect of painful stimulation can be detected over the contralateral parietal lobe. These EEG changes could be related to inhibitory process occurring in the somatosensory area. Acknowledgements The present study was supported by the Danish National Research Foundation.
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