Subcortical structures involved in pain processing:... : PAIN (original) (raw)
1. Introduction
Pain is considered to be a complex multi-dimensional experience, comprising sensory-discriminative, affective and emotional aspects (Melzack and Wall, 1999). The nociceptive system is essential for reaction to potential life-threatening situations and has to fulfil several requirements: reception and analysis of nociceptive sensory input, shift of attention towards pain processing, retention of pain-related information in working memory, encoding the episode, to avoid similar stimuli in the future, and providing information about the stimulus location for the motor system to prepare and guide a defense. Additionally, the experience of pain is significantly linked to emotional processes including fear, stress and subsequent autonomic responses. Subcortical structures are substantially involved in a variety of those aspects accompanying pain perception. For instance, basal ganglia and cerebellum are involved in motor preparation (Toni et al., 1998; Weiller et al., 1996), thalamus in arousal and attention (Portas et al., 1998), hypothalamus in mediating autonomic (Lumb and Lovick, 1993) and anti-nociceptive (Wang et al., 1990) responses, amygdala in emotional and affective components (Morris et al., 1996) and hippocampus in memory and learning processes (Parkin, 1996).
However, little is known about the role of subcortical structures in nociceptive information processing. One crucial aspect regarding defensive behavior is whether spatial information of the provoking stimulus is processed within subcortical parts of the nociceptive network. Previous neuroimaging pain studies have repeatedly, but inconsistently, reported signal changes in response to pain in the cerebellum (Becerra et al., 1999; Brooks et al., 2002; Casey et al., 1996; Coghill et al., 2001; Ploghaus et al., 1999; Xu et al., 1997), amygdala (Becerra et al., 1999; Bornhövd et al., 2002; Derbyshire et al., 1997; Schneider et al., 2001), hippocampus (Derbyshire et al., 1997; Ploghaus et al., 2000), midbrain (Casey et al., 1996; Iadarola et al., 1998), and putamen (Coghill et al., 2001; Xu et al., 1997).
A very basic form of spatial coding is achieved by asymmetry of hemispheric representation, i.e. greater response contralateral than ipsilateral (or vice versa) with respect to the stimulated body side. Given that some subcortical structures (basal ganglia, cerebellum) are at least partially involved in motor preparation related to anti-nociceptive behavior it is essential for these structures to receive information about the location of the noxious stimulus. We therefore hypothesized that these subcortical structures would show an asymmetric, i.e. contra or ipsilateral representation, whereas other subcortical structures more concerned with coding the affective dimension of pain (e.g. amygdala) would show symmetric i.e. bilateral activation to painful stimuli. This can be seen in analogy to cortical pain processing, where spatial information regarding painful stimuli is represented in a contralateral manner in SI and SII and posterior insula but not in the anterior cingulate cortex (ACC) or the anterior insula (Brooks et al., 2002; Coghill et al., 2001; Ploner et al., 1999).
Most previous functional neuroimaging studies were not able to test for ipsi/contralateral spatial representation of painful stimuli, because they only applied unilateral painful stimuli (Becerra et al., 1999; Derbyshire et al., 1997; Xu et al., 1997; Davis et al., 1998), precluding a direct comparison between left- and right-sided painful stimulations. Furthermore, most studies have used contact heat (Brooks et al., 2002; Casey et al., 1996; Coghill et al., 2001) or electrical stimuli (Davis et al., 1995), which at least tonically, activate mechano-receptors, thus potentially confounding pain with tactile responses.
The inconsistency of subcortical activations in previous studies can also be related to the low spatial resolution of positron emission tomography (PET) (Derbyshire et al., 1997; Hsieh et al., 1996; May et al., 1998; Xu et al., 1997). Spatial resolution becomes important when assessing small structures like subcortical nuclei in the thalamus or basal ganglia. Furthermore, blocked designs as used in PET (but also in early fMRI) studies pooled neuronal responses over an extended period of time and did not allow relating the measured responses to individual pain stimuli. Thus, these paradigms usually suffer from the inability to fully randomize the side of stimulation as is necessary to test for spatial coding.
To avoid these confounds, we used a thulium(Tm)–YAG (yttrium–aluminum–granate) laser, generating short (1ms), phasic pain stimuli without concomitant tactile components, in combination with single-trial event-related fMRI to study subcortical BOLD responses to randomized nociceptive stimuli applied to either hand. The Tm–YAG laser allows for unpredictable randomized stimulus presentation thus avoiding spatial pain expectancy. Subjects were not required to rate the perceived pain intensity or to respond to the stimulus in any other way, so as to avoid task-related bias in subcortical responses evoked by additional attentional, working memory or motor components (Bornhövd et al., 2002; Buchel et al., 2002).
The aim of our present study was (i) to identify subcortical areas, which respond to nociceptive stimuli, and (ii) to determine whether these activations preserve spatial location (ipsilateral/contralateral) of the nociceptive input. We tested our hypothesis that pain-evoked responses in subcortical structures related to the motor and defense system (e.g. basal ganglia, cerebellum) are asymmetric (i.e. ipsilateral or contralateral), whereas activation in subcortical structures involved in coding the affective component of pain (e.g. amygdala) are symmetric.
2. Methods
2.1. Subjects
Fourteen healthy subjects (13 males, one female) all right-handed, aged 21–41 years (mean 25.8) gave written informed consent to participate in the study, which was conducted in accord with the declaration of Helsinki and approved by the local Ethics committee. All the subjects had normal pain thresholds, no history of neurological or psychiatric disease, and were free to withdraw from the study at any time.
2.2. Laser stimulation
A Tm:YAG infrared laser (Neurolaser, BAASEL Lasertech, Germany) was used to apply computer-controlled brief radiant pain stimuli. The Tm:YAG laser emits near-infrared radiation (wavelength 1.96mm, spot diameter 5mm, pulse duration 1ms) with a penetration depth of 360mm into the human skin. The laser stimulus allows precise restriction of the deposited heat energy to the termination area of primary nociceptive afferents (20–570mm), without damaging the epidermis or affecting the subcutaneous tissue (Spiegel et al., 2000). All ferromagnetic components belonging to the laser head used inside the scanner room were replaced by brass parts. The main laser device was located in the magnetic resonance (MR) control room, and connected to the laser head in the magnet room with a 10m optical fiber, transmitting the laser light. Individual pain thresholds for the site of stimulus application were derived psychophysically for all volunteers in a separate experiment.
2.3. Experimental protocol
In two consecutive fMRI sessions, 40 selective nociceptive cutaneous laser stimuli were applied to the dorsum of either hand in a fully randomized order. To avoid sensitization and habituation, the stimulus site on each hand was slightly changed after each stimulus. The choice of parameters for our painful stimulus (600mJ and 1ms duration) was based on previous fMRI and psychophysical experiments, indicating that 600mJ stimuli evoke a very brief but clearly ‘pin-prick-like’ painful sensation without any warmth or tactile components (Bornhövd et al., 2002; Bromm et al., 1984; Buchel et al., 2002; Spiegel et al., 2000). To minimize spatial (i.e. body-side) and temporal pain expectancy the side of painful stimulation and the inter-stimulus-interval were randomized between 8 and 12s. Subjects were not able to observe the procedure of stimulus application. Since all stimuli were clearly painful, rating of the perceived pain intensity was not requested to minimize additional motor or working memory components. After scanning all subjects reported that the stimuli were moderately painful.
2.4. Image acquisition
MR scanning was performed on a 1.5T magnetic resonance imaging (MRI) system (Siemens Vision). A high resolution (1×1×1mm3 voxel size) T1 weighted structural MRI was acquired for each volunteer using a 3-D FLASH sequence. A total of 205 fMRI scans (32 axial, 3mm thick slices each, 1mm gap) were acquired using a gradient echo, echo-planar (EPI) T2* sensitive sequence (TR 2560ms, TE 40ms, flip angle 90°, matrix 64×64, field of view 210×210mm2). The subjects' head was positioned in a standard head coil with foam pads.
2.5. Image processing and statistical analysis
Image processing and statistical analysis were carried out using SPM99 (Friston et al., 1995; Worsley and Friston, 1995) (http://www.fil.ion.ucl.ac.uk/spm). All volumes were realigned to the first volume (Friston et al., 1995), spatially normalized (Friston et al., 1995) to a standard EPI template (Evans et al., 1993) and finally smoothed using a 6mm isotropic Gaussian kernel. The T1 weighted structural data was co-registered to the functional scans by normalizing it to a T1-weighted template in the same space as the T2* EPI template used to normalize the functional data set. Data analysis was performed using the general linear model and modeling the different trials (pain right, pain left) as delta functions convolved with the canonical hemodynamic response function as implemented in SPM99. The design matrix for each subject contained both sessions. Voxel-wise regression coefficients for all regressors were estimated using least squares within SPM99 (Friston et al., 1995). Effects were tested with appropriate linear contrasts of the regression coefficients (parameter estimates), resulting in a _t_-statistic for every voxel. All contrasts pertained to both sessions, which can be seen as testing for the average activation over both sessions.
These _t_-statistics constitute statistical parametric map (SPM). SPMs are interpreted by referring to the probabilistic behavior of Gaussian random fields (Worsley, 1994). The threshold was set to P<0.05 corrected for multiple comparisons. For the subsequent assessment of asymmetric activations, those subcortical regions, which significantly activated for the main effect of pain were defined as regions of interest. In these regions, we corrected for the individual volume (red nucleus and amygdala for 10mm sphere each, cerebellar hemispheres for 50mm sphere, putamen for a box 25×5×5mm3 and hippocampus for a 30×10×10mm3 box).
These parameters were chosen by approximating the size of each structure in the Montreal Neurological Institute template as provided by SPM.
2.6. Assessment of asymmetric activation
In a first step we identified regions, which significantly activated for the main effect of pain (i.e. pooled over stimulation of the left and the right hand). Within these brain regions, we then tested for asymmetry of the activation, i.e. greater activation contralateral than ipsilateral or vice versa with respect to the stimulated hand. This can be seen as a hemisphere by stimulus interaction. In brief, we assessed homologue regions in the right and left hemisphere that showed greater activation for R>L and for L>R hand stimulation, respectively. For example, if the first comparison (R>L) reveals activation in left primary sensory cortex with a _t_-value of 3.6 and the second contrast (L>R) reveals activation in the right primary sensory cortex with a _t_-value of 4.2 one would conclude that primary sensory cortex shows an asymmetric activation pattern with stronger activation for the contralateral hand. To spatially overlay homologue left and right brain areas, the data for the second contrast were mirrored along the _y_-axis (R–L flipped). This then enabled us to use voxel-based statistics as implemented in SPM to test for this hemisphere by task interaction. To fulfil our strict criteria of asymmetric activation (contralateral or ipsilateral to the stimulus), we used the minimum _t_-value of both contrasts (conjunction analysis) as the final result. In the hypothetical example outlined above, this minimum _t_-value would be _t_=3.6 from the R>L contrast. The different response properties (symmetric vs. asymmetric) can be illustrated by the fitted BOLD response (±SEM) to the laser stimulus (see figures). This fitted response resembles the BOLD response averaged over all volunteers as fitted by the general linear model (i.e. canonical hemodynamic response).
3. Results
We dissociated between two functionally different response patterns:
- Regions that are activated bilaterally, irrespective of whether the right or left hand is stimulated, i.e. regions that do not show a task by hemisphere interaction.
- Regions that show a quantitative asymmetric activations, e.g. predominantly contralateral or ipsilateral activation pattern with respect to the stimulus side.
We also tested for lateralized responses, i.e. responses that are always in either the right or the left hemisphere irrespective of the stimulated hand. However, no significant response of this type was found. Activations in the thalamo-cortical system were also observed but were beyond the scope of this paper and will be reported elsewhere. In short, cortical neuronal response for the main effect of pain was observed in primary and secondary somatosensory cortex, anterior cingulate cortex, insula and thalamus. Activations were asymmetric (contralateral) in SI, SII, posterior insula and lateral thalamic nuclei, whereas activation in medial thalamic nuclei and anterior insula was bilateral.
3.1. Bilateral subcortical activations
The following regions activated significantly for the main effect of pain (pooled over stimulation of the left and right hand (Table 1). The anterior medial temporal lobe (MTL), presumably the amygdalae, an area slightly posterior in the hippocampal complex (Fig. 1(b)), an area in the midbrain, most likely the red nuclei and the lateral aspect of the putamen. Cerebellar activation was observed in a broad region comprising the lateral aspects of the cerebellar hemispheres.
Subcortical regions activated significantly for the main effect of pain (pooled over stimulation of the left and right hand)a
Pain-related activations overlaid on a structural T1 weighted MRI used for spatial normalization. Bilateral laser-evoked fMRI responses are depicted in blue. The graphs show the fitted response to single painful stimuli applied to the left (blue line) or right (red line) hand for the right (right column) and left (left column) hemispheres. The dotted lines show the standard error of the mean (SEM). Bilateral symmetric pain-related responses are shown (a) in the amygdala (blue, 18, −6, −12 and −15, −6, −15 mm) and (b) more posterior in the MTL in the hippocampal complex (blue, 24, −18, −12 and −21, −21, −12 mm).
Within these regions we then tested for a hemisphere by the side of stimulation interaction.
3.1.1. Symmetric bilateral subcortical activations
A symmetric, non-lateralized, bilateral activation in response to unilateral painful stimulation of either side was observed in the amygdalae (Fig. 1(a)) and the hippocampal complex (Fig. 1(b)).
3.1.2. Asymmetric subcortical activations
An asymmetric representation of the BOLD signal (significantly greater activation in the hemisphere contralateral to painful stimuli in either hemisphere) was observed in the red nucleus (Fig. 2(a)) and the putamen (Fig. 2(b)). The cerebellar hemispheres displayed the opposite response pattern, with greater BOLD signal changes in the hemisphere ipsilateral to painful stimulation for both hemispheres (Fig. 2(c)). Although highly significant in the main effect of pain, the hemisphere by stimulus interaction in the cerebellum was only significant at P<0.001 uncorrected.
Pain-related activations overlaid on a structural T1 weighted MRI used for spatial normalization. Bilateral laser-evoked fMRI responses are depicted in blue, lateralized responses as revealed by the conjunction-analysis (for details see Section 2) are depicted in green. Lateralized activations are mirror symmetric due to the hemisphere by task interaction analysis. Note that although the statistical parametric maps are symmetric, the underlying activation time-courses of corresponding (R–L) voxels are not necessarily identical. This is illustrated in the graphs showing the fitted response to single painful stimuli applied to the left (blue line) or right (red line) hand for the right (right column) and left (left column) hemispheres. The dotted lines show the standard error of the mean (SEM). Asymmetric, pain-related responses are shown in (a) the red nucleus (green, ±12, −21, −12 mm; _Z_=3.0, P<0.05 corrected), (b) the putamen (green, ±27, 9, 3 mm; _Z_=2.8, P<0.05 corrected) and (c) the cerebellum (green, ±21, 54, 27 mm; _Z_=2.8, P<0.001 uncorrected).
4. Discussion
By using randomized (i.e. unpredictable) application of touchless laser pain stimuli to either hand in combination with single-trial fMRI, we have identified subcortical regions responding to nociceptive stimuli. Additionally, we differentiated subcortical structures by their response pattern: While the amygdalae and the hippocampal complex showed a bilateral symmetric response to unilateral nociceptive stimulation, the red nuclei, putamen and cerebellum displayed differential (i.e. asymmetric) activation in response to right- or left-sided stimulation indicating that spatial information about the provoking (i.e. nociceptive) stimulus is preserved in these structures.
4.1. Pain stimulus and experimental design
This study deviates from prior work in certain important aspects. The laser-stimulus exclusively activates nociceptive pathways (Bromm et al., 1984; Bromm and Treede, 1984; Spiegel et al., 2000). This avoids bias of concurrent activation of tactile fibers (e.g. Aβ), which is known to be processed differently and could bias pain-related responses. The brief and touchless laser stimulus enabled us to stimulate the right and the left hand in a randomized order. Total randomization is of major importance to minimize bias due to sustained attention, affective components and localized expectancy of pain, as occurs with a permanently fixed thermode or electrical stimulator (Buchner et al., 2000; Sawamoto et al., 2000). The brief pain sensation evoked by the laser stimulus is ideally suited to assess fMRI responses to nociception as compared to phenomena linked to tonic or chronic pain.
Although any painful stimulus inevitably leads to reflexive attentional shifts (Buchel et al., 2002; Peyron et al., 1999), we tried to minimize additional cognitive load e.g. working memory components by omitting pain intensity ratings in this experiment. Indirect proof that we have successfully avoided additional cognitive load comes from the fact that we did not find activation in the dorsolateral prefrontal (DLPF) cortex and posterior parietal (PP) cortex. These structures have been linked to attentional processing in the context of pain (Peyron et al., 1999). In a previous laser fMRI study, we used strictly unilateral and therefore predictable painful stimulation and the subjects were requested to rate the perceived intensity. In this study, we found substantial activation in the DLPF and PP cortices irrespective of the perceived pain intensity (Bornhövd et al., 2002). In the current study, in which the location of the stimulus was unpredictable and pain rating was not requested, no such activation was found, even at lower thresholds. This strengthens the view that these latter areas are associated with attentional or working memory mechanisms rather than pain processing per se (Coghill et al., 2001; Peyron et al., 1999).
Furthermore, we did not find predominance of either the right or the left hemisphere irrespective of the stimulated hand (‘hemispheric lateralization’). This contrasts with the previous work by Coghill et al. (2001), who reported a right hemispheric dominance for somatosensory processing (including pain) and might be due to differences in the pain stimuli used (prolonged tonic heat pain vs. short phasic laser pain).
Previously used laser stimulation to the left hand and foot did not show asymmetric responses in a PET study (Xu et al., 1997). This might be related to (i) the low spatial and temporal resolution of PET or (ii) to the long stimulus duration. In this study, trains of laser stimuli (60ms) with a frequency of 0.5Hz were used.
4.2. Amygdala
The bilateral symmetric response to pain in the amygdala is most likely mediated by spino-(trigemino)-amygdala pathways projecting to large receptive field nociceptive neurons (Bernard and Besson, 1988). The bilateral fMRI response to pain is in accordance with the observation that 50% of these neurons respond similarly to stimulation of all body parts (Bernard et al., 1992). These response properties and their extensive connections to anterior cingulate cortex, which also displays symmetric responses to pain (Coghill et al., 2001; Sikes and Vogt, 1992), support the view that this area contributes to emotional processing (i.e. aversive nature) of painful events rather than sensory-discriminative aspects of pain (Bornhövd et al., 2002; Buchel et al., 1998; LaBar et al., 1998). Amygdala activation might also reflect activation of a ‘defensive behavioral system’, which controls transmission of nociceptive impulses to the brain through modulatory circuits. One major pathway of this descending endogenous pain control system is mediated by projections of the amygdala to the periaqueductal gray matter (PAG) and contributes to fear, stress and expectation induced analgesia (Borszcz and Streltsov, 2000; Fields, 2000; Fox and Sorenson, 1994; Mena et al., 1995).
4.3. Hippocampal complex
A clearly bilateral symmetric response to painful stimulation was also observed in the hippocampal complex. Reports of pain-related responses in the hippocampal complex have been rare and contradictory. Hippocampal activation has been reported in response to mild and moderate heat pain (Derbyshire et al., 1997) and in a pain-learning paradigm when pain was not expected (Ploghaus et al., 2000). A recent study by Ploghaus et al. (2001) demonstrated anxiety-induced hyperalgesia being associated with activation in the hippocampal formation. Evidence that pain processing is a primary function of the hippocampal complex comes from animal data demonstrating septo-hippocampal neurons responding to noxious peripheral stimulation (Dutar et al., 1985). The receptive fields of these neurons are predominantly large and bilateral, which would explain the bilateral response observed in our study. Another explanation to account for hippocampal responses to pain in our paradigm would be consistent with comparator theories of hippocampal function, including novelty detection (Grunwald et al., 1998; Henke et al., 1997; Vinogradova and Dudaeva, 1972). Even though subjects were familiar with the painful stimulus (pain threshold estimation) the total randomization of the stimulus interval prevented exact prior knowledge of when the stimulus would occur. Interestingly, combining the two theories, at the molecular level novelty and pain induce similar changes to hippocampal acetylcholine release in the rat (Ceccarelli et al., 1999). From a biological point of view, direct nociceptive projections to the hippocampus do not contrast with this view, since (unless in chronic pain) nociceptive information is typically novel and of very high priority.
Altogether the bilateral symmetric responses of amygdala and hippocampal complex (limbic system) to unilaterally applied nociceptive stimuli as revealed in our study are in line with the proposed context-dependant modulatory role of these areas on pain perception, in which time-course and context of stimulus appearance are presumably more important than stimulus location.
4.4. Activation sites with asymmetric response pattern
Presenting stimuli to the right and left sides of the body and determining which brain areas show differential (i.e. asymmetric) responses depending on the stimulus side allows to identify in which subcortical structures spatial information of nociceptive information is preserved. A consistently stronger response to contralateral, or ipsilateral stimulation of an area, reflected by the asymmetric response pattern, indicates that the respective neurons have predominantly contralateral/ipsilateral receptive fields. This indicates that the spatial information with respect to the body side is preserved. This information is essential for the generation of defensive behavior, which might explain our observation of asymmetric responses in subcortical areas, mainly involved in motor function and reactive behavior.
However, in our paradigm, the subjects' ability to react was restricted by positioning and the instructions not to move during imaging. Therefore, it cannot be ruled out that the asymmetric response is also partially due to the inhibition of movement of the affected body side.
4.5. Putamen
Activation of the putamen in response to painful stimulation has been reported in previous neuroimaging studies of pain (Coghill et al., 1999; Hui et al., 2000; Iadarola et al., 1998; Xu et al., 1997). In support of our hypothesis, our data show an asymmetric (i.e. stronger for the side contralateral to simulation) response pattern in the lateral aspect of the putamen. This agrees with electrophysiological data reporting a somatotopic arrangement of nociceptive neurons within the striatum of the rat (Richards and Taylor, 1982). The involvement of the basal ganglia in motor functions has well been established (Alexander et al., 1990; DeLong et al., 1984). Thus the asymmetric response pattern might reflect preparation and/or inhibition of motor reactions related to pain, in particular withdrawal behavior, which is aimed at the limb or hemi-body affected by the provoking stimulus. The basal ganglia are believed to process and integrate somatosensory (including nociceptive) information relevant to guide movement (Chudler and Dong, 1995; Nishino et al., 1991). Neuroanatomical evidence suggests that nociceptive information may reach the basal ganglia by several afferent sources (e.g. cerebral cortex, thalamus and dorsal raphe nucleus (Chudler and Dong, 1995)). Electrophysiological studies exploring the non-nociceptive and nociceptive response properties of basal ganglia neurons, indicate that (i) many basal ganglia neurons are activated exclusively or differentially by noxious stimulation (Schneider and Lidsky, 1981) and (ii) some of these even encode stimulus intensity (Chudler and Dong, 1995), which might be related to grading motor responses.
4.6. Cerebellum
Inconsistently, bilateral cerebellar activation associated with contralateral primary motor cortex (M1) activation has been reported in previous imaging studies of pain (Brooks et al., 2002; Coghill et al., 2001; Ploghaus et al., 1999; Xu et al., 1997), but activation of motor areas in response to pain has not been evaluated systematically (Peyron et al., 2000). Our study provides evidence of predominant ipsilateral representation of nociceptive stimuli, which is conceptually in line with the contralateral activation of M1 or premotor cortex, reported by other studies (Casey et al., 1996; Casey et al., 2001; Coghill et al., 2001). It is also in agreement with data in the cat confirming that nociceptive (C-fiber) input reaches the cerebellum via the ipsilateral dorsal funiculus (Ekerot et al., 1991). There is no clinical evidence that cerebellar lesions or stimulation in humans affect pain sensation. Thus, cerebellar activation has not been considered to be primarily associated with pain perception but rather with the initiation of a motor response. However, some animal data indicate that the cerebellum contributes more to pain processing than just motor control (Dey and Ray, 1982). They demonstrated that microinjections of morphine into the anterior cerebellum produces profound analgesia in rats, and in the monkey alteration of nociception by cerebellar stimulation was shown. (Siegel and Wepsic, 1974). Further studies are necessary to define whether ipsilateral cerebellar activation is related to nociceptive processing per se, motor preparation (readiness to move), or a combination of these two.
4.7. Red nucleus
Conceptually in line with the asymmetric response pattern of putamen and cerebellum, a lateralized response to unilateral painful stimulation was also observed in the red nucleus. The red nucleus comprises an important subcortical relay station of a massive descending motor tract (rubro-spinal tract). Accordingly, the asymmetric response in this region might again, analogous to putamen and cerebellum, reflect motor processes associated with pain. Except for its well established role in the motor system, recent studies suggest red nucleus involvement in (modulatory) pain processing and aversive events. In support of this view signal changes in the red nucleus have also been observed during classical aversive conditioning (Buchel et al., 1998). Electrophysiological animal data demonstrate (i) that red nucleus neurons respond to peripheral noxious stimulation and (ii) that electrical stimulation of red nucleus neurons modulates thalamic nociceptive transmission (Huang et al., 1992; Steffens et al., 2000). Remarkably neurons were most responsive to contralateral noxious stimulation in accord with the asymmetric response observed in our study (Matsumoto and Walker, 1991).
5. Conclusion
In conclusion, using the randomized application of laser pain stimuli in combination with event related fMRI, we demonstrated that (i) noxious information is relayed through amygdala, hippocampal complex, putamen, red nucleus and cerebellum and more importantly (ii) that spatial information of the nociceptive stimulus is preserved subcortically in putamen, red nucleus and cerebellum. These structures are mainly involved in motor function and reactive behavior, linking their activation to pain avoidance and defense.
Acknowledgements
We thank the Physics and Methods group at the Cognitive Neuroscience Laboratory in Hamburg, the Department of Neuroradiology and the technical staff at the Department of Neurophysiology for their support with the laser and Desiree Gonzalo for suggestions on an earlier draft of this paper. This work was supported by grants from Volkswagenstiftung, BMBF and EU.
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Keywords:
Nociception; Single-trial functional magnetic resonance imaging; Laser; Subcortical; Amygdala
© 2002 Lippincott Williams & Wilkins, Inc.