Caudal cingulate cortex involvement in pain processing: an... : PAIN (original) (raw)
1. Introduction
Functional imaging studies in humans have revealed activations in multiple regions of cingulate cortex in response to both experimental pain stimulation and clinical pain sensations (see Derbyshire, 2000; Peyron et al., 2000 for recent reviews of this literature). The most commonly reported area is the mid-cingulate or caudal anterior cingulate cortex (ACC) region (areas 24 and 32′ of Vogt et al., 1995), with perigenual or rostral anterior cingulate (BA 24, 25 and 32) and posterior cingulate cortex (PCC, BA 23 and 31) being activated less frequently.
Source localisation of multi-channel pain evoked potential recordings (specifically laser evoked potentials, LEPs) has also been used to identify possible cerebral generators of pain-related signals. Electrophysiological recordings have the advantage over positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) of millisecond temporal resolution. Such studies have identified dipolar sources of the most prominent LEP peak in deep, medial regions of the head that appear to reflect cingulate cortex activation (Tarkka and Treede, 1993; Bromm and Chen, 1995; Valeriani et al., 1996; Bromm and Lorenz, 1998; Valeriani et al., 2000; Bentley et al., 2001; Opsommer et al., 2001; Bentley et al., 2002). However, half of these studies have used spherical head models in the source localisation analysis, with no anatomical information (Tarkka and Treede, 1993; Bromm and Chen, 1995; Valeriani et al., 1996, 2000). Spherical head models do not account for individual differences in anatomy such as skull thickness, which is an important factor in the conduction of electrical signals to the scalp (Koles, 1998). The lack of anatomical information also makes the precise cerebral localisation of sources impossible.
Only four published LEP source localisation studies (Bromm and Lorenz, 1998; Bentley et al., 2001; Opsommer et al., 2001; Bentley et al., 2002) used realistically shaped head models derived from structural images of the subjects' brains. However, one of these studied the longer latency ultralate (C-fibre-evoked) LEPs (Opsommer et al., 2001) and the remaining three reported results from single subjects only (Bromm and Lorenz, 1998; Bentley et al., 2001; Bentley et al., 2002). No study to date has shown the inter-individual variability in the location of the cingulate source of LEPs, analysed using realistic head models. Such studies are necessary to assess individual differences in this component of pain processing.
The aim of the current study was to accurately localise the cingulate source of LEPs in a group of healthy volunteers, and to assess the degree of variation in anatomical location between individuals.
2. Methods
2.1. Subjects
The study was approved by the local research ethics committee. Data were recorded from five young right-handed volunteers (three females, two males, mean age: 26 years), who gave their informed consent. They were all in good health and not taking medication at the time of recording.
2.2. Laser stimulation
During each LEP recording, painful CO2 laser stimuli (150ms pulse duration, 15mm beam diameter) were delivered to the right dorsal forearm, at 10s intervals. Stimuli were randomly moved around a 5×3cm2 area, to avoid habituation/sensitisation and possible skin damage. Subjects wore protective goggles for safety and earplugs to mask acoustic interference from the laser. Four subjects received two blocks of 60 stimuli, and the remaining subject (subject 2) received one block. Subjects rated each stimulus on a 0–10 scale for pain intensity, approximately 3s after the stimulus. In all cases, only the responses to those stimuli rated as 5–8 were included in the averages presented in this paper. Stimulus intensity was tailored to each individual and was altered where necessary during the experiment in order to maintain subjective ratings of 4 and above (i.e. painful) (mean energy range used: 2.2–3.0J).
2.3. LEP recording
LEPs were recorded from 62 scalp electrodes (positioned according to the 10–20 system), referenced to linked earlobes (Quik-Cap system, Neuro Scan, Inc.). Electroencephalogram (EEG) data were sampled at a rate of 1000Hz, with a gain of 500, and bandpass filters of 0.15–30Hz (SynAmps, Neuro Scan, Inc.). The vertical and horizontal electro-oculogram was also recorded for the purposes of ocular artefact reduction. The impedance of all electrodes was below 5kOhms.
2.4. MRI acquisition
A structural magnetic resonance image (MRI) of each subject's brain was acquired on a different day to the LEP recording (1T Siemens scanner, T1-weighted image, 256×256pixels, each 0.94×0.94mm2, 108 sagittal slices, each 1.67mm thick).
2.5. Co-registration of anatomical and functional data
For all subjects, five points on the head were used to co-register the anatomical and functional data: the left and right pre-auricular points and nasion (PAN points), and positions approximating the vertex and inion. They were visualised on the MRI using fish oil capsules fixed in the correct positions with collodion glue. After the scan, the positions of the capsules on the subject's head were measured using a digitiser (Polhemus ‘Fastrak’), which was also used to measure the electrode positions at the end of each LEP recording session. The positions of the capsules and the electrodes were co-registered using three points on the face, which formed the reference frame for the digitiser on both occasions. In order that the positions of these registration points could be accurately reproduced on different days, individual facial features (such as moles) were used where possible. If this was not possible, the PAN points were used. The digitiser was operated by the same person on both occasions, in order to minimise subjective differences in determining the positions of these points.
2.6. Data analyses
Continuous EEG data were corrected for ocular artefact (Edit module of Scan 4.0 software, Neuro Scan, Inc.), prior to epoching. A 500ms pre-stimulus interval was used for baseline correction. Any epochs containing artefact, or that corresponded to stimuli that were rated lower than 5 or greater than 8 on the scale, were rejected. This left between 31 and 64 (mean: 50) artefact-free epochs for each subject. Remaining epochs were averaged and smoothed with a 10Hz low pass filter (96db/oct slope) (after verifying that there was no loss of power in the main frequency bands).
Source localisation analysis was performed only on the most prominent LEP peak (P2) for each data set, using CURRY 4.0 software (Neuro Scan, Inc.). In each case, a single fixed dipole was fitted to the time window that corresponded to the P2 peak (approximately 350–600ms). Realistic head models were used in the analysis for all subjects, which were created from each individual's MRI using the boundary element method (BEM) (Fuchs et al., 1998).
3. Results
For all subjects, the most prominent LEP component was the P2 peak, which was maximal at electrode Cz (vertex) in all cases (Fig. 1). P2 peak latency at Cz ranged from 400ms (subject 2) to 540ms (subject 3) (mean peak latency: 476ms, standard deviation: 52ms).
Averaged LEP, with respect to a linked ears reference, at electrode Cz for each subject. The large positive deflection at about 400–500 ms is the P2 peak. (Note: negativity is plotted upwards).
The source of the P2 peak was localised to cingulate cortex for all five subjects (Fig. 2). The best residual variance ranged from 1.7 (subject 1) to 7.4% (subject 5) (mean=3.9±2.4 %). For subjects 2, 3 and 4, the precise anatomical location was at the border of caudal area 24′ (ACC) with area 23 (PCC) in the left hemisphere. For subject 1, the dipole was located slightly more dorsally, at the border of area 32′ (ACC) with area 31 (PCC), again in the left hemisphere. For subject 5, the dipole was positioned more caudally, at the border of areas 23 and 31 (PCC), but in the right hemisphere.
Anatomical positions, in cingulate cortex, of the dipole sources explaining the P2 peak of the LEPs for each subject. The dipoles are represented by the yellow poles, and in each case the origin of the dipole is at the centre of the circle. The size of the pole indicates the magnitude of the dipole, whereas its direction reflects dipole orientation. The dipole source of each subject's data has been co-registered with their own structural MRI (from left to right: sagittal, coronal and axial orientations); the white cross-hairs show, for each subject, the positions of the MRI slices in all orientations. (A, anterior; P, posterior; L, left; R, right).
4. Discussion
The aim of the current study was to accurately localise the cingulate source of LEPs in a group of five healthy volunteers, using realistic head models that account for individual differences in anatomy. The results of the study demonstrated that the P2 LEP peak was consistently modelled by a dipole source in caudal cingulate cortex, although there was some degree of variability in the precise anatomical location. These results provide evidence for a role of caudal cingulate cortex in pain processing in humans.
The majority of subjects (subjects 1–4) exhibited a source at the border of area 24/32′ (ACC) and area 23/31 (PCC) in the left hemisphere (i.e. contralateral to the side of stimulation). For subject 5, the dipole was positioned at the border of areas 23 and 31 in right PCC; this ipsilateral activation may be explained by the relatively high residual variance of the dipole fit for this subject (7.4%), indicating that this source is less reliable than those of the other subjects.
Recent reviews of the pain functional imaging literature (Derbyshire, 2000; Peyron et al., 2000) demonstrate that cingulate responses to right-sided somatic pain in normal volunteers are predominantly contralateral or bilateral. The present study is in accordance with this observation. Our method reveals only the location of the maximal electrophysiological signal, and not the extent of the response, thus a bilateral response with a contralateral dominance cannot be excluded.
To date, only three published studies have specifically addressed the laterality of cingulate responses to experimental pain. Of these, one reported predominantly right-sided activations (Brooks et al., 2002), whereas two showed contralateral responses (Davis et al., 1997; Coghill et al., 2001). Functional imaging studies of clinical pain syndromes by Hsieh et al. (1995, 1996, 1999) have reported right-lateralised ACC responses, although studies by other groups have shown a left-lateralised cingulate response to migraine pain (Weiller et al., 1995) and no cingulate response at all to neuropathic pain (Peyron et al., 1998). The relevance of these clinical pain syndromes to our experimental laser pain stimulus delivered to healthy volunteers is, however, uncertain. A large number of imaging studies have examined responses to noxious stimulation delivered to either the left or right side of the body in normal volunteers, with the majority reporting contralateral or bilateral cingulate responses during pain experience (reviewed in Derbyshire 1999, 2000; Vogt and Derbyshire, 2002). The laterality of our present results is therefore consistent with the majority of published studies to date.
The location of LEP sources at the border of the caudal division of ACC with PCC supports our previous studies (Bentley et al., 2001, 2002) and is also consistent with other electrophysiological studies. Bromm and Lorenz (1998) used a realistic head model in CURRY to fit a moving dipole to LEPs elicited by painful laser stimulation of the left temple, and reported the best fit at 240ms when the dipole was located in PCC. Lenz et al. (1998) used subdural electrodes to record LEPs from the medial wall of the hemisphere in response to painful laser stimulation of the face. LEPs were recorded from electrodes overlying regions of mid-cingulate cortex that are close to the source locations in the present study.
The latency of the cingulate source of the present study is comparable to others in the literature. Brief laser stimuli selectively activate A-delta and C-fibre nociceptive afferents (Bromm et al., 1984) and the latency of late LEPs, including those of the present study, is consistent with the activation of A-delta fibres (Bromm and Treede, 1987), which conduct at a velocity of 4–30m/s (Bromm and Lorenz, 1998). Variations in LEP latency between studies are partly due to differences in stimulation site, with longer conduction distances eliciting longer latency responses, and vice versa. A shorter latency than that observed in our study might be expected, for example, when stimulating the forehead (Bromm and Treede, 1987). Latency is also influenced by stimulus duration; a longer laser stimulus that elicits the same pain intensity as a shorter stimulus (i.e. by using reduced power for longer), results in an increase in the time taken for the temperature at the nociceptors to reach their activation threshold. The latencies observed in our study are consistent with the site and duration of stimulation.
The cingulate sources of the present study correspond with those from a number of pain studies using other imaging techniques. Gelnar et al. (1999), for example, reported fMRI signal changes at the border of caudal ACC and PCC during thermal pain sensation. Vogt et al. (1996), using PET and MRI co-registration to study individual responses to pain, reported multiple cingulate activations including regions of caudal ACC and PCC in the majority of individuals. More recently, Kwan et al. (2000) also demonstrated individual pain-related cingulate activations in the ventral portion of caudal ACC and in PCC using fMRI.
In a recent review of functional imaging results using noxious stimuli, Derbyshire (2002) suggested that subregional cingulate activation varies depending on the mode of stimulation. Rostral cingulate is more commonly activated in response to tonic experimental pain while caudal cingulate is more commonly activated in response to phasic pain (Vogt and Derbyshire, 2002). The present results are therefore consistent with the majority of phasic experimental pain studies that activate more caudal cingulate areas.
A possible limitation of our study is that we did not use a non-painful stimulus as a control. It is possible, therefore, that our observed cingulate response is general to stimulation rather than being specific to pain. This possibility seems unlikely, however, as several groups have studied responses to both non-painful and painful stimulation and have demonstrated involvement of the ACC only during the painful stimulation (Jones et al., 1991; Casey et al., 1994; Coghill et al., 1994; Davis et al., 1995; Kitamura et al., 1995, 1997; Gelnar et al., 1999; Kwan et al., 2000) or have demonstrated the ACC response to painful stimulation to far exceed that to non-painful stimulation (Porro et al., 1998; Yamasaki et al., 2000; Büchel et al., 2002). In addition, a number of studies have reported a positive correlation of ACC responses with increasingly painful stimulus intensity, suggesting that the ACC has an intrinsic involvement in pain processing (Derbyshire et al., 1997; Coghill et al., 1999; Porro et al., 1998; Büchel et al., 2002).
Although caudal cingulate is more readily activated by painful than non-painful stimulation, this does not mean that caudal cingulate should be regarded as a ‘pain centre’. Neurons in caudal ACC have heterogeneous properties including pre-motor discharge properties (Shima et al., 1991), with complimentary direct corticospinal projections (Dum and Strick, 1991), as well as reciprocal connections with primary motor cortex (MI) and the supplementary motor area (SMA) (Morecraft and van Hoesen, 1992). These observations have led to the suggestion that caudal ACC may be responsible for pre-motor processing and response selection (Vogt et al., 1996, 1997).
Evidence for a role of the PCC in visuospatial cognition has been provided by several studies. Olson et al. (1993) demonstrated that, during the performance of spatial attention tasks, the firing rate of monkey PCC neurons depends on the size and direction of the preceding eye movement, and suggested a role of the PCC in determining the location of a visible object relative to the body. A recent fMRI study by Mesulam et al. (2001) showed that the PCC was the only brain area to demonstrate task-related signal changes that were correlated with the speed of target detection, only when spatial attention displayed a cue-induced anticipatory shift. The authors suggested that this reflects a relatively specific involvement of the PCC in spatial attention, rather than a more general role in motor speed.
Conversely, Gelnar et al. (1999) have suggested that PCC activation in response to noxious stimulation may be somatosensory in origin, and not a motor or visuospatial response, as a result of Apkarian and Shi's (1998) description of direct nociceptive spinothalamic input to caudal cingulate and PCC regions in the monkey. In addition, several studies in rabbits have suggested an involvement of the PCC in avoidance learning. Gabriel et al. (1991a) recorded multi-unit activity in area 29 of rabbit PCC whilst rabbits were trained to step in response to a warning tone to avoid a foot-shock, and to ignore a different tone not followed by shock. Avoidance learning was impaired in animals with cingulate cortex lesions, particularly when the lesions encompassed area 29 (Gabriel et al., 1991b). These effects are likely to be mediated by anatomical connections between PCC and systems involved in spatial memory, such as the hippocampus (Sutherland and Hoesing, 1993). Alternatively, neuronal activity in caudal ACC and PCC may relate to affect associated with the noxious stimulus.
A role of caudal ACC and PCC in affect is supported by the results of a PET study by Tolle et al. (1999), which demonstrated that regional cerebral blood flow increases in caudal ACC correlated with the unpleasantness of noxious thermal stimulation; the location of the caudal ACC activation was comparable with that of the cingulate dipole sources of the present study. Zubieta et al., (2001) also reported an increase in endogenous opioid binding in a similar cingulate region that correlated with the unpleasantness rating of induced masseter pain. A recent meta-analysis of functional imaging studies (Maddock, 1999) demonstrated that the retrosplenial cortex (including PCC areas 23 and 31) is the cortical region most consistently activated by emotionally salient stimuli.
Taken together, these findings suggest a possible role of caudal ACC and PCC in the direction of anticipatory attention towards emotionally salient stimuli. Such a process, together with spatial memory, is necessary for the avoidance of potentially painful and hence harmful stimuli and might explain the involvement of this area in the current study and in several functional imaging studies of human pain processing. Further studies are necessary to test this hypothesis.
Acknowledgements
The authors are grateful to the Arthritis Research Campaign (ARC), Janssen-Cilag and the Dr Hadwen Trust for Humane Research for supporting this work. The authors also thank Brent Vogt for his advice on cingulate cortex anatomy.
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Keywords:
Laser pain evoked potentials; Pain; Cingulate cortex; Source localisation; CURRY
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