Cerebral Responses to Noxious Thermal Stimulation in Chronic Low Back Pain Patients and Normal Controls by Stuart Derbyshire | Papers by Stuart

NeuroImage 16, 158 –168 (2002) doi:10.1006/nimg.2002.1066, available online at http://www.idealibrary.com on Cerebral Responses to Noxious Thermal Stimulation in Chronic Low Back Pain Patients and Normal Controls S. W. G. Derbyshire, A. K. P. Jones,* F. Creed,† T. Starz,‡ C. C. Meltzer,‡ D. W. Townsend,‡ A. M. Peterson,‡ and L. Firestone Department of Anesthesiology and Critical Care Medicine, ‡PET Facility, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; *University of Manchester Rheumatic Diseases Centre, Clinical Sciences Building, Hope Hospital, Salford M6 8HD, United Kingdom; and †University Department of Psychiatry, Rawnsley Building, Manchester Royal Infirmary, Manchester M13 9WL, United Kingdom Received April 25, 2001 Changes in regional cerebral blood flow (rCBF) have previously been demonstrated in a number of cortical and subcortical regions, including the cerebellum, midbrain, thalamus, lentiform nucleus, and the insula, prefrontal, anterior cingulate, and parietal cortices, in response to experimental noxious stimuli. Increased anterior cingulate responses in patients with chronic regional pain and depression to noxious stimulation distant from the site of clinical pain have been observed. We suggested that this may represent a generalized hyperattentional response to noxious stimuli and may apply to other types of chronic regional pain. Here these techniques are extended to a group of patients with nonspecific chronic low back pain. Thirtytwo subjects, 16 chronic low back pain patients and 16 controls, were studied using positron emission tomography. Thermal stimuli, corresponding to the experience of hot, mild, and moderate pain, were delivered to the back of the subject’s right hand using a thermal probe. Each subject had 12 measurements of rCBF, 4 for each stimulus. Correlation of rCBF with subjective pain experience revealed similar responses across groups in the cerebellum, midbrain (including the PAG), thalamus, insula, lentiform nucleus, and midcingulate (area 24 ) cortex. These regions represented the majority of activations for this study and those recorded by other imaging studies of pain. Although some small differences were observed between the groups these were not considered sufficient to suggest abnormal nociceptive processing in patients with nonspecific low back pain. © 2002 Elsevier Science (USA) Key Words: pain; human; brain; positron emission tomography; imaging; regional cerebral blood flow. INTRODUCTION A significant number of functional imaging studies investigating the central responses to noxious stimuli in normal volunteers are now published (Jones et al., 1053-8119/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved. 1991, 1998; Talbot et al., 1991; Casey et al., 1994, 1996; Coghill et al., 1994; Hsieh et al., 1995a; Craig et al., 1996; Vogt et al., 1996; Andersson et al., 1997; Rainville et al., 1997; Aziz et al., 1997; Davis et al., 1997, 1998; Derbyshire and Jones, 1998; Derbyshire et al., 1994, 1997, 1999; May et al., 1998). These studies have indicated that a large number of central structures are involved in elaborating pain experience including the midbrain, cerebellum, thalamus, lentiform nucleus, and insula, anterior cingulate, prefrontal, and primary and secondary somatosensory cortices. Rather than any single dominant “pain center” there is evidently a widespread “neuromatrix” involved in the processing of acute noxious stimuli (Melzack, 1989). The variously activated regions have been interpreted with regard to their role in cognition, sensation and affect as well as to known projections of the spinothalamic tract (Apkarian and Hodge, 1989; Craig et al., 1994; Derbyshire, 1999; 2000; Jones, 1999). Just as the psychology of pain is understood as an integration of sensation, cognition and affect, so the neurobiology of pain is increasingly understood as an integration of activity in variable neuronal networks. These networks have been described in detail elsewhere (Derbyshire, 1999; Treede et al., 1999). The sensory discriminatory aspects of the experience are thought to be processed in the lateral thalamus and its subsequent projection to S1 and perhaps S2. The cognitive components are thought to be mediated in part by the projections of the medial system to the anterior cingulate cortex and further regulated by the prefrontal cortex. Affective responses to pain are associated with activity in the more rostral section of the anterior cingulate cortex (Vogt et al., 1993; Rainville et al., 1997). In addition, motor priming and inhibition may be reflected by activity in the motor cortices, lentiform nucleus and cingulate motor areas, while responses in the anterior insula may reflect affective responses and/ or autonomic regulation combined with responses in the rostral cingulate. 158 CEREBRAL RESPONSES TO NOXIOUS THERMAL STIMULATION 159 TABLE 1 Previous Study Results Reported regions Study Derbyshire et al. (1999) Jones and Derbyshire (1997) Silverman et al. (1997) Derbyshire et al. (1994) Naliboff et al. (2001) Mertz et al. (2000) Methods 6 dental patients, phasic heat pain 6 arthritis patients, phasic heat pain 6 IBS patients, gut distension 6 AFP patients, phasic heat pain 12 IBS patients, gut distension 18 IBS patients, gut distension Tha — — — C1 L1 1 Ins LN 9/10 44/46 ACC 24 ACC 24 C1 — — — B1 1 I1 — — — R1 1 — — — — — 1 — — — B1 B1 NA 39/40 C1 — — — — NA S1 S2 B1 C1 — — — — C1 C1 B1 — 1 NA — — — — — — — — R1 — NA NA Note. The results of previous studies using PET to investigate experimental pain in patients with clinical pain. The numbers under “Reported regions” refer to Brodmann’s areas: Tha, thalamus; Ins, insular cortex; LN, lentiform nucleus; ACC, anterior cingulate cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; C, contralateral; B, bilateral; I, ipsilateral; R, right; L, left; NA, not assessed; 1 indicates increased rCBF; 2 indicates decreased rCBF. A number of studies have examined the central correlates of acute pain responses in patients suffering from different clinical pain disorders (Jones and Derbyshire, 1997; Silverman et al., 1997; Derbyshire et al., 1994, 1999; Mertz et al., 2000; Naliboff et al., 2001). The results of these studies are summarized in Table 1. It can be observed from Table 1 that during standardized experimental stimulation atypical facial pain (AFP) and irritable bowel syndrome (IBS) patients have shown an increased response in the cingulate cortex (Derbyshire et al., 1994; Mertz et al., 2000; Naliboff et al., 2001). Studies involving patients suffering pain with a clear nociceptive origin (arthritis and surgical pain), in contrast, have not demonstrated increased cingulate responses (Derbyshire et al., 1999; Jones and Derbyshire, 1997). The relevance of these differences remains uncertain (Read, 2001; Mayer et al., 2001) but we have suggested that response in anterior cingulate represents a generalized hyperattentional response to noxious stimuli that may apply to other types of functional pain (Derbyshire et al., 1994). This study is an extension of our previous work to patients suffering non-specific chronic low back pain (NSLBP). NSLBP was chosen because of the lack of observable pathology in the lumbar spine, resistance to treatment and association with affect and illness behavior (Fordyce, 1995). Jensen et al. (1994) have demonstrated that subjects with NSLBP have similar levels of pathology to normal controls matched for age and sex. Although this finding does not rule out the possibility of detecting a physical abnormality in the future it does warn against the over-interpretation of normal structural change. Interventions aimed at reducing the emotional and cognitive burdens of the subject’s back pain have shown consistent modest therapeutic success compared with more standard medical procedures (Nachemson, 1992; Fordyce, 1995, 1996; Loeser, 1996). In this study we aimed to investigate the central responses to noxious stimulation in patients suffering NSLBP compared with a group of control subjects. By inflicting a moderate pain stimulus we expected to sufficiently stress the nociceptive system to reveal differences in nociceptive processing between the NSLBP patients and controls in the prefrontal and anterior cingulate regions. METHODS Subjects Fourty-six subjects were recruited. Eight subjects later expressed reservations and were withdrawn, one subject could not tolerate the MRI environment, one subject had an abnormal finding following their MRI and two subjects were unable to remain off medication for the required two weeks before the study and were excluded from further investigation. In addition data were lost from one subject following a problem with the IV line and another following a software failure on the scanner. PET data were successfully collected from 16 NSLBP patients and 16 control subjects. The average age of the control group, consisting of 5 males and 11 females, was 35.6 (standard deviation (SD) 7.6). The average age of the patient group, consisting of 4 males and 12 females, was 45.4 (SD 7.7). The difference between the ages was significant (t 3.5, P 0.001). All 46 subjects gave informed written consent prior to the study. Design The central responses of all subjects to an increasing, intermittent ramp of nonnoxious and noxious heat were compared to reveal the components of the heat pain response that are independent of spatial and temporal discrimination. Twelve measures of rCBF were obtained from each of the 32 subjects. Four measures were obtained during noxious heat stimulation described as moderately painful, four during mild pain and four during nonnoxious heat stimulation. To avoid 160 DERBYSHIRE ET AL. any possible order effects the series commenced with nonnoxious heat in 16 subjects, mild pain in 8 subjects, and moderate pain in 8 subjects and alternated thereafter. During the stimulation, subjects received five 15-s ramps of increasing heat which at their peak were consistently described as either moderately painful (rated from 0 to 100, with 0 no pain and 100 worst pain imaginable; 60 was anchored as moderate pain), mildly painful (40 was anchored as mild pain), or nonpainful hot (0 —for further details see Table 2). The thermode was 2.5 1 cm. Temperatures were ramped from 25°C to the noxious or nonnoxious temperature and back again over a 15-s cycle. Subjects had their eyes closed during the stimulation and quiet was maintained in the scanner room throughout the stimulation periods. Apparatus All the thermal stimuli were produced by a Somedic thermal threshold stimulator (Fruhstorfer et al., 1976) that delivers reproducible intermittent ramps of increasing heat to the skin via a water-cooled probe. A state-of-the-art Siemans/CTI ECAT EXACT HR PET camera (Knoxville, TN) with fully retractable septa was used for the study. The field of view of the scanner (15.5 cm) allowed the whole brain to be studied simultaneously and the detectors provided a transaxial resolution of approximately 4 mm for the center of the image increasing to 8 mm radially and 5 mm tangentially (Adam et al., 1997). MRI scans of the lower back were obtained for all subjects with a 1.5T scanner. The studies consisted of four spin-echo sequences: two sagittal views with a repetition time and echo time (TR/TE) of 500/10 ms and 4000/100 ms and two axial views with a TR/TE of 4000/100 ms and 750/15 ms. Technical specifications included a slice thickness of 3 mm with an interslice thickness of 1 mm, a field of view of 24 cm, and a matrix of 192 by 256 pixels. The T1-weighted axial sequences were stacked slices extending from the inferior aspect of L2 through the inferior aspect of S1. Procedure NSLBP patients were recruited through the rheumatology clinics within the University of Pittsburgh Medical Center. Patients with prior history of neurological deficit or indication of such a deficit following the MRI were excluded. Controls were recruited through advertisement. MRI scans were scheduled for all subjects one week prior to their PET study. MRI scans of the head and lower back were obtained for PET-MRI coregistration and clinical evaluation, respectively. MRI scans of the CNS were reviewed for abnormalities by a senior radiologist prior to the PET study. Two experienced neuroradiologists read all the MRIs of the lower back. The two neuroradiologists did not know the clinical status of the subjects. All identifying information and dates were obscured. Readings were carried out in groups of 4 to 11 studies per session. The readers independently evaluated the status of the five intervertebral disks in the lumbosacral spine in all 32 subjects. Ratings of the presence and severity of degenerative spine changes were based on assessment of disk signal reduction (evaluated on the T2weighted images), disk height reduction, and marrow endplate signal changes, and the presence of a diffuse bulging annulus. Disk herniations (defined as including both disk protrusion and extrusion) were localized as to level, spatial orientation (i.e., lateral, paracentral, central), and size (i.e., small, moderate, large). Additionally, readers noted the presence or absence of a high intensity zone of nuclear material protruding beyond the confines of the vertebral body on the sagittal T2-weighted images. Immediately prior to the PET studies, thresholds for innocuous and noxious heat stimuli to the back of the right hand were determined for each subject. The subject held one of two control switches that were wired in parallel to the thermal stimulator whilst the investigator held the other switch. Once the subject was shown that they could turn the stimulator off, the experimenter began the first ramp of heat. The subject was instructed to switch the heat off as soon as it became just perceptibly painful. This was repeated six times. After the sixth time, without moving the probe, the subject was asked to let the heat increase until it became no longer tolerable. It was stressed that the machine would switch off at 50°C and that the subject was not expected to reach that high a temperature. This was repeated three times to give a total of nine measures. The first three measures were discarded to account for habituation, the next three were averaged to give a measure of pain threshold and the final three recordings were averaged to give a measure of pain tolerance. In general, the temperature used during the scan as non-painful heat was 2°C below threshold for pain, the temperature used for moderate pain was 2°C below pain tolerance and the temperature for mild pain a further 1°C lower. These temperatures were confirmed as non-painful, mildly or moderately painful by the subject and adjusted where necessary. All subjects completed the Hospital Anxiety and Depression (HAD) scale (Zigmond and Snaith, 1983). In addition, the patients completed visual analogue scales to describe the intensity and “bothersomeness” of their lower back pain at that moment and were evaluated for abnormal illness behavior using the five Waddell criteria (Waddell, 1980). Each subject was positioned in the scanner so that the axis of the scanner was approximately parallel to the glabellar-inion line. A transmission scan was performed using an external ring source of positrons to CEREBRAL RESPONSES TO NOXIOUS THERMAL STIMULATION 161 provide an image of regional tissue density for the correction of emission scans for tissue attenuation. rCBF in each subject was measured 12 times by recording the distribution of cerebral radioactivity following intravenous bolus infusion of the freely diffusible positron emitting 15O-labeled tracer, H 2O 15. For each measurement, individuals received 12-mCi bolus of H 2O 15 through an automated injector. A 60-s scan was triggered automatically when the head count reached 60,000 counts/s, approximately 20 –30 s after the start of the bolus. Eight minutes between each injection allowed for the decay of background radiation to less than 10% of the recorded peak. The transmission scan and 12 rCBF measurements were completed in a single session lasting just under 2.5 h. The first thermal stimulus commenced 5 seconds after the start of the bolus injection of H 2 15O and was completed prior to the start of the scan. This was to allow for early sensitization effects. Four more thermal stimuli were delivered, ramping over 15 s, with the first beginning as the scan triggered. To avoid any possible order effects the series commenced with the selected stimulation in a rotated fashion. During the time of stimulation the lights were dimmed and silence maintained. The subjects were instructed to stay motionless with eyes closed and to call out only if the stimulus became overly painful. After each measurement verbal confirmation was obtained that subjects’ had appropriately experienced the stimulation as hot, mildly, or moderately painful and a VAS rating recorded. PET Data Analysis The object of the analysis of these studies was to correlate the changes in rCBF with increasingly painful heat stimulation for each group and to assess the commonalities and differences between the patients and controls. To make these calculations the following procedures were carried out using SPM99 (Wellcome Trust Centre for the Study of Cognitive Neurology), described in detail elsewhere (Friston et al., 1995, 1996). The implemented model was a fixed-effect model meaning that the results described only pertain to the specific groups studied and cannot be extrapolated to the larger population of normal subjects and NSLBP patients. Correction for head movement between scans was carried out by aligning them all with the first scan using Automated Image Registration (AIR) software (Woods et al., 1992). Each realigned set of scans from every subject was coregistered with his or her own head MRI image, with the nonbrain components edited out, and reoriented into the standardized anatomical space of the average brain provided by the Montreal Neurological Institute (MNI). To increase the signal to noise ratio and accommodate variability in functional anatomy, each image was smoothed in X, Y, and Z dimensions with a Gaussian filter of 10 mm (FWHM). At each voxel a model was fitted that regressed rCBF on two nuisance effects and one effect of interest. The first nuisance effect was global activity; changes in global activity between scans were accounted for with subject-specific covariates. The other nuisance effect was time; two covariates, linear and quadratic, were used to account for this effect. The effect of interest was the verbal rating of stimulus intensity; the significance of the slope of verbal rating versus rCBF, accounting for the nuisance effects, was presented as a statistical parametric map (SPM). Brain regions with a large statistic correspond to structures whose rCBF shares a substantial amount of variance with subjective stimulus intensity rating. In principle this analysis is more powerful than subtraction as it models all the variability associated with reported stimulus intensity rating. We have previously demonstrated this analysis to reveal the major regions of interest at a higher significance value than when using subtraction techniques (Derbyshire et al., 1997). The correlation structure for the controls and patients were assessed separately and were then investigated for conjunction effects and differential responses (Friston et al., 1996). A conjunction determines whether both group slopes are significantly different from zero. This is in contrast to whether the average intergroup slope is different from zero, which could be driven by one group alone. A conjunction (as implemented in SPM99) is the minimum of two statistic images or, equivalently, conjunction regions are the intersection of suprathreshold regions across two statistic images. A voxel only appears as significant in the conjunction if both groups have significant activation at T 1.3 threshold and is therefore a measure of significant shared responses in two groups. For display purposes in all analyses, any cluster 23 voxels in extent with a signal intensity corresponding to an uncorrected threshold of P 0.01 is shown. This is consistent with other work on the functional imaging of noxious stimuli (Derbyshire et al., 1997; Hsieh et al., 1995a,b; Silverman et al., 1997; Naliboff et al., 2001) and reduces the possibility of false negative reporting (Derbyshire, 1999). To reduce the risk of overinterpreting false-positive findings, interpretative weight is given to a particular cluster based on the statistical significance of that region when correcting for the voxels in the whole brain or within a structure having a hypothesized relation with noxious experience. RESULTS Questionnaire Responses and Clinical Evaluation Table 2 shows the average results of the HAD questionnaire, the radiological evaluation of each subjects lower back, the Waddell examination for abnormal illness behavior and the subjects rating of intensity and 162 DERBYSHIRE ET AL. CEREBRAL RESPONSES TO NOXIOUS THERMAL STIMULATION 163 FIG. 3. The pixels indicating a positive rCBF correlation with the subjective pain rating in the controls (top left), the patients, the conjunction of the controls and patients and the differences between the controls and patients color coded as for Figs. 1 and 2. The SPM is superimposed on the surface projections of the standard MNI image. “bothersomeness” of pain from their lower back. The patients were significantly more anxious than the control subjects (t 1.7, P 0.05, one-tailed) but only showed a trend toward greater depression (t 1.3, P 0.10, one-tailed). To obtain a numeric measure of disease in the lumbar spine, minimal disease was assigned 0, minimalmild was assigned 1, mild 2, mild-moderate 3, moderate 4, moderate-definite 5, and definite disease 6. There was a slight trend towards a greater rating of FIG. 1. The pixels indicating a positive rCBF correlation with the subjective pain rating in the controls (top, red-yellow scale), the patients (blue-pink scale), the conjunction of the controls and patients (green-turquoise scale) and the differences between the controls and patients (bottom, controls greater than patients (Ctrl NSLBP) red-yellow scale and patients greater than controls (NSLBP Ctrl) pink-blue scale). The correlations are shown as statistical parametric maps with a T value coded according to the color bars shown on the right. The SPM images are thresholded at an uncorrected P 0.01 for descriptive purposes only. Significance pertains only to those regions described in the text and in Tables 4 and 5. The SPM is superimposed selected axial views of the standard MNI image provided with SPM99. The number above each axial slice refers to the relative distance to the AC–PC line (joining the anterior and posterior commisures), situated at 0 mm. The anterior part of the brain corresponds to the top of the image, the posterior parts to the bottom. The left side of each image is the left side of the brain (neurological orientation). NSLBP, nonspecific low back pain patients; Ctrl, control subjects. FIG. 2. The pixels indicating a positive rCBF correlation with the subjective pain rating in the controls (left, red-yellow scale), the patients (blue-pink scale), the conjunction of the controls and patients (green-turquoise scale) and the differences between the controls and patients (right, controls greater than patients (Ctrl NSLBP) red-yellow scale and patients greater than controls (NSLBP Ctrl) pink-blue scale). The correlations are shown as statistical parametric maps with a T value coded according to the color bars shown on the right and thresholded as for Fig. 1. The SPM is superimposed on two sagittal views of the left hemisphere (top) and right hemisphere (bottom). The slices are 2 mm (behind) and 10 mm (front) deep from the midline. Ctrl, control subjects; NSLBP, nonspecific low back pain patients. 164 DERBYSHIRE ET AL. TABLE 2 Pain and Clinical Assessment Results Anx (sd)* Controls Patients 5.6 (2.9) 7.3 (2.9) Dep (sd) 2.9 (2.5) 4.1 (2.4) MRI (sd) 1.3 (1.3) 1.9 (1.7) Wadd (sd) 0 1.8 (1.5) LBP Int (sd) LBP Aff (sd) 0 40.4 (26.4) 0 44.5 (23.8) Note. The results of the questionnaires and clinical evaluations averaged for the controls and patients separately. Anx, HAD anxiety rating; Dep, HAD depression rating; MRI, results of the MR lumbar evaluation (see text); Wadd, Waddell score; LBP Int, intensity rating of the patients’ lower back pain; LBP Aff, affective rating of the patients’ lower back pain. *Significant difference between groups; t 1.7, P 0.05; t 1.3, P 0.1; t 1.1, P 0.13. The Waddell score is described in detail elsewhere (Waddell et al., 1980), in brief the test consists of five simple procedures to assess sensitivity to light touch, axial loading and passive rotation of the shoulders and pelvis, and the effects of straight leg raising with distraction and the presence or absence of a stocking distribution of sensory deficit in the leg. The measurements of low back pain consisted of two 100-mm scales anchored at “Not at all intense” and “Most intense pain imaginable,” and “Not at all bothersome” and “Most bothersome pain imaginable.” disease in the patients compared with the control subjects (t 1.1, P 0.13, one-tailed). None of the control subjects reported any pain in their lower back, at the time of the study, and none had a positive response to any of the Waddell tests. In contrast, the patients had a minor Waddell response with an average of two abnormal illness behaviors for each patient. Experimental Pain Ratings Table 3 shows the temperature of the probe used for the experiences of heat (not painful), mild, and moderate pain in the control and patient groups and the associated visual analogue score (VAS). As would be expected, in both the control and patient group there was a highly significant effect of condition for the temperature (F 2,45 37.9, P 0.001 and F 2,45 28.3, P 0.001 for the controls and patients respectively) and VAS rating (F 2,45 135.7, P 0.001 and F 2,45 186.7, P 0.001). Post hoc t test confirmed that each increment in temperature and VAS was significant. Two-way ANOVA assessed the main effects across the groups and revealed a main effect of rating (F 2,90 321.0, P 0.001), a marginal effect of group (F 1,90 3.7, P 0.058) and a significant group rating interaction (F 2,90 3.5, P 0.05). Post-hoc t test revealed the source of the interaction as a significantly greater VAS rating of the moderate pain stimulus in the patients (t 3.4, P 0.01). A second two-way ANOVA found a significant main effect of temperature (F 2,90 63.6, P 0.001) but with no effect of group (F 1) or interaction (F 1). In summary, therefore, the patient group can be said to have received the same stimulation intensities at each level of stimulation with a higher VAS rating for the most intense stimulus. The effect of pain experience on rCBF was assessed separately for the patient and control groups and for conjunctions and differential responses. The results are illustrated as SPM in Figs. 1–3. rCBF Correlation with Intensity Rating To formally assess the linear nature of the rCBF response with the subjects’ VAS ratings, rCBF was correlated with each VAS score for the two groups separately and then assessed for regions of common and differential response. The results are displayed in Figs. 1–3 on selected axial and medial slices and on the lateral surface, respectively. Both groups show highly significant bilateral responses in the cerebellum, midbrain, and PAG region, thalamus and lentiform nucleus. Figure 1 also shows greater activation of the ipsilateral insula in the controls but equivalent activation in the contralateral insula. Figure 2 clearly shows bilateral activation of the midcingulate region in both groups with a greater anterior extent in the controls and greater posterior extent in the patients. The lateral surface projections (Fig. 3) revealed contralateral TABLE 3 Experimental Noxious Heat Temperatures and Associated Ratings NP Controls Patients Temp (SD) 41.5 (1.5) 41.1 (1.9) NP VAS (SD) 7.9 (8.2) 6.3 (6.7) MiP Temp (SD) 44.5 (1.4) 44.4 (1.6) MiP VAS (SD) MoP Temp (SD) 45.6 (1.3) 45.8 (1.8) MoP VAS (SD) 40.5 (10.1) 42.6 (10.3) 60.2 (8.8) 70.6 (10.8) Note. The average temperatures used during rCBF measurement and the associated VAS ratings. Temperatures are shown in Celsius with the VAS (scale: 0, “no pain” to 100, “worse pain imaginable”) pain measurement associated with each of the three heat stimuli (non-painful, mild and moderate pain) for the controls and patients separately. NP, nonpainful; Temp, temperature; SD, standard deviation; VAS, visual analogue score; MiP, mild pain; MoP, moderate pain. *Significant difference between groups; t 3.4, P 0.001. CEREBRAL RESPONSES TO NOXIOUS THERMAL STIMULATION 165 TABLE 4 rCBF Correlation with VAS Rating Brain region (x, y, z coordinates) Control Subjects Right midbrain/cerebellum (6, 34, 34) Midbrain/PAG (4, 24, 8) Left thalamus ( 16, 12, 8) Right thalamus (16, 22, 4) Left lentiform nucleus/ insula ( 22, 12, 4) Right lentiform nucleus (28, 2, 4) Right perigenual cingulate cortex (A 24) (8, 28, 24) Midcingulate cortex (A 24 ) (4, 12, 32) Left prefrontal cortex (BA 9) ( 28, 34, 28) Left inferior parietal cortex (BA 40) ( 52, 44, 24) Right inferior parietal cortex (BA 40) (56, 44, 24) Patients Cerebellum (0, 64, 20) Midbrain/PAG (0, 22, 8) Right thalamus/lentiform nucleus (14, 6, 4) Right insula/lentiform nucleus (34, 4, 8) Right insula (50, 2, 12) Left anterior cingulate cortex (BA 24) ( 6, 0, 40) Right anterior cingulate cortex (BA 24/32) (4, 26, 28) Left premotor cortex (BA 6/4) ( 10, 14, 68) T score P value corrected P value SV corrected 4.7 4.5 4.3 4.5 4.8 4.1 5.1 4.8 4.2 3.7 4.2 0.038 0.116 0.216 0.122 0.036 0.133 0.012 0.036 0.275 0.849 0.287 0.000 0.000 0.002 0.001 0.000 0.004 0.000 0.000 0.007 0.043 0.007 3.7 6.1 5.5 4.9 5.7 4.5 4.6 4.4 0.816 0.000 0.002 0.022 0.001 0.103 0.074 0.182 0.035 0.000 0.000 0.000 0.000 0.002 0.002 0.004 Note. The regions of rCBF significantly correlated with pain ratings for the control subjects and back pain patients. The areas are tabulated in terms of the brain region and their Brodmann’s areas (BA). The x, y, z coordinates plot each peak (defined as the pixel with the highest T score within each region) according to the MNI atlas. The P value Corrected column shows the Eular corrected P values for the whole brain. The P value SV corrected shows the Eular corrected P values for a small volume centered around the coordinates shown. The small volume corrections were based on a sphere of 90 voxels (PAG), 452 voxels (thalamus and lentiform nucleus), or 1072 voxels (all remaining cortical regions and the cerebellum). The rCBF changes are displayed as SPM in Fig. 1, 2, and 3. activation of the dorsolateral prefrontal cortex (BA 9/46) in the control subjects and ipsilateral activation in the patients. This right, ipsilateral response in the patients, however, reached criteria for conjunction indicating that the ipsilateral, right, prefrontal response in controls was just below threshold for the individual group analyses. The greater ipsilateral prefrontal response in the controls, however, reached criteria for difference between the groups. Details of the coordinates and associated T scores for these regions are shown in Table 4. DISCUSSION As for previous studies of rCBF response during painful experience this study reveals a large number of activated regions including the midbrain, thalamus, anterior insula, lentiform nucleus, prefrontal cortex, and anterior cingulate cortex (see Derbyshire, 1999, 2000, for review). Similar to our previous study of AFP there is a striking degree of overlap in the patterns of response between the patient and control group both in the spatial extent and intensity of central activation. Our conjunction analysis formally demonstrated concurrent activation in the bilateral cerebellum, midbrain, thalamus, lentiform nucleus and midcingulate cortex and in the ipsilateral insula and prefrontal cortex. Studies with irritable bowel syndrome (IBS), another functional disorder, also indicate reasonable overlap between controls and patients (Mertz et al., TABLE 5 rCBF Group Differences Brain region (x, y, z coordinates) Control Subjects Patients Midcingulate cortex (A24 ) (4, 10, 28) Left prefrontal cortex (BA 9/10) ( 32, 36, 24) Left insula ( 32, 18, 4) Patients Control Subjects Posterior cingulate cortex (BA 23) ( 12, 34, 4) T score P value corrected P value SV corrected 3.8 3.6 3.0 0.764 0.904 1.000 0.034 0.050 0.047* 3.5 0.933 0.056 Note. The regions of rCBF differences between the two groups. The regions are tabulated as for Table 4 and the small volume corrections based on a sphere of 1072 voxels except in the insula region where significance could only be obtained with a sphere of a maximum 90 voxels. 90 voxels corresponds to a single resel, the smallest independently resolvable region for this data set. 166 DERBYSHIRE ET AL. 2000; Naliboff et al., 2001). These findings demonstrate the consistency and reliability of central responses during noxious experience in controls and patients with functional disorder and demonstrate that there is not a new “pain region” that is activated in NSLBP patients. Unlike most previous comparisons of control and patient populations, however, differences in the pattern and intensity of activation between the two groups were not very apparent. Previous failures to observe differences between patients and controls (Silverman et al., 1997) may have been a consequence of minimal rCBF measurements in small numbers of subjects rendering the signal to noise ratio very low and the probability of a negative finding high. The number of subjects employed for the current study and the number of replications per condition is much greater than for our and others’ previous work. In addition, PET sensitivity and the sophistication of analysis have both improved by orders of magnitude since earlier studies (Adam et al., 1997). These improvements in design and technique mean it is unlikely that our current result can be attributed to false negative. Differences in technique when stimulating the viscera as opposed to the soma may explain some of the inconsistency but the failure to find differences is also in contrast to our previous findings with AFP (Derbyshire et al., 1994) and rheumatoid arthritis (Jones and Derbyshire, 1997) that used the same design. Similar to NSLBP, AFP is a poorly defined entity with no known organic cause and associations with depression. Previously we reported greater anterior cingulate and lesser prefrontal response in AFP patients. The interpretation of this as a generalized hyperattentional response to noxious or potentially noxious stimuli led us to suggest similar mechanisms might be operating in other chronic pain conditions with a poorly defined peripheral etiology. As both the patients and controls studied here showed largely the same anterior cingulate responses, with perhaps greater response in controls, and similar prefrontal response that hypothesis is not strongly supported. The greater left sided prefrontal response in the control subjects might be viewed as evidence for reduced attentional control during acute pain in patients with NSLBP. Prefrontal responses to phasic heat pain are reported in approximately two thirds of studies but appear predominantly on the right lateral surface regardless of the side of stimulation (Derbyshire, 2000). The results from the controls in the present study are therefore unusual in activating the left prefrontal cortex more than the right. In addition, the NSLBP patients studied here activated right prefrontal cortex, consistent with many other studies of phasic pain but inconsistent with our previous study of AFP (Derbyshire et al., 1994). There are also a number of confounding conditions that separate our two groups, including the experi- ence of chronic pain itself. The experience of ongoing pain may lead to a general reduction in response to additional acute pain possibly because of competition for common neurophysiological resources as has been suggested for other disorders (Woodruff et al., 1997) and other clinical pain conditions (Derbyshire, 1999). More specifically, hypofrontality has been observed in depressed patients relative to normal controls (Davidson et al., 1999) and depression is strongly associated with stroke damage to the left prefrontal cortex (Rogers et al., 1998). Thus the slightly greater depression in the NSLBP patients may be sufficient to explain the reduced prefrontal response. Similar associations with depression and reduced metabolic activity have also been reported in the anterior cingulate cortex (Baker et al., 1997; Bench et al., 1992). The alleviation of depression with the antidepressant sertraline has been shown to correlate with increasing metabolic activity of the anterior cingulate and, in a separate study, anterior cingulate activity has been used to predict treatment responders (Buchsbaum et al., 1997; Mayberg et al., 1997). Thus the greater anterior cingulate activity observed in the control subjects may also be a consequence of the differences in depression. Similarly, Bremner et al. (1999) reported a decrease in blood flow in the anterior cingulate in posttraumatic stress disorder (PTSD) patients during exposure to traumatic pictures and sound. The small differences in anxiety between our groups, therefore, might also be contributing to the anterior cingulate differences observed. A study of anticipatory anxiety related to electrical shock, however, has demonstrated anterior cingulate activation (Chua et al., 1999) although perhaps with less intensity than often observed with painful stimulation. The greater activity in the posterior cingulate cortex (BA 23) indicated in the patients is difficult to interpret. While traditionally this region has been implicated in visuospatial orientation (Vogt et al., 1996), it has recently been suggested that posterior cingulate regions are frequently activated by emotionally salient stimuli and play an important role in episodic memory (Maddock, 1999). Patients with neuropathic pain have been found to increase blood flow in posterior cingulate areas 23 and 31 (Hsieh et al., 1995b), while studies of acute nociceptive responses showed reduced blood flow in these same areas (Coghill et al., 1994; Vogt et al., 1996). The adjacent retrosplenial cortex (areas 29 and 30) is also activated more often in experiments that involve unpleasant stimuli (fearful, disgusting or sad words and images) than in those involving pleasant (happy) stimuli (Maddock, 1999). Increased activation of this brain region has also been reported in major depression (Ho et al., 1996) and activity correlates with anxiety symptoms in affective disorders (Bench et al., 1992; McGuire et al., 1994; Perani et al., 1995; Reiman, CEREBRAL RESPONSES TO NOXIOUS THERMAL STIMULATION 167 1997). Activation of this region, therefore, might also relate to the differences in anxiety and depression between our groups. The back pain patients in this study did not have a particularly high Waddell response (see Table 2) indicating that they did not exhibit the abnormal illness behavior that is typical with AFP. They also had a more moderate incidence of depression and anxiety. We cannot exclude the possibility that NSLBP with a positive Waddell response in addition to depression might show similar responses to those observed with AFP. One implication of this study, however, is that as patients with chronic pain become more closely matched for affective disorder so too does their profile of neuronal activity to noxious stimulation. The differences observed in the current study do not provide compelling evidence for an alternate neural processing of pain in patients with NSLBP. ACKNOWLEDGEMNTS Support for this project was provided by the Medical Research Council (ROPA Award No. 8 DEE 171). We thank Donna Milko, James Ruszkiewicz, and Marsha Dachille for their technical support and invaluable assistance, Thomas Beyer for additional technical information, Thomas Nichols for statistical guidance, and James Rankin for providing us with his guide to lumbar pathology. REFERENCES Adam, L. E., Zaers, J., Ostertag, H., Trojan, H., Bellemann, M. E., and Brix, G. 1997. Performance evaluation of the whole-body PET scanner ECAT EXACT HR following the IEC standards. IEEE Trans. Nucl. Sci. 44: 1172–1179. Andersson, J. L. R., Lilja, A., Hartvig, P., Långstrom, B., Gordth, T., ¨ Handwerker, H., and Torebjork, E. 1997. Somatotopic organization along the central sulcus for pain localization in humans as revealed by positron emission tomography. Exp. Brain Res. 117: 192–199. Apkarian, A. V., and Hodge, C. J. 1989. Primate spinothalamic pathways: I. A quantitative study of the cells of origin of the spinothalamic tract. J. Comp. Neurol. 288: 447– 473. Aziz, Q., Andersson, J. L. R., Valind, S., Sundin, A., Hamdy, S., Jones, A. K. P., Foster, E. R., Langstrom, B., and Thompson D. G. 1997. Identification of human brain loci processing esophageal sensation using positron emission tomography. Gastroenterology 113: 50 –59. Baker, S. C., Frith, C. D., and Dolan, R. J. 1997. The interaction between mood and cognitive function studied with PET. Psychol. Med. 2: 565–578 Bench, C. J., Friston, K. J., Brown, R. G., Scott, L. C., Frackowiak, R. S., and Dolan R. J. 1992. The anatomy of melancholia focal abnormalities of cerebral blood flow in major depression. Psychol. Med. 22: 607–15. Bremner, J. D., Staib, L. H., Kaloupek, D., Southwick, S. M., Soufer, R., and Charney, D. S., 1999. Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: A positron emission tomography study. Biol. Psychiatry. 45: 806 –16. Buchsbaum, M. S., Wu, J., Siegal, B. V., Hackett, E., Trenary, M., Abel, L., and Reynolds, C. 1997. Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol. Psychiatry 41: 15–22. Casey, K. L., Minoshima, S., Morrow, T. J., and Koeppe, R. A. 1996. Comparison of human cerebral activation patterns during cutaneous warmth., heat pain., and deep cold pain. J. Neurophysiol. 76: 571–581. Casey, K. L., Minoshima, S., Berger, K. L., Koeppe, R. A., Morrow, T. J., and Frey, K. A. 1994. Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J. Neurophysiol. 71: 802– 807. Chua, P., Krams, M., Toni, I., Passingham, R., and Dolan, R. 1999. A functional anatomy of anticipatory anxiety. Neuroimage 9: 563– 571. Coghill, R. C., Talbot, J. D., Evans, A. C., Meyer, E., Gjedde, A., Bushnell, M. C., and Duncan, G. H. 1994. Distributed processing of pain and vibration by the human brain. J. Neurosci. 14: 4095– 4108. Craig, A. D., Reiman, E. M., Evans, A., and Bushnell, M. C. 1996. Functional imaging of an illusion of pain. Nature 384: 258 –260. Craig, A. D., Bushnell, M. C., Zhang, E. T., and Blomqvist, A. 1994. A thalamic nucleus specific for pain and temperature sensation. Nature 372: 770 –773. Davidson, R. J., Abercombie, H., Nitschke, J. B., and Putnam, K. 1999. Regional brain function and disorders of emotion. Curr. Opin. Neurobiol. 9: 228 –234. Davis, K. D., Kwan, C. L., Crawley, A. P., and Mikulis, D. J. 1998. Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli J. Neurophysiol. 80: 1533–1546. Davis, K. D., Taylor, S. J., Crawley, A. P., Wood, M. L., and Mikulis, D. J. 1997. Functional MRI of pain and attention-related activations in the human cingulate cortex. J. Neurophysiol. 77: 3370 – 3380. Derbyshire, S. W. G. 1999. Meta-analysis of thirty-four independent samples studied using positron emission tomography (PET) reveals a significantly attenuated central response to noxious stimulation in clinical pain patients. Curr. Rev. Pain 3: 265–280. Derbyshire, S. W. G. 2000. Exploring the pain “neuromatrix.” Curr. Rev. Pain 6: 467– 477. Derbyshire, S. W. G., and Jones, A. K. P. 1998. Cerebral responses to a continual tonic pain stimulus measured using positron emission tomography. Pain 76: 127–135. Derbyshire, S. W. G., Jones, A. K. P., Collins, M., Feinmann, C., and Harris, M. 1999. Cerebral responses to pain in patients suffering acute post dental extraction pain measured by positron emission tomography (PET). Eur. J. Pain 3: 103–113. Derbyshire, S. W. G., Vogt, B. A., and Jones, A. K. P. 1998. Pain and Stroop interference tasks activate separate processing modules in anterior cingulate cortex. Exp. Brain. Res. 118., 52– 60. Derbyshire, S. W. G., Jones, A. K. P., Gyulai, F., Clark, S., Townsend, D. and Firestone, L. L. 1997. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 73: 431– 445. Derbyshire, S. W. G., Jones, A. K. P., Devani, P., Friston, K. J., Feinmann, C., Harris, M., Pearce, S., and Watson, J. D. G. 1994. Frackowiak R. S. J. Cerebral responses to pain in patients with atypical facial pain measured by positron emission tomography. J. Neurol. Neurosurg. Psychiatry 57: 1166 –1173. Fordyce, W. E. (Ed.) 1995. Back pain in the workplace: Management of disability in non-specific conditions. IASP Press, Seattle. Fordyce, W. E. 1996. Response to Thompson/Merskey/Teasell. Pain 65: 112–114. Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J. P., Frith, C. D., and Frackowiak, R. S. J. 1995. Statistical parametric maps in 168 DERBYSHIRE ET AL. Mertz, H., Morgan, V., Tanner, G., Pickens, D., Price, R., and Shyr, Y. 2000. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distension. Gastroenterology 118: 842– 8. Nachemson, A. L. 1992. Newest knowledge of low back pain: a critical look. Clin. Orthop. 279: 8 –20. Naliboff, B. D., Derbyshire, S. W. G., Munakata, J., Berman, S., Mandelkern, M., Chang, L., and Mayer, E. A. 2001. Cerebral activation in irritable bowel syndrome patients and control subjects during rectosigmoid stimulation. Psychosom. Med. 63: 365– 375. Perani, D., Colombo, C., Bressi, S., Bonfanti, A., Grassi, F., Scarone, S., Bellodi, L., Smeraldi, E., and Fazio, F. 18F-FDG PET study in obsessive-compulsive disorder. 1995. A clinical/metabolic correlation study after treatment. Br. J. Psychiatry 166: 244 –50. Rainville, P., Duncan, G. H., Price, D. D., Carrier, B., and Bushnell, M. C. 1997. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 277: 968 –971. Reiman, E. M. 1997. The application of positron emission tomography to the study of normal and pathologic emotions. J. Clin. Psychiatry 58 (Suppl 16): 4 –12. Rogers, M. A., Bradshaw, J. L., Pantelis, C., and Phillips, J. G. 1998. Frontostriatal deficits in unipolar major depression. Brain Res. Bull. 47: 297–310. Silverman, D. H. S., Munakata, J. A., Ennes, H., Mandelkern, M. A., Hoh, C. K., and Mayer, E. A. 1997. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 112: 64 –72. Talbot, J. D., Marret, S., Evans, A. C., Meyer, E., Bushnell, M. C., and Duncan, G. H. 1991. Multiple representations of pain in human cerebral cortex. Science 251: 1355–1358. Treede, R. D., Daniel, R., Kenshalo, D. R., Richard, H. Gracely, R. H., and Jones A. K. P. 1999. The cortical representation of pain. Pain 79: 105–111. Vogt, B. A., Derbyshire, S. W. G., and Jones, A. K. P. 1996. Pain processing in four regions of human cingulate cortex localized with coregistered PET and MR imaging. Eur J. Neurosci. 8: 1461–1473. Vogt, B. A., Sikes, R. W., and Vogt, L. J. 1993. Anterior cingulate cortex and the medial pain system. In Neurobiology of Cingulate Cortex and Limbic Thalamus: A Comprehensive Treatise (Vogt B. A., Gabriel, M., Eds.), pp. 313–344. Birkhauser, Boston. Waddell, G., McCulloch, J. A., Kummel, E., and Venner, R. M., 1980. Nonorganic physical signs in low-back pain. Spine 5: 117–125. Woodruff, P. W. R., Wright, I. C., Bullmore, E. T., Brammer, M., Howard, R. J., Williams, S. C. R., Shapleske, J., Rossell, S., David, A. S., McGuire, P. K., and Murray, R. M. 1997. Auditory hallucinations and the temporal cortical response to speech in schizophrenia: A functional magnetic resonance imaging study. Am. J. Psychiatry 154: 1676 –1682. Woods, R. P., Cherry, S. R., and Mazziotta, J. C., 1992. A rapid automated algorithm for accurately aligning and reslicing positron emission tomography images. J. Comput. Assist. Tomogr. 16: 620 – 633. Zigmond, A. S., and Snaith, R. P. 1983. The hospital anxiety and depression scale. Acta. Psychiatr. Scand. 67: 361–370. functional imaging: A general approach. Hum. Brain Mapp. 2: 189 –210. Friston, K. J., Price, C. J., Fletcher, P., Moore C., Frackowiak, R. S. J., and Dolan, R. J. 1996. The trouble with cognitive subtraction. Neuroimage 4: 97–104. Fruhstorfer, H., Lindblom, U., and Schnidt, W. G. 1976. Method for quantitative estimation of thermal thresholds in patients. J. Neurol. Neurosurg. Psychiatry 39: 1071–1075. Ho, A. P., Gillin J. C., Buchsbaum M. S., Wu, J. C., Abel, L., and Bunney, W. E. 1996. Brain glucose metabolism during non-rapid eye movement sleep in major depression. A positron emission tomography study. Arch. Gen. Psychiatry 53: 645–52. Hsieh, J. C., Stahle-Backdahl, M., Hagermark, O., Stone-Elander, S., Rosenquist, G., and Ingvar, M. 1995a. Traumatic nociceptive pain activates the hypothalamus and the periaqueductal gray: A positron emission tomography study. Pain 64: 303–314. Hsieh, J. C., Belfrage, M., Stone-Elander, S., Hansson, P., and Ingvar, M. 1995b. Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain 63: 225–236. Jones, A. K. The contribution of functional imaging techniques to our understanding of rheumatic pain. 1999. Rheum. Dis. Clin. North. Am. 25: 1123–52. Jones, A. P., Hughes, D. G., Brettle, D. S., Robinson, L., Sykes, J. R., Aziz, Q., Hamdy, S., Thompson, D. G., Derbyshire, S. W. G., Chen, C. A. N., and Jones, A. K. P. 1998. Experiences with functional magnetic resonance imaging at 1 tesla. Br. J. Radiol. 71: 160 –166. Jones, A. K. P., Brown, W. D., Friston, K. J., Qi, L. Y., and Frackowiak, R. S. J. 1991. Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc. R. Soc. Lond. 244: 39 – 44. Jones, A. K. P., and Derbyshire, S. W. G., 1997. Reduced cortical responses to noxious heat in patients with rheumatoid arthritis (RA). Ann. Rheum. Dis. 56: 601– 607. Jensen, M. C., Brant-Zawadzki, M. N., Obuchowski, N., Modic, M. T., Malkasian, D., and Ross, J. S. 1994. Magnetic resonance imaging of the lumbar spine in people without back pain. N. Eng. J. Med. 331: 69 –73. Loeser, J. 1996. Editorial comment: Back Pain in the Workplace: II. Pain 65: 7– 8. Maddock, R. J. 1999. The retrosplenial cortex and emotion: New insights from functional neuroimaging of the human brain. Trends Neurosci. 22: 310 – 6. May, A., Kaube, H., Buchel, C., Eichten C., Rijntjes M., Juptner M., Weiller, C., and Diener, H. C. 1998. Experimental cranial pain elicited by capsaicin: A PET study. Pain 74: 61– 66. Mayberg, H. S., Brannan, S. K., Mahurin, R. K., Jerabeck, P. A., Brickman, J. S., Tekell, J. L., Silva, J. A., McGinnis, S., Glass, T. G., Martin, C. C., and Fox, P. T. 1997. Cingulate function in depression: A potential predictor of treatment response. Neuroreport 8: 1057–1061. McGuire, P. K., Bench, C. J., Frith, C. D., Marks, I. M., Frackowiak, R. S., and Dolan, R. J. 1994. Functional anatomy of obsessivecompulsive phenomena. Br. J. Psychiatry 164: 459 – 68. Melzack, R. 1989. Phantom limbs, the self and the brain: The D. O. Hebb memorial lecture. Can. Psychol. 30: 1–16.