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Anesth Analg 2005;101:449-456 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000158468.84424.5D
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Abstract |
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Pain-related cerebral activation in functional magnetic resonance imaging shows less consistent signals that decay earlier than in conventional task-related activation. This may result from pain’s top-down inhibition mediated by cognitive or hemodynamic interaction that could affect activation by other modalities. Using event-related functional magnetic resonance imaging, we examined whether pain affects cerebral activation by a saccade task through such cross-modal interaction. Six right-handed volunteers underwent whole-brain echo-planar imaging on a 3.0 T magnetic resonance imaging scanner while they received thermal pain stimulus at 50°C on the right forearm (P; n = 6), performed a visually guided saccade task (V; n = 6), and went through a simultaneous pain-plus-saccade paradigm (PV; n = 5). Averaged functional activation maps were synthesized and signal time courses were analyzed at activation clusters. P activated the bilateral secondary somatosensory cortex (S2). V activated the posterior, supplementary, frontal eye fields, and visual areas. PV enhanced the S2 activation and activated additional pain-related areas, including the bilateral premotor area, right insula, anterior, and posterior cingulate cortices. In contrast, V-related activation was attenuated in PV. We propose that pain caused cross-modal suppression on the oculomotor activity and that an oculomotor task enhanced pain-related activation by triggering attention toward pain.
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Introduction |
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Pain experience has been found by functional imaging studies to activate multiple, discrete cortical and subcortical areas in the human brain (1,2). In functional magnetic resonance imaging (fMRI), blood oxygenation level-dependent (BOLD) contrasts induced by pain tend to be statistically less robust, less consistent, and to decay earlier than those by visual and motor tasks (3). This nature of pain-related cerebral activation may be attributable to pain’s multidimensional nature, including sensory, affective, and cognitive components (1), which probably involves top-down brain activities that influence afferent sensory processing in the brain. Therefore, the pain-induced brain status may affect BOLD contrasts induced by the other cognitive tasks in different neural networks, and it may also be modified by the presence of concomitant cognitive tasks that could affect attentional states.
In the current study, we tested a hypothesis that concomitant pain stimulus and visually guided saccade task may show cross-modal interaction between the different nonoverlapping neural networks, as revealed by BOLD-based fMRI. Very high field MRI (3.0 T) was used to enhance the sensitivity to BOLD signal changes. Event-related fMRI experiments with brief periods of stimuli were performed to uncover temporal characteristics of cerebral activation and to prevent possible habituation to the stimulus/task. Voxel-wise temporal averaging was performed to enhance the signal-to-noise ratio and to obtain reliable signal time courses in voxel-of-interest (VOI) analysis. Cerebral activation maps and BOLD signal amplitudes were compared among three experiments: pain, saccade, and pain-plus-saccade stimulus/task trials.
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Methods |
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Written informed consent was obtained from six healthy volunteer subjects (29–38 yr in age; one female and five males). All were right-handed and had no history of neurological or psychiatric disorders or medications. Subjects had not taken any psychoactive drugs or analgesics for a period of 24 h before the study. The protocol was approved by the IRB of the University of Pittsburgh.
Each subject was examined with three experiments in one imaging session: a pain stimulus at the right forearm (P), a visually guided saccade task (V), and a combined pain-plus-saccade paradigm (PV). All the tasks were designed in an event-related paradigm (4) consisting of 60 cycles of a 1-s stimulus phase followed by a 14-s control phase, lasting 15 min in total. These stimuli/tasks were given to each subject in a counterbalanced order during the fMRI image acquisition.
A Peltier-type thermal stimulator (TSA-2001; Medoc, Israel) was used to deliver hot pain stimulus during the pain experiments (5). It was equipped with an MRI-compatible nonferrous thermode (3 x 3 cm2 surface) and a 12-meter cable and controlled with commercial software (COVAS; Medoc) on a personal computer from outside the scanner room. The thermode was fixed on the subject’s volar surface of the right forearm with a Velcro belt. Each subject was asked to rate stimulus intensity and unpleasantness separately with an integer between 0 and 10 (6). On this scale, 0 indicated "no sensation" or "not at all unpleasant" and 10 indicated "the most intense pain imaginable" or "the most unpleasant feeling imaginable" for the intensity or unpleasantness, respectively. A score of 5 was anchored to "just painful" sensation or "just unpleasant" feeling.
In P and PV, each subject was given 60 cycles of 1-s hot pain stimulus at 50°C, which was preceded and followed by approximately 2-s transitions at a ramp rate of 10°C · s–1 and followed by approximately 10-s control stimulus at 32°C. Immediately after each pain stimulus session of 60 cycles, the subject was asked to give the scores of pain intensity and unpleasantness verbally through a microphone in the scanner.
During V and PV, subjects were given saccade cues on a projection screen placed above their chest and viewed in an angled mirror fixed to the head coil. The saccade cues were presented with in-house stimulus presentation software (7) on a personal computer.
V consisted of 60 cycles of 1-s saccade followed by 14-s control fixation. The saccade target was a solid white circle and the fixation target was a white cross hair; both targets subtended 0.75° of visual angle on a black background. The saccade target was presented at 0°, 3°, or 6° of visual angle to the left or right along the horizontal plane and moved unpredictably with a 0.5 probability to the left or right every 0.75 s in a 3° step from its previous position. Consequently, 2 saccade movements were triggered in 1 s during each cycle. During the control phase the subject gazed at the cross hair at the center of the screen.
In PV, both the pain stimulus and saccade cues were presented concomitantly such that the start of thermal stimulus was synchronized with that of saccade cues. Because of the 2-s transition from the start to the plateau of the pain stimulus, subjects received the 50°C-pain stimulus approximately 1 s after performing the visually guided saccade task.
MRI scans were conducted using a whole-body 3.0 T scanner (Signa; General Electric Medical Systems, Milwaukee, WI) with a volume head coil. Subjects lay supine in the MRI scanner with their heads immobilized by foam padding and pillows. A visual feedback system providing subjects with information on the head position helped them to keep a stationary position (8). Subjects were protected from acoustic scanner noise by earplugs. Functional images were obtained with a T2*-sensitive, single-shot, gradient-echo echo-planar pulse sequence with the following parameters: repetition time (TR) = 3000 ms; echo time (TE) = 25 ms; flip angle (FA) = 90°; imaging matrix = 64 x 64; field of view = 20 x 20 cm; slice thickness = 3 mm; and slice gap = 1.5 mm. Fourteen slices were acquired covering the major part of the cerebrum from the primary sensorimotor cortex to the thalamus in an axial orientation. The imaging trial consisted of 300 consecutive scans (15 min) for each task. After all the functional scans, a structural MRI of the whole brain was obtained using a three-dimensional high-resolution acquisition (fast spoiled gradient-recalled at steady-state) for anatomical reference with the following parameters: TR = 25 ms; TE = 5 ms; FA = 40°; imaging matrix = 256 x 192; field of view = 24 x 18 cm; slice thickness = 1.5 mm; no slice gap; and 124 axial slices.
Raw MRI data were preprocessed with in-house (LxConvert) and fScan software (7) to be used for the following image processing. One PV functional data set from one subject was excluded from analysis because of a data storage error. Therefore, the numbers of data sets successfully analyzed were 6, 6, and 5 for the P, V, and PV experiments, respectively. Image processing and statistical analysis of the functional data sets were performed using in-house customized modules of AVS software (Advanced Visual Systems, Waltham, MA) on a UNIX workstation. These AVS modules average single-event cycles over each functional data set, depict averaged signal time courses, and generate voxel-wise t-statistical maps. The averaged signal time course consisted of 5 segments of 3 s each, lasting 15 s in total. Based on a typical BOLD signal time course with hemodynamic delay (the first segment), the second and third segments were considered as the activated phase and the fourth and fifth segments as the recovery phase. Voxel-wise t-tests were performed between the activated and recovery phases across all 60 cycles, and a voxel was considered activated if its t-value was more than 2.0, which corresponded to a chance probability of P < 0.05 without correction for multiple comparisons (degrees of freedom = 238). By convention, such statistical differences are referred to as "activation." The functional activation maps (t-maps) generated by the AVS modules were overlaid onto the anatomical reference image and transformed into standardized stereotaxic space (Talairach space) using AFNI software (9,10). To compensate for normal variation in anatomy across subjects, the stereotaxically resampled three-dimensional t-maps were smoothed with a Gaussian filter of 4 mm full-width-half-maximum. The t-maps were merged across all the subjects by averaging the t-statistics at each voxel to guard against nonequal magnetic resonance signal variances among subjects (11). The same threshold of t > 2.0 was used for the merged t-maps. The anatomical brain images were also merged to produce an average reference image with a Gaussian filter of a root-mean-square radius of 0.5 mm. Activated clusters with a volume <3 contiguous voxels, approximately 0.1 mL, were excluded from analysis (12).
VOIs were chosen as voxels showing the highest averaged t-value (local maxima) in the most intensely activated clusters in the P, V, and PV experiments. At each VOI, signal time courses were sampled in each subject, standardized with the baseline determined as the median value between the first and fifth segments, and averaged across subjects. The maximum percentage signal intensity changes (BOLD contrasts) were compared between P and PV and between V and PV with paired Student’s t-tests. The differences in BOLD contrasts between the single (P, V) and the dual (PV) paradigms were computed for each individual and compared between the pain-related and the visually guided saccade-related activation clusters across subjects with a paired Student’s t-test. Statistical differences at P < 0.05 were considered significant.
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Results |
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The demographics of subjects and the pain rating scores are summarized in Table 1. All subjects described the pain stimulus as painful and unpleasant in both P and PV (pain rating scores
5). The scores did not differ between P and PV for either pain intensity (paired Student’s t-test; P = 0.70) or pain unpleasantness (P = 0.70). There was a significant correlation between the pain intensity and pain unpleasantness scores (r = 0.645; P = 0.0215).
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P activated the right inferior parietal lobule and the left postcentral gyrus (Table 2, Fig. 1); these belong to the Brodmann’s cytoarchitectonic area 40 and are generally considered to include the secondary somatosensory cortex (S2) in humans (13,14).
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V activated the cortical areas associated with oculomotor control (15,16), including the posterior, supplementary, frontal eye fields, and the striate and extrastriate visual cortices (Table 2, Fig. 2).
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The S2 activation was enhanced by PV compared with P, as indicated by increased t-values at local maxima (Table 2) and increased volumes of activation clusters (Fig. 1). PV activated more areas than were expected from the sum of P- and V-related activation, i.e., the bilateral premotor area (PMA), right insula, right anterior (ACC) and posterior cingulate cortices (PCC) (Table 2, Fig. 2). These areas have been commonly reported to be associated with pain perception (1).
Conversely, the saccade-related activation induced by PV tended to be weaker than that induced by V, as indicated by smaller t-values of local maxima in 5 of 8 activation clusters that were shared by both V and PV (Table 2). Figure 2 shows decreased sizes of activation clusters at the supplementary eye field and intraparietal sulcus in PV compared with those in V.
Thirteen voxel locations were chosen as VOIs for BOLD signal time course analysis, as shown in Figures 3 and 4. Seven of them were considered related to pain and compared between P and PV; the rest were considered related to visually guided saccade and compared between V and PV. These voxels were at local maxima of major activation clusters of each experiment, except five voxels of P at the bilateral PMA, right insula, ACC, and PCC; these were not activated by P but chosen at the identical coordinates with the local maxima in PV for comparison (Table 2).
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Figure 3 shows the temporal progression of signal changes at the seven pain-related voxels. The BOLD signals generally reached the peak at the second or third image (3–9 s after stimulus) and returned near the baseline at the fifth image (12–15 s after stimulus), which reflects a typical hemodynamic delay of 4–6 s (17). PV tended to induce larger signal changes than P in all pain-related voxels. In contrast, PV tended to induce smaller signal changes than V in all saccade-related voxels (Fig. 4). Overall, PV increased BOLD contrasts of the pain-related activation by 0.09% ± 0.15% (mean ± sd) compared with P, whereas it decreased those of the saccade-related activation by –0.09% ± 0.14% compared with V. Such changes were significantly different (P < 0.0001) between the pain-related and saccade-related activation.
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Discussion |
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Our results showed that the concomitant performance of a pain stimulus and a visually guided saccade task resulted in cerebral activation with an apparently paradoxical pattern of interaction: the pain-related activation was enhanced whereas the saccade-related activation was attenuated. Such cross-modal interaction can be explained by a shift of attention from the saccade task to pain. Even if the saccade task was performed equally well in V and PV, the pain stimulus may have distracted the subjects’ attention from the saccade task, thus attenuating the saccade-related activation in PV. Conversely, a visual cue for the saccade task, also working as a cue for the pain stimulus, may have aroused the subjects’ attention and expectation toward pain, resulting in the enhancement of pain-related cerebral activation. Attention to or distraction from a pain stimulus enhances or attenuates pain-related brain activity, respectively, especially in the ACC (18–20). Expectation of pain, triggered by a conditioned visual cue, activates brain regions close to pain-related areas, such as the medial frontal lobe, insular cortex, and cerebellum (21).
Activation of the descending pain inhibitory system by a pain stimulus could be associated with unknown interactions among certain cortical and subcortical structures that may be involved in cognitive and motivational processes (22). Such pain-induced top-down brain activity may have suppressed the saccade-related activation and, conversely, its competitive distraction by the saccade task enhanced the pain-related activation in PV. Evidence for electrophysiological interaction among somatosensory, visual stimuli, and attention has been demonstrated at the primary and S2 cortices by magnetoencephalography (23).
A possible alternate mechanism for the paradoxical interaction may be the fluctuation of global cerebral blood flow (CBF) superimposed over the regional increases of CBF evoked by local neuronal activation. The global CBF decreases in response to somatic pain stimulus, as demonstrated in an earlier positron emission tomography study using a chemical pain stimulus with intradermal capsaicin that implied that pain stimulus directly activated the sympathetic innervation of cerebral blood vessels (24). Such decrease in global CBF can be so profound—up to about 20% (24)—that regional CBF increase induced by local neuronal activation could be significantly offset to produce BOLD signals of smaller amplitude on the assumption that changes in global and regional CBF are additive (25). An analogous interaction between regional and global CBF was observed in the case of visual stimulus-induced BOLD contrasts at the visual cortex that were attenuated significantly by hyperventilation-induced global CBF reduction (26). The visually guided saccade task in the present study required the subjects’ cognitive efforts, however, and may have increased global CBF (27), reversed the pain-induced reduction of global CBF, and thereby enhanced the pain-related activation. Performance of a cognitive task increases global CBF persistently even beyond cessation of the task (27), which implies that baseline global CBF may increase more than expected from the sum of regional CBF increases associated with local neural activation. In our current study, however, we did not measure the global CBF fluctuation, which leaves the effects of global-regional hemodynamic interaction only speculative. Measurement of baseline magnetic resonance signals at inactive brain areas, or perfusion imaging, may offer a future solution to test this hypothesis.
The pain-related activation observed at the S2, PMA, insula, ACC, and PCC accords with earlier brain imaging studies. The S2 activation showed higher amplitude of BOLD signals on the contralateral (left) hemisphere than on the ipsilateral side in P, in accordance with our previous fMRI study with a block-design paradigm of the same thermal stimulus (Fig. 3) (3). Such contralateral dominance disappeared in PV, possibly as the result of saturation of enhanced BOLD response, as the amplitude of BOLD signals is limited by the duration of a stimulus or task (17). The S2 is involved in nociception as part of the lateral nociceptive system and in the other integrative aspect of sensation (1,13). The rest of the pain-related activation clusters were only observed when in conjunction with the saccade stimulus, but they were generally considered as involved in pain perception. The PMA is commonly activated by both painful and nonpainful somatosensory stimulation and is generally considered to mediate motor preparation (28). The insular cortex has been among the most reliably activated regions by pain as well as the S2 and may be involved in the discrimination of pain stimulus intensity and general sensory integration (29). The ACC has nociceptive neurons (30) and is considered to mediate affective-motivational (18) and cognitive-evaluative (19) aspects of pain as part of the medial nociceptive system (1). The present ACC activation belongs to the midcingulate region probably associated with cognitive processes, such as attentional shifting, response selection, and motor inhibition (29). The PCC also receives direct nociceptive inputs from the thalamus. The present PCC activation may belong to the somatosensory region between the motor and visuospatial subdivisions of the cingulate cortex (31,32). Despite the right-sided pain stimulus, all of these pain-related activation clusters except the S2 appear to dominate on the right hemisphere, which may imply the enhanced attention to pain in PV. Similar right-hemispherical dominance in the prefrontal and parietal cortical activation was observed by positron emission tomography in relation to attentional/awareness components of pain (19,33).
The visually guided saccade task, both in V and PV, reproduced previously reported activation at the dorsal cortical areas serving the control of saccadic eye movements, namely the posterior, supplementary, and frontal eye fields (15,16), robustly with higher t-values than the pain-related activation clusters in P. This may reflect consistency of BOLD signals across the cycles and less variability in the location of activation clusters across the subjects compared with the pain-related activation. The saccade stimulus also activated the visual areas at relatively smaller t-values than the dorsal cortical areas; this activation may reflect image processing of the visual cue. The cluster centered at the middle temporal gyrus (Brodmann’s area 19), activated by V, is considered part of the extrastriate visual areas particularly involved in visual perception of motion (16).
The present study has the following limitations. First, simple statistical comparison between the activated and recovery phases of time course segments may not have been robust enough to eliminate false-negative activation. Development of correlation analysis between signal intensity time courses and hemodynamic response functions may enhance the sensitivity to BOLD signal changes (34). Second, the very short duration of stimuli (1 s) inherent to the single event-related paradigm design limited the maximum amplitude of hemodynamic response (17), which resulted in approximately <0.5% of BOLD signal changes and less statistical robustness than that in our previous block-design fMRI study (3). Such short stimuli may have minimized the possible effects of habituation (35), but the lack of randomization may have confounded the results with the effects of expectation (21). Third, we did not monitor the visually guided saccade task performance because an MRI-compatible eye-tracking device (16) was not available to us. Such a device could have helped in controlling the efficiency of the saccade task performance. Finally, the peak of the pain stimulus was delayed by 1–2 s after the saccade stimulus in PV, which may not have revealed the maximum effects of interaction. However, because this delay was well under the TR of 3 s, we were able to expect similar BOLD signal time courses with the same hemodynamic delay for both the pain and saccade paradigms, which justified the present methods of analysis.
In conclusion, we have observed paradoxical, cross-modal interaction between the pain- and visually guided saccade-induced cerebral activation by analyzing BOLD signal time courses: the pain-related activation was enhanced, whereas the saccade-related activation was attenuated. Such interaction can be explained by a cross-modal shift of attention from the saccade task to pain or alternatively by the global and local hemodynamic interactions that may uniquely underlie pain-induced brain states.
We thank the following people: Denise Davis, BS, RT, for technical help in MRI scanning procedures; Benoit Desjardins, MD, PhD, for programming the AVS software modules for analysis of single event-related fMRI data; James Voyvodic, Ph.D., for providing paradigm presentation (CIGAL) and data processing software (fScan); and Mr. Peter Kese, for providing data processing software (LxConvert).
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Footnotes |
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Supported, in part, by a Clinical Scholar Research Award from the International Anesthesia Research Society, Cleveland, OH (to Dr. Firestone), Grant PO1 NS35949 from the National Institutes of Health, Bethesda, MD (to Dr. Thulborn), and General Electric Medical Systems, Milwaukee, WI.
Presented, in part, at the 32nd Annual Meeting of the Society for Neuroscience in Orlando, FL, November 2–7, 2002, and at the 10th Annual Meeting of the Organization for Human Brain Mapping in Budapest, Hungary, June 13–17, 2004.
Accepted for publication January 19, 2005.
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