| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1
Section of Neuroradiology, Department of Diagnostic Radiology, Yale University
School of Medicine, Box 208042, 333 Cedar St., New Haven, CT 06520-8042.
2
Department of Applied Physics, Yale University School of Medicine, Yale
University, New Haven, CT 06520.
3
Department of Psychiatry, Yale University School of Medicine, New Haven, CT
06520.
Received December 14, 2000;
accepted after revision May 17, 2001.
Address correspondence to R. K. Fulbright.
Abstract
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
SUBJECTS AND METHODS. Twelve healthy adults underwent functional MR imaging using a gradient-echo echoplanar technique while a cold pressor test, consisting of cold and pain tasks, was applied first to one foot and then to the other. The cold task involved the application of cold water (14-20°C) that was not at a painful level. For the pain task, the water temperature was then lowered to a painful temperature (8-14°C) and subsequently to the pain threshold (3-8°C). Images acquired at room temperature before the cold and pain tasks served as a baseline task. Composite maps of brain activation were generated by comparing the baseline task with the cold task and the cold task with the pain task. The significance of signal changes was estimated by randomization of individual activation maps.
RESULTS. Cold-related activation (p < 0.01) was found in the postcentral gyrus bilaterally, laterally, and inferiorly to the primary motor-sensory area of the foot and at a site near the second somatosensory site. Activation also occurred in the frontal lobe (the bilateral middle frontal gyri and the right inferior frontal gyrus), the left anterior insula, the left thalamus, and the superior aspect of the anterior cingulate gyrus (seen at one slice location). Pain-related activation (p < 0.01) included the anterior cingulate gyrus (seen at four slice locations); the superior frontal gyrus, especially on the right; and the right cuneus.
CONCLUSION. Compared with the basic sensory processing of pain, the affective dimension of pain activates a cortical network that includes the right superior frontal gyrus, the right cuneus, and a large area of the anterior cingulate gyrus.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The purpose of our study was to use functional MR imaging (fMR imaging) to identify regions of activation associated with the subjective experiences of pain. Pain was produced by a variant of the tonic cold pressor test [23]. In the cold pressor test, the volunteer's foot was immersed in water of constantly decreasing temperatures to produce a progression of subjective experiences that included aspects of sensory stimulation (cold water), pain tolerance, and pain threshold. A tonic stimulus, as used in the cold pressor test, produces a robust, long-lasting second pain experience that has a stronger affective component than the first pain experience [24].
The cold pressor test was applied to both feet at different times to focus on brain activation associated with the subjective sense or affective dimension of pain rather than with the sensory processing aspects of the stimulus. As the cold progresses from sensory sensation of coolness to pain, a self-rating of pain helps to engage the affective dimension of pain. Cognitive operations of self-monitoring are required. Efforts to maximize pain tolerance can lead to cognitive coping mechanisms such as thoughts of self-distraction or thoughts about compliance with the researchers to help ensure a successful experiment.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
During fMR imaging, the cold pressor test was applied four times—two 4-min runs for each foot in an alternating sequence starting with the right foot. The study was designed not to look at each foot separately during the cold and pain tasks but to include an equal number of trials of right- and left-foot stimulation and then to determine the cortical response. The chosen foot for the cold pressor test was placed in the bottom of an empty basin before each run. The basin was positioned on the MR imaging table so that the subjects could keep their feet flat in the basin and their legs relaxed. A cushion under the subject's knees helped to stabilize the position of the leg and foot. The foot that was not being stimulated was wrapped in towels. Functional images were collected for 30 sec while the foot was in a dry basin at room temperature (baseline task). Cold water, at a temperature based on the subject's perception tested beforehand, was then poured into the basin up to the level of two overflow outlets so that the whole foot, including the ankle, was immersed, and a constant water filling was achieved (cold task). This cold phase lasted approximately 45 sec. Ice water at a temperature of 1-2°C was then added to lower the temperature until the subjects indicated unbearable pain (pain task). During the pain task, the subjects were instructed to indicate their feelings of pain with the left hand based on a four-step scale: one finger, first clear feeling of pain (mild pain); two fingers, moderate pain; three fingers, severe pain; and four fingers, unbearable pain (maximal pain tolerance level). When the subjects indicated their maximal pain tolerance level, the foot was immediately taken out of the basin and functional imaging was stopped. The cold task required approximately 3 min 5 sec to complete. A pulse oximeter on the tip of the right index finger measured heart rate throughout the procedure.
Imaging
fMR imaging was performed on a 1.5-T imager (Signa; General Electric
Medical Systems, Milwaukee, WI) equipped with resonant gradients (Advanced
NMR, Wilmington, MA). Subjects lay supine in the magnet with their heads
immobilized by a neck support, foam wedges, and a restraining band drawn
around the forehead. Scout images in the sagittal plane were acquired with
parameters of TR/TE, 600/13; field of view, 24 cm; imaging matrix, 256 x
192; and contiguous sections, 5 mm. Eight anatomic images were acquired in an
axial—oblique plane parallel to the anterior and posterior commissures,
with parameters of 500/13; field of view, 40 x 40 cm; imaging matrix,
256 x 192; and thick sections, 8 mm with a 1-mm gap. One hundred twenty
activation images were collected at each of the same eight locations using a
single-shot, echoplanar gradient-echo sequence with parameters of 2000/45;
flip angle, 45°; field of view, 40 x 20 cm; imaging matrix, 128
x 64; and thick sections, 8 mm with a 1-mm gap. Activation images were
acquired while the subjects performed the cold pressor task just
described.
Data Analysis
Before the statistical analysis, motion estimation and motion correction
were performed [25]. Of the 48
imaging runs (four runs in 12 patients), two runs (one run from two patients)
were discarded because of translation greater than 1 mm or rotation greater
than 1.5°. The images from the remaining 46 runs did not exceed the motion
criteria mentioned previously and were motion-corrected for three translation
directions and for three possible rotations. The motion-corrected images were
spatially filtered using a gaussian filter with a full-width at half-maximum
value of 6.5 mm. For each run in each subject, images of the baseline period
were compared with the images of the cold task, and images from the cold task
were compared with those from the pain task. Using t statistics
corrected for linear drift
[26], a t value for
each voxel was obtained from each run and then averaged across runs to provide
a t value for each voxel for the cold and pain tasks, respectively.
These t test comparisons created two activation maps for each
subject, one for the cold task compared with the baseline task and another for
the pain task compared with the cold task. The activation maps and the
anatomic images from individual subjects were transformed by inplane
transformation and slice interpolation into a normalized three-dimensional
grid defined by Talairach and Tournoux
[27].
The activation maps from individual subjects were used as a derived measure of a task-related activity and were combined to obtain a composite activation map. A randomization procedure was used to estimate p values. The sign of the activation measure (the t value) for each voxel was reversed in randomly generated subsets of subjects. The mean value of the activation measure was then recalculated. This procedure was repeated 1000 times, generating a distribution of the null hypothesis. The proportion of times that the observed activation measure (calculated without sign reversal) was more extreme than a randomized value represents a p value; it is the proportion of times we would expect to obtain a mean activation as great as or greater than the one obtained if the null hypothesis (no difference between tasks) were true. The p value for each voxel (p = 0.01, uncorrected) was overlaid on the mean anatomic image (a group composite of the T1-weighted images) for display. Two theoretic considerations support uncorrected t values. First, t values of spatially proximate voxels are highly correlated so that the actual number of independent comparisons is several times fewer than the number of voxels. This intercorrelation among nearby voxels results from physiologic coupling, the smoothing of data before the calculation of individual t maps using a gaussian filter with a full width at half-maximum of 6.5 mm, and the smoothing of data when combining data across subjects incidental to interindividual differences in structural and functional anatomy. Second, a cluster requirement was applied to the final composite activation maps that resulted from the randomization procedures so that a voxel was considered to show a significant difference between conditions only if it was in a cluster of voxels that met the same significance criterion. We used a cluster requirement that identified clusters of five significant voxels, rather than individual significant voxels, with a significance threshold of p = 0.01. To determine if a change in heart rate could account for activation changes, we compared the average pulse rate calculated from the entire period of the baseline task, cold task, and pain task.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Figures 1A,1B,1C,1D,1E and 2A,2B,2C,2D show regional brain activation during cold- (Fig. 1A,1B,1C,1D,1E) and pain-related tasks (Fig. 2A,2B,2C,2D). In each figure, the red—yellow areas represent brain regions that were more active (p < 0.01) during the cold task compared with the baseline task (Fig. 1A,1B,1C,1D,1E) or during the pain task compared with the cold task (Fig. 2A,2B,2C,2D). The blue—purple areas indicate brain regions that were more active (p < 0.01) during the baseline task than during the cold task (Fig. 1A,1B,1C,1D,1E), or during the cold task compared with the pain task (Fig. 2A,2B,2C,2D). The cold task resulted in anterior cingulate activation in one slice location (Fig. 1A). Cold-related activation was seen in bilateral postcentral gyri (Figs. 1B and 1C), including a site in the right subcentral gyrus that is in or slightly superior to the secondary sensory cortex (Fig. 1D). The postcentral gyrus activity was lateral and inferior to the typical location of the foot motor-sensory area. Additional areas activated include sites in the bilateral middle frontal gyri (Figs. 1B and 1C), the right inferior frontal gyrus (Fig. 1C), the left anterior insula (Fig. 1D), and the anterior aspect of the left thalamus (Fig. 1E). Greater activation in the baseline task than in the cold task was seen in the right middle frontal gyrus (Fig. 1A), the superior frontal gyrus bilaterally (Figs. 1A, 1B, and 1D), the anterior cingulate gyrus (Figs. 1D and 1E), the precuneus (Fig. 1A), the angular gyrus bilaterally (Figs. 1A and 1B), the middle temporal gyrus bilaterally (Fig. 1C), the left superior occipital gyrus (Fig. 1C), the left posterior cingulate gyrus (Fig. 1D), and the middle occipital gyrus bilaterally (Figs. 1D and 1E).
|
|
|
|
|
|
|
|
|
The pain task resulted in anterior cingulate gyrus activation that was seen on multiple slices (Figs. 2A,2B,2C). On the more superior slice (Fig. 2A), the anterior cingulate gyrus activation was posterior to the activation seen in the cingulate gyrus with the cold task. A greater area of frontal lobe activation was seen in the pain task compared with the cold task, including sites in the medial aspect of the superior frontal gyrus bilaterally (Figs. 2A and 2B) and more laterally in the right superior frontal gyrus adjacent to the superior frontal sulcus (Figs. 2B. and 2D). Of the five areas activated in the superior frontal gyrus, two were in the right hemisphere, one was in both hemispheres, and one was in the left hemisphere. At a lower threshold (p < 0.05, not shown), activation in the right superior frontal gyrus and sulcus regions was also seen at the same slice location as Figure 2C, suggesting further that the right frontal lobe is engaged by the affective dimension of pain more than the left frontal lobe. The pain task also activated a site in the right cuneus (Fig. 2B).
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The pain-related activation we report in the anterior cingulate has been noted in previous functional imaging studies of pain [7, 8, 12, 13, 15, 18, 22, 31]. The ascending pathways that transmit painful stimuli—the spinohypothalamic pathway, the spinopontoamygdaloid pathway, and the spinothalamic pathway—have components that converge to limbic structures, especially the anterior cingulate gyrus [32,33,34]. A positron emission tomographic study that used hypnosis to increase or decrease the ratings of unpleasant pain found more activation in the anterior cingulate gyrus during the strongly unpleasant condition compared with the less unpleasant condition [18]. Another positron emission tomographic study using noxious heat suggested that the anterior cingulate gyrus is important in the encoding of pain unpleasantness [19]. Our results are consistent with these recent functional imaging studies that emphasize the importance of the anterior cingulate gyrus in the affective dimension of pain.
Although the anterior cingulate appears to be active in pain-related tasks, imaging studies of cognition have also reported activation of the anterior cingulate gyrus, suggesting a possible role for this area in more general aspects of arousal and attention [35]. The impulse to withdraw from the noxious stimulus is also likely to be an essential feature of the experience of pain. In the laboratory setting, inhibition of that impulse is concomitant with the experience of pain. An fMR imaging study compared activation in patients with Tourette's syndrome when they inhibited their urge to tic with activation when they allowed themselves to tic freely [36]. Activation associated with the effort to inhibit movement was marked in the anterior cingulate gyrus. The function of the anterior cingulate gyrus in pain processing may include determining emotional valence and response priorities [4].
We found pain-related activation in the superior frontal gyri, slightly lateralized to the right side, and in the right cuneus, confirming that cortical systems other than the anterior cingulate gyrus are associated with the experience of pain. In an imaging study that used the cold pressor test to induce pain [37], right frontal activation was also noted, although that study was limited by use of low-resolution xenon inhalation and the absence of a nonpain sensory-stimulation comparison condition. Right superior frontal gyrus activation has been reported previously in studies that compared warm and painfully hot conditions [31], although these activations were more posterior than those noted in our study. In other positron emission tomographic studies, heat stimuli have been applied to the dorsal surface of the left hand [22] and to the dorsum of the right hand [7, 38]. The study using a left-hand stimulation task found stronger contralateral (right hemispheric), rather than ipsilateral, activation in the anterior cingulate cortex and dorsolateral prefrontal cortex, as well as bilateral activations in the thalamus and insula [22]. In both studies with right-hand stimulation, increases in regional cerebral blood flow in the contralateral cingulate cortex, thalamus, and lenticular nucleus were seen, but ipsilateral (right hemispheric) activations also occurred in the frontal pole, medial frontal area, inferior parietal cortex, and inferior frontal gyrus [7, 38]. Other studies have reported greater subjective and physiologic responses when stimuli are presented to the right rather than the left hemisphere [39] and greater activation of the right rather than the left hemisphere with emotion-related stimuli [40]. The right lateralized pain-related activation observed in our study is also consistent with previous electroencephalographic studies showing lateralized frontal activation in association with unpleasant or negative affective experiences [39, 40] and a predominance of right hemisphere activation independent of side of stimulation with painful carbon dioxide administration to the nasal mucosa [41]. The activation in the right cuneus is adjacent to the posterior parietal cortical areas which, in primates, have neural connections with somatosensory regions [42]. A previous imaging study of heat-induced pain in humans reported activation in a similar region [18]. This region's function may be to integrate somatosensory input with other sensory stimuli and with cognitive processes like attention, learning, and memory [4].
It has been proposed that the right hemisphere mediates withdrawal-related behaviors, whereas the left mediates approach behaviors [43]. That a right hemispheric dominance might also hold for painful experiences and associated emotional processing has been suggested by studies of patients with ongoing peripheral neuropathy and cluster headaches [17, 44]. In patients with peripheral neuropathy, brain activation in the right anterior cingulate gyrus was independent of the origin of the pain from the right or left leg. Patients with cluster headaches who had painful attacks provoked by nitroglycerin showed a preferential role of the right hemisphere (caudal anterior and rostrocaudal cingulate, temporopolar regions, and the supplementary motor area) in processing the affective—cognitive dimensions of clinical pain syndromes [17].
The brain regions active during the cold task, similar to the insula, thalamus, and the second somatosensory site, an area near the subcentral gyrus, have been active during pain tasks in other studies [7, 8, 10, 13, 31, 45]. Brain regions with increased signal intensity in the baseline task compared with the cold task could result from anticipation of the stimulus or other mental processes active during the baseline task. Three sites, the left superior frontal gyrus, the right cuneus, and the right superior frontal gyrus, had increased signal intensity in the baseline condition compared with the cold task and in the pain task compared with the cold task. These three areas might be involved in both the anticipation and the subjective experience of the painful stimulus. Negative activation also occurred in the pain task that was centered primarily over the choroid plexus of the ventricles. The cause of this ventricular activation is unclear because it is not seen in both tasks, but it might represent a paramagnetic effect in a structure that is extremely vascular.
Previous studies have reported painrelated activation in the thalamus [7, 10, 46] and variable activation in the somatosensory cortex [7, 8, 10, 18, 46]. We found left thalamic activation during the cold period, consistent with the role of this structure in processing sensory information. The absence of pain-related activation in either the left or right thalamus suggests that the area of the thalamus showing increased activation during the pain period may have also shown activation from baseline to cold, or the increased activation could result from the low level of new sensory stimulation during the pain period. We did not find activation in the primary somatosensory area of the foot during either the cold or pain conditions. This lack of activation might be due to modulation of the activation of the primary sensory area by cognitive factors such as attention and previous experience [47] or to habituation to the relatively constant somatosensory stimulation during both the cold and pain conditions.
In conclusion, our study used fMR imaging and the cold pressor test to identify brain regions that were active during the cognitive component of the pain experience. The anterior cingulate gyrus, the right frontal lobe, and the right cuneus are regions that play a role in the affective dimension of pain.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. V. Saarela, Y. Hlushchuk, A. C. d. C. Williams, M. Schurmann, E. Kalso, and R. Hari The Compassionate Brain: Humans Detect Intensity of Pain from Another's Face Cereb Cortex, January 1, 2007; 17(1): 230 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-s. Ray Li, C. Huang, R. T. Constable, and R. Sinha Imaging Response Inhibition in a Stop-Signal Task: Neural Correlates Independent of Signal Monitoring and Post-Response Processing J. Neurosci., January 4, 2006; 26(1): 186 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Matharu, T. Bartsch, N. Ward, R. S. J. Frackowiak, R. Weiner, and P. J. Goadsby Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study Brain, January 1, 2004; 127(1): 220 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. A. Strigo, G. H. Duncan, M. Boivin, and M. C. Bushnell Differentiation of Visceral and Cutaneous Pain in the Human Brain J Neurophysiol, June 1, 2003; 89(6): 3294 - 3303. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
