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Twelve right-handed volunteers were studied (seven males, five females; mean ± SD, 26 ± 3 years). All subjects gave informed consent, and the study was approved both by the Oxfordshire Committee for Research Ethics and the University of Western Ontario Ethics Review Board. Data were acquired on a Varian/Siemens 4T whole-body scanner with a bird-cage head coil. Head movements were restrained with foam pads. Contiguous slices were prescribed parallel to the AC-PC line and covered the entire brain volume. BOLD contrast multishot echo-planar images were obtained with the following acquisition parameters: TR = 2.5 s, TE = 15 ms, 8-mm slice thickness, field of view = 22 cm by 22 cm, 64 by 64 by 15 matrix. Structural images were obtained with a standard T1-weighted pulse sequence.
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Noxious and warm thermal stimuli were applied to the dorsum of the left hand with a 3 cm by 3 cm Peltier thermode, designed and built in-house. In the scanner, an adaptive procedure was used to identify two stimuli consistently described by the subject as "painfully hot" and "dearly warm, but not painful." Three color light-emitting diodes (LEDs; red, green, blue) were mounted at the subjects' feet and could be viewed through a mirror in the magnet bore. During the experiment, subjects received five noxious and five innocuous stimulations in pseudo-random (PR) order. Each type of stimulation was consistently signaled by a certain color LED for each subject (randomized across subjects), which preceded the onset of thermal stimulation by a PR interval (mean ± SD, 7.5 ± 5 s) and remained on during the 11 s of thermal stimulation. Between conditioning trials subjects had a rest period of PR duration (mean ± SD, 26.5 ± 9 s) signaled by the third LED. Subjects were instructed to determine the contingency between LED color and thermal stimulation. After the experiment, subjects rated the two thermal stimuli on two 11-point visual analog scales of pain intensity and unpleasantness.
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Image processing and statistical analysis were carried out with MEDx 3.0 (Sensor Systems). All volumes were realigned, smoothed with a 3.5 mm by 3.5 mm by 5 mm (full width at half maximum) Gaussian kernel, and the average of every volume was normalized to the same mean value. Voxel-by-voxel linear detrending and wavelet temporal filtering were applied. Activation maps were calculated by Student's parametric unpaired t test, spatially normalized to Talairach space, and cluster detection was performed on all voxels above z = 2 to determine clusters significantly activated in the experimental task conditions (P < 0.01). Group-combined activation maps show cluster volumes common to at least three subjects (Figs. 1 to 3A). In contrast, cluster centers of mass for individual subjects (Figs. 1 to 3B) and group coordinates were derived from data for all individual subjects showing significant activation. Group-averaged time courses (Figs. 1 to 3. C and D) show mean ± SEM of fMRI percent signal change over the period of the scan for the highest z-score voxel within each cluster. Regional shifts in activation were examined for significance by t tests (P < 0.05), and time courses were tested for significant linear or quadratic trends by polynomial contrasts analysis of variance (P < 0.05).
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Observed activations included thalamus, basal ganglia, and primary and secondary somatosemory cortices (23).
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0345349000
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Activations for the light preceding pain relative to pain itself [subjects activated (cluster total): medial frontat lobe. 6 (8); insula, 3 (3); cerebellum, 6 (8)] were significantly anterior to activations for pain relative to the light preceding pain [subjects activated (cluster total): medial frontal lobe. 7 (9); insula, 8 (8); cerebellum 6 (11)] in the medial frontal lobe (P = 0.002) and the insula (P = 0.045), and significantly lateral in the cerebellum (P = 0.003). Talairach coordinates for the light preceding pain relative to pain were as follows [x (mm), y (mm), 2 (mm)]: medial frontal lobe [-7, 47, 16], insula [38, 19, 4], cerebellum [-3, -60, -19]; and for pain relative to the light preceding pain: medial frontal lobe [2. 6, 34], insula [39, 4, 9], cerebellum [-6, -56, -26].
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No regional shifts in activation between warm stimulation relative to baseline [subjects activated (cluster total): medial frontal lobe, 3 (4); insula, 1 (1); cerebellum 4 (4)] and expectation of warm stimulation relative to baseline [subjects activated (cluster total): medial frontal lobe, 4 (5); insula, 2 (2); cerebellum, 4 (5)] were observed in the medial frontal lobe (P = 0.51), the insula (P = 0.70), or the cerebellum (P = 0.83). Brain activation in these regions during the light preceding warm stimulation relative to baseline appears to be related to an expectation of pain during initial trials of this type, that is, before the contingency between lights and thermal stimuli is learnt This was confirmed by interview after the experiment and is paralleled by higher fMRI signal intensity on early relative to late presentations of the light preceding warm stimulation (Figs. 1 to 3C).
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22
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0003369049
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Macmillan, London
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This dissociation contrasts with William James's theory that anticipation depends on activity in the same networks that process the actual experience [W. James, Text-Book of Psychology (Macmillan, London, 1892)].
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The Talairach y coordinate lies anterior to the mean, but within the distribution, of coordinates of anterior cingulate cortex activation reported in PET studies on pain [J.-C. Hsieh, M. Belfrage, S. Stone-Elander, P. Hansson, M. Ingvar, Pain 63, 225 (1995)].
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We thank D. Dobson for help with building the Peltier device, S. Smith for advice on image analysis, and E. Rzepniewski and R. Passingham for comments on the manuscript. A.P. holds a Rhodes Scholarship. I.T., S.C., and P.M.M. are funded by the Medical Research Council (UK). This work also was supported by the McDonnell-Pew Programme in Cognitive Neuroscience.
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