Institute of Human Physiology and , 1 Department of Neuroradiology, University of Ancona, Ancona and , 2 Epilepsy Centre, Ancona Regional Hospital; I-60020 Ancona, Italy
Mara Fabri, Institute of Human Physiol-ogy, University of Ancona, Via Tronto 10/A, 60020 AnconaTorrette, Italy. Email: m.fabri{at}popcsi.unian.it.
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Abstract |
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Introduction |
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In the present work the pattern of cortical activation evoked by mechanical painful stimulation of one hand was investigated with fMRI in a group of normal volunteers and on three patients with complete surgical resection of the corpus callosum per-formed to solve medically intractable epilepsy, to establish: (i) whether activation of PO cortex by unilateral noxious stimuli was present in both hemispheres and (ii) whether ipsilateral pain-related activation of PO might be mediated by the corpus callosum. These data were compared with the activation patterns evoked by tactile stimulation.
These results have been presented in abstract form (Fabri et al., 1999b).
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Materials and Methods |
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Subjects were placed in a 1.0 T scanner (Signa Horizon, General Electric Medical System, Milwaukee, WI) equipped with 23 mT/m gradients with their head restrained within a standard polarized head coil. They were instructed to keep their eyes closed, find a comfortable position and relax, avoiding even minimal movement; their ears were plugged. Func-tional MR images were acquired in axial or coronal planes with a single-shot T2*-weighted gradient-echo EPI sequence (TR 3000 ms, TE 60 ms, flip angle 90°, field of view 28 x 21 cm, matrix 96 x 64, 1 Nex, scan time 2.5 min). Coronal planes were orthogonal to the sagittal plane and parallel to the floor of the IVth ventricle. Axial planes were orthogonal to both the sagittal and the coronal planes. Ten contiguous 7 mm-thick axial (Fig. 2A) or coronal (Fig. 2B
) sections were selected from a brain region containing the postcentral gyrus (PCG) and PO (see Fig. 2
); from each selected section, 50 axial or coronal functional images were acquired during a 2.5 min stimulation cycle (one image/3 s). Overall, 500 axial or coronal functional images were thus obtained. Then high-resolution anatomical images [spoiled gradient-recalled (SPGR), 2D, TR 100 ms, TE 12 ms, flip angle 70°, field of view 28 x 21 cm, thickness 7 mm, matrix 256 x 256, 1 Nex, scan time 3 min 17 s for 10 images] were acquired in the same axial or coronal planes so that the functional images could be super-imposed on the anatomical images; the latter also allows visualization of blood vessels, which are possible sources of BOLD signals. In most subjects, four scanning sequences were acquired (tactile and painful stimulation of both hands, in the axial or the coronal plane; Table 1
).
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Tactile stimulation consisted of brushing the subject's palm and fingers in proximo-distal direction with a rough sponge at a frequency of ~1 Hz. In all patients and in three of the six controls, stimulation was applied first to the right and then to the left hand during different scans; in the remaining three controls stimulation was applied only to the right hand (see Table 1). The stimulation session lasted 2.5 min and consisted of two 30 s stimulation periods preceded, divided and followed by a 30 s rest periods.
Painful stimulation was obtained by displacing the palm skin with a sharp wooden probe (tip diameter 0.40.5 mm), at 1 s intervals, to evoke pinprick pain. This kind of stimulation has been shown to be effective in activating both high-threshold mechanoreceptors with myelinated fibres (A) and polymodal nociceptors with unmyelinated fibres (C) (Burgess and Perl, 1967
; Perl, 1968
; Bessou and Perl, 1969
; Kumazawa and Perl, 1977
; Torebjörk, 1974
; Perl, 1984
). In two of the three patients and in four of the six controls, stimulation was applied first to the right and then to the left hand during different scans; in the remaining patient and the two controls only the right hand was stimulated (see Table 1
). This paradigm consisted of two 30 s stimulation periods preceded, divided and followed by a 30 s rest periods.
At the end of the stimulation session, all subjects were asked to describe their own perception of the painful stimulus by choosing among one of these definitions: not painful; not painful but annoying; painful but tolerable; and intolerably painful. All subjects reported that the stimulus was painful but tolerable. Since the perceptual threshold of pain and sharpness has been shown to be much higher than that of both A and C nociceptors (Adriaensen et al., 1983
; Greenspan and McGillis, 1991
), normal pain perception requires considerably more than threshold activation of nociceptors; the patients' mention of a painful sensation is thus likely to indicate suprathreshold activation of nociceptors.
As control for the stimulus-related changes of signal intensity (Yetkin et al., 1996), the experimenter made the same movement 1015 cm above the subject's hand also during the rest periods of both paradigms; in this way, any differences between the rest and the stimulation signal could be ascribed only to the administration of the stimulus.
Data Analysis
At the end of the experimental session, the images acquired were transferred to a Unix workstation (General Electric Advantage Windows 1.2) and analysed by means of custom-designed General Electric software (Functool). The software calculates a correlation coefficient that relates the time-course data to a reference function, which is a periodic square wave (Xiong et al., 1996). The first two images from each section levels (corresponding to 6 s) were not included in the analysis with a view to eliminating the transient scanner behaviour and performing the calculation on a steady state. The correlation coefficient is related to the t-parameter of Student's t-test by a precise relationship and thresholded by a confidence level selected by the operator; its value was usually 0.00001 or 0.0001, entailing a probability of 0.001 or 0.01% that the signal increase is unrelated to the reference function. For each section level, a parametric map was obtained by superimposing the 50 functional images acquired during the stimulation cycle and the anatomical image from the same section level. With the aid of a colour scale, the map displayed the degree of correlation of each pixel value with the square wave (red pixels indicate strong correlation, blue pixels poor correlation). For each activated zone, defined as a group of at least two adjacent red pixels, a region of interest (ROI) was selected and for each ROI the software displayed the signal variation that occurred during the stimulation cycle. The area of the ROI was kept as uniform as possible among subjects and cortical areas. The signal change was then displayed as a graph where the X-axis is a temporal scale reporting the progressive number of the functional images acquired (one image/3 s) and the Y-axis represents the signal change expressed as a percentage of the signal obtained from the brain during the acquisition of the first image (baseline or 0%) of the first rest period (see Fig. 3E,F
). When the signal increase, observed in ROIs selected from activated areas within regions anatomically corresponding to SI, posterior parietal (PP) cortex (in the PCG), SII (in PO, in the upper bank of the sylvian sulcus, SS), insula and Cin, was temporally correlated with the stimulus pattern, the activation in these areas was attributed to tactile or painful stimulation of the hand. Signal increases not showing temporal correlation with the stimulus pattern were considered false positives. The signal increase ranged from 2 to 5% above the baseline, depending on the cortical area studied.
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Further details on image acquisition, tactile stimulation paradigm and data analysis have been published elsewhere (Fabri et al., 1999a; Polonara et al., 1999
).
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Results |
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In line with previous reports (Fabri et al., 1999a; Polonara et al., 1999
), cortical activation to tactile stimulation of one hand was consistently observed in SI in the anterior parietal (AP) cortex of the contralateral hemisphere and in PO (Fig. 3A
) and the PP cortices of both hemispheres (Table 2
). The mean Talairach stereotaxic coordinates of touch-related activation foci in contralateral and ipsilateral PO (Table 3
) corresponded to the accepted localization of area SII in man (Burton et al., 1997
; Frot and Mauguière, 1999b
; Disbrow et al, 2000
). Activation foci were also detected in other cortical regions of the contralateral hemisphere: Cin in three cases, the precentral gyrus and In in two cases (Table 2
).
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Callosotomized Patients
The three patients (DDC, DDV, RN) had undergone the complete resection of the corpus callosum (Fig. 1) and were studied 36123 months from callosotomy.
As in control subjects, the contralateral pattern of cortical activation to unilateral tactile stimulation of the hand included activation foci in SI, PO (Fig. 3C) and PP (Table 4
) as well as in Cin (one case; Table 4
) and the precentral gyrus. At variance with normal subjects, no cortical activation was evoked by tactile stimulation of one hand in the ipsilateral hemisphere (Table 4
; Fig. 3C
). Similar results were obtained from all patients. Figure 3C and E
show data from patient DDV. Tactile stimulation of the right hand activated a region in the contralateral PO (Fig. 3C
) in which the signal increased by ~2% above the baseline during the stimulation periods (Fig. 3E
). The mean Talairach stereotaxic coordinates of touch-related activation foci in contra-lateral PO were x = 50, y = 27 and z = 19 (Table 5
). No activated zones were observed in the ipsilateral PO. These results are in agreement with previous descriptions (Fabri et al., 1999a
, Fabri et al2001
).
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The analysis of these data indicates that painful stimulation of either hand activated similar regions of PO in both hemispheres and generally evoked activation foci in PO regions more anterior and/or more medial than those activated by tactile stimulation (compare, for example, touch-evoked focus 1 in Fig. 3A and pain-evoked focus 1 in Fig. 3B
). In addition, painful stimulation often evoked multiple activation foci in PO in each hemisphere; in these cases, at least one of them overlapped with that evoked by tactile stimulation (Fig. 3
) (Davis et al., 1998
).
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Discussion |
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The noxious stimulus used in this study consisted of pricking the palm with a sharp wooden probe, a type of mechanical stimulation that has been shown to activate both A and C nociceptors (Burgess and Perl, 1967
; Perl, 1968
; Bessou and Perl, 1969
; Torebjörk, 1974
; Kumazawa and Perl, 1977
; Perl, 1984
). The painful sensation, slight but distinctly felt by all subjects, indicates that both A
and C nociceptors were activated by this kind of stimulus (Adriaensen et al., 1983
; Greenspan and McGillis, 1991
).
In two previous papers we reported that patients with com-plete or partial callosotomy involving the fibres running in the posterior third of the body of the callosal commissure failed to exhibit activation of ipsilateral PO after tactile stimulation of one hand (Fabri et al., 1999a, Fabri et al2001
). In the present study, two of those same subjects and a third patient also subjected to complete callosal resection, showed activation of ipsilateral PO after unilateral painful stimulation, suggesting that this activa-tion was selectively evoked by the noxious stimulus.
A psychophysical study of a totally callosotomized patient (Stein et al., 1989) has shown that each hemisphere may be aware of the ipsilateral noxious stimulus, provided it is very intense, suggesting that at least some aspects of pain percep-tion from the ipsilateral body surface do not require the interhemispheric transfer of information. The possibility of the extracallosal activation of ipsilateral PO has been suggested by several investigators: for instance, the simultaneous activation of ipsilateral and contralateral PO recorded in latency studies in normal subjects (Kagiki et al., 1995
; Kitamura et al., 1995
, 1997
; Ploner et al., 1999
; Kanda et al., 2000
) has been explained with uncrossed subcortical pathways. However, successive activation of contralateral PO and ipsilateral PO with a delay compatible with callosal transmission time has also been observed (Frot et al., 1999
).
By showing that unilateral painful stimulation of the hand evokes bilateral activation of PO in totally callosotomized patients, the present study: (i) confirms previous results that PO is bilaterally involved in pain processing and (ii) demonstrates that activation of ipsilateral PO is at least partially independent of callosal transmission, being probably mediated by extracallosal pathways: uncrossed subcortical pathways (Frot and Mauguière, 1999a), subcortical commissures, or both.
In conclusion, two somatosensory modalities, touch and nociception, appear to activate PO bilaterally in different ways: both tactile and pain afferents reach the contralateral PO via the lateral lemniscal system, and the ipsilateral PO through the contralateral hemisphere and corpus callosum (Fabri et al., 1999a); painful afferences also gain access to the ipsilateral PO via extracallosal pathways. Consequently, bilateral activation of PO may occur simultaneously. This finding supports the hypothesis of a major role for PO in pain processing (Treede et al., 2000
). It thus seems likely that the pain system has a simpler organization than the tactile system (Ploner et al., 1999
, 2000
). This may mean that pain perception requires reaction to, and avoidance of, harmful stimuli rather than sophisticated sensory capacities.
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Notes |
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References |
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