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The Journal of Neurophysiology Vol. 80 No. 3 September 1998, pp. 1533-1546
Copyright ©1998 by the American Physiological Society
1 Department of Surgery (Division of Neurosurgery) and 2 Department of Medical Imaging, University of Toronto; and 3 Playfair Neuroscience Unit, The Toronto Hospital Research Institute, Toronto, Ontario M5T 2S8, Canada
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Davis, Karen D., Chun L. Kwan, Adrian P. Crawley, and David J. Mikulis. Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli. J. Neurophysiol. 80: 1533-1546, 1998. Positron emission tomography studies have provided evidence for the involvement of the thalamus and cortex in pain and temperature perception. However, the involvement of these structures in pain and temperature perception of individual subjects has not been studied in detail with high spatial resolution imaging. As a first step toward this goal, we have used functional magnetic resonance imaging (fMRI) to locate discrete regions of the thalamus, insula, and second somatosensory cortex (S2) modulated during innocuous and noxious thermal stimulation. Results were compared with those obtained during tactile stimulation of the palm. High resolution functional images were acquired on a 1.5 T echospeed GE MR system with an in-plane resolution of 1.7 mm. A modified peltier-type thermal stimulator was used to deliver innocuous cool and warm and noxious cold and hot stimuli for 40-60 s to the thenar eminence of normal male and female volunteers. Experimental paradigms consisted of four repetitions of interleaved control and task stimuli. A pixel by pixel statistical analysis of images obtained during each task versus control (e.g., noxious heat vs. warm, warm vs. neutral temperature, etc.) was used to determine task-related activations. Painful thermal stimuli activated discrete regions within the lateral and medial thalamus, and insula, predominantly in the anterior insula in most subjects, and the contralateral S2 in 50% of subjects. The innocuous thermal stimuli did not activate the S2 in any of the subjects but activated the thalamus and posterior insula in 50% of subjects. By comparison, innocuous tactile stimulation consistently activated S2 bilaterally and the contralateral lateral thalamus. These data also demonstrate that noxious thermal and innocuous tactile-related activations overlap in S2. The data also suggest that innocuous and noxious-related activations may overlap within the thalamus but may be located in different regions of the insula. Therefore, we provide support for a role of the anterior insula, S2, and thalamus in the perception of pain; whereas the posterior insula appears to be involved in tactile and innocuous temperature perception. These data demonstrate the feasibility of using fMRI for studies of pain, temperature, and mechanical stimuli in individual subjects, even in small regions such as thalamic nuclei. However, the intersubject variability should be considered in future single subject imaging studies and studies that rely on averaged group responses.
The thalamic and cortical contribution to pain and temperature perception in humans is not clearly understood despite a large number of animal studies (Willis and Westlund 1997 Subjects
A total of 12 healthy subjects (9 male, 3 female) ranging in age from 21 to 38 yr recruited from the University of Toronto and Toronto Hospital community participated in the study. All but two subjects were right handed. All subjects gave informed consent to procedures approved by the University of Toronto Human subjects review committee. Before entry into the study, each subject was given test stimuli with the thermal stimulator to ensure that the stimuli delivered a tolerable level of pain. The subjects were instructed in the basic design of the experiment and were fully aware of the duration and intensity of pain that they would need to endure. Subjects were free to withdraw from the study at any time.
Imaging sequences
A 1.5 T MRI system (Echospeed GE Medical Systems, Milwaukee, WI) was used to obtain all images. Subjects were placed supine on the MRI table and made comfortable in this position to reduce head movement. A standard quadrature head coil was used and was packed with pillows and foam padding. The lights were dimmed, and a support was placed under their knees if desired. Further instructions given to the subjects were to relax and keep their eyes closed during scanning. To study activation in the thalamus, insula and S2, a total of six 4 mm contiguous axial slices parallel to the AC-PC line were selected. The most inferior slice was set as close to the AC-PC line as possible but varied from ~1 mm above to 2 mm below the AC-PC line. Functional images were obtained with a gradient echo sequence using a spiral trajectory through " k" space (Glover and Lee 1995 Thermal stimulator
A computer-controlled peltier-type thermal stimulator (TSA 2001, Medoc Advanced Medical Systems) was used to deliver thermal stimuli to the thenar eminence of each subject's right hand. Interference between the thermal stimulator and the MRI was avoided by taking several precautions: All metal screws in the probe head were replaced with nonferromagnetic screws. The stimulator's main operating unit and computer were placed outside the imaging room in the console room. The stimulator cable and head were fed into the MRI room from the console room through a shielded wall opening. A heavy gauge metal sleeve was placed around the stimulator cable and grounded to provide additional shielding.
Experimental protocol
Each subject underwent a "cool-cold pain" experiment followed by a "warm-heat pain" and then a tactile experimental session (see Fig. 1). After each pain experiment, a verbal rating of pain intensity was obtained from the subject. The subject was asked to rate the overall intensity of pain on a scale from 0 (no pain) to 10 (most intense pain imaginable) for the entire sequence.
Tasks
COOL-COLD PAIN TASK.
The experiment began with the thermode held at a neutral temperature (32°C) for 40 s. A staircase protocol then was used to progressively cool the skin. The thermode temperature was lowered in 4°C steps at 2°C/s to 28, 24, and 20°C. Each new cool plateau was maintained for 10 s. In pilot studies, it was observed that a staircased cooling stimulus (rather than a ramp-and-hold) provided a detectable perception of cool. Following the innocuous cooling stimuli, the thermode was lowered at 2°C/s to ~2°C and was maintained at this painfully cold temperature for 40 s before returning to baseline at 9°C/s. This paradigm was repeated for a total of four presentations each of the cool and cold pain stimuli (see Fig. 1A).
WARM-HEAT PAIN TASK.
A period of 5-10 min lapsed between the end of the cool-cold pain experiment and the start of the warm-heat pain experiment during which time the skin could acclimatize to a neutral temperature. The warm-heat pain task began with the thermode held at a neutral temperature of 35°C for 40 s (the slight difference in neutral temperatures in the two thermal tasks facilitated rapid cooling/warming). All warming steps were at 1°C/s and maintained for 10 s. The first warm step raised the thermode temperature to 40°C and subsequent 1°C warming steps were delivered in a staircase fashion to 41, 42, and 43°C. Immediately after the warm ramp stimuli, noxious heat stimuli were applied in a sinusoidal-like manner: the thermode temperature was raised at 2°C/s to 47.5°C for 5 s. The temperature then was lowered to a nonnoxious temperature of 43°C for 1 s and rapidly raised back to 47.5°C. A total of seven cycles of this sinusoidal-like pattern of noxious heating stimuli interrupted with a brief nonnoxious pulse was delivered to the skin to evoke a painful percept while avoiding skin damage (see Fig. 1B). A total of four repetitions of the warm-heat pain sequence was presented to each subject.
TACTILE TASK.
A blunt wooden probe was used to deliver tactile stimuli. The stimuli were applied to the palm and digits in a stroking motion at ~2 strokes/s from proximal to distal. The stimulus was applied for 60 s and was alternated with 60-s stimulus-free periods for a total of four repetitions (see Fig. 1C).
Analysis
A pixel by pixel statistical analysis of images obtained during each task versus control was used to determine task-related activations with Analysis of Functional Neuroimages (AFNI) software (R. Cox, Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, WI). The warm and cool stimuli served as the control for the heat pain and cold pain tasks, respectively. The neutral thermal stimuli served as the control for the warm and cool tasks. The control for the tactile task was the rest (i.e., no stimulus) period. AFNI was used to locate all pixels that showed an overall change in signal intensity during the tasks compared with control at r
General findings
Task-related activations could be identified in all subjects that entered the study. In general, activations were small in size, typically 2-3 pixels. The thalamic activations tended to be somewhat smaller in size than the activations in the insula and S2. The mean percent signal intensity change during each task ranged from 3.4 to 4.4%. The mean r value for all ROIs was 0.24 ± 0.003 (mean ± SE). The tactile task evoked the most consistent findings among subjects. A substantial intersubject variability was found for the innocuous and noxious thermal tasks. This variability is appreciated best by noting various task-related activations for each subject (see Table 1) and the incidence of activations for the subject sample studied (see Table 2). There was no obvious difference between the findings in the male and female subjects, but a small female sample (n = 3) precluded detailed gender analyses. An analysis of the population findings in each task is given in the following text.
Tactile-related activations
An example of tactile-related activations in one subject is shown in Fig. 3. Application of the tactile stimulus activated the thalamus, insula, and S2 in this subject (subject 3 in Table 1). The thalamic activation shown in Fig. 3B is clearly in the lateral part of the nucleus in a region consistent with the location of the ventroposterolateral nucleus (VPL). This ROI consisted of two pixels. The somewhat larger, bilateral S2 activations in this subject are shown in Fig. 3C. The multiple ROIs in the contralateral S2 in this subject were a typical result, and indeed only three subjects had only one ROI within the contralateral S2. Conversely, the ipsilateral S2 typically contained only one ROI.
Innocuous thermal-related activations
Innocuous thermal-related activations were found for only half the subjects and were scattered throughout the thalamus. There were significantly more innocuous thermal-related activations in the contralateral thalamus compared with the ipsilateral thalamus (P < 0.05). These activations were, however, more prevalent around the anterior, medial, lateral, and posterior edges of the thalamus. An example of a rather anterior cool-related thalamic activation is shown in Fig. 3D. The cool stimuli also activated the insula in only half of the subjects, although not necessarily the same subjects that showed thalamic activation (see Table 1). Most of the cool-related activations were found in the posterior insula (P < 0.05), ipsilaterally or contralaterally. Warm-related insular activations were found in only one-third of the subjects. An example of one of these warm-related activations in the anterior insula is shown in Fig. 3G. The S2 was not activated in any subject during either the warm or cool task. The basal ganglia were only activated in three subjects during the cool task and one subject during the warm task. All warm and cool-related activations are shown in Fig. 5. It should be noted that two subjects did not show any activation in the regions inspected (i.e., thalamus, insula and S2, basal ganglia) during the warm or cool task. However, the tactile and noxious tasks (during the same experimental session as the innocuous thermal tasks) did evoke responses in these subjects.
Noxious thermal-related activations
The pain evoked by the noxious cold and noxious heat stimuli was similar in intensity but differed in quality (see previous sections). However, the incidence and location of activations within S2 and the insula were similar during noxious heat and noxious cold (P > 0.05) (see Tables 1 and 2 and Fig. 6). The lack of activation observed in any of the brain regions inspected did not depend on the intensity of pain evoked as evidenced by the individual subject responses (see Table 1) and the overall population of subjects with (i.e., responders) or without (i.e., nonresponders) pain-related activations (see Table 3). The contralateral S2 was activated by both the noxious cold and noxious heat tasks in approximately one-half of the subjects. Examples of pain-related S2 activations are shown in Fig. 3, F and I. There was no apparent segregation of heat and cold pain activation sites within S2. Both noxious thermal tasks activated the insula in >50% of subjects. These insula activations were found either ipsilaterally or contralaterally in similar proportions (P > 0.05). However, there was a preponderance of anterior insula activations (versus posterior insula activations) regardless of laterality (P < 0.05; see Fig. 3, E and H). There was also a trend toward more middle-ventral activations than dorsal activations. Task-related responses in the thalamus were identified in >50% of subjects during application of either the painful cold or hot stimuli. Contralateral thalamic activation was identified in nearly all of these subjects. However, ipsilateral thalamic activations also were identified in many subjects, especially during the cold pain task (see Table 2). There were significantly more pain-related activations in the contralateral versus ipsilateral thalamus (P < 0.05). The majority of the ipsilateral and contralateral activations were found within the lateral and/or posterior thalamus. However, a few medial thalamic activations also were identified. Task-related activations also were identified within the contralateral anterior thalamus, especially during the cold pain task. The basal ganglia were activated in four subjects during the noxious cold task and in seven subjects during the noxious heat task. These activations were on the ipsilateral and contralateral side (P > 0.05).
Comparison of activations across modalities
A composite figure of all activations during the tactile, innocuous and noxious thermal tasks is shown in Fig. 7. This composite allows for comparison of activations across all tasks based on stimulus intensity (i.e., innocuous vs. noxious) and modality (cooling vs. heating, thermal vs. tactile). The color-coding of modalities clearly identifies the clustering of posterior insula activations with innocuous stimuli (P < 0.05), in contrast to the clustering of anterior insula activations during noxious stimuli (P < 0.05). The medial thalamic activations can be seen to be composed of both innocuous and noxious thermal stimuli. There were also clusters of activations from all task modalities in the lateral thalamus, possibly the VPL. There also appears to be an overlap of tactile- and noxious thermal-activations in the contralateral S2.
This study has used fMRI to investigate the incidence and location of activations within the thalamus, S2, and insula during application of innocuous (tactile, cool, warm) and noxious (cold, heat) stimuli to the glabrous skin of normal subjects. These data add to the sparse number of studies of the thalamic and cortical involvement in pain and temperature processing in humans. The data also demonstrate the feasibility of fMRI in studies of pain and temperature perception. Furthermore, the data illustrate the intersubject variability and technical limitations that need to be taken into consideration in future imaging studies of pain and temperature perception in normal subjects and patients with sensory abnormalities.
Technical considerations
The strategy used in most fMRI studies to optimize signal-to-noise and acquire data from large regions of the brain, is to image relatively thick brain slices (6-8 mm) with large voxels in as short an imaging time as possible. This low spatial resolution may be inadequate to reveal small pain-related activations predicted by the small numbers of nociceptive and thermoreceptive thalamic and cortical neurons localized in human studies (Davis et al. 1997a Tactile-related activations
Responses to innocuous tactile stimulation of the hand produced a relatively consistent pattern of activation across subjects that typically included the contralateral lateral thalamus, posterior insula, and bilateral S2. The small but robust thalamic responses to sensory stimuli are consistent with the location of VPL and the small tactile hand region of human ventrocaudal thalamus [typically a few millimeters (Davis et al. 1996 Innocuous temperature-related activations
The innocuous thermal stimuli resulted in a relatively low incidence of activations in thalamus and cortex and a high intersubject variability in the location of these activations. Warm- and cool-related activations were scattered throughout the lateral and medial thalamus in only 50% of the subjects. These data were not surprising because warm- and cool-responsive central neurons have been difficult to locate in any particular thalamic region in the monkey (Burton et al. 1970 Patterns of pain-related activations
Most interesting were the data that revealed that the same thermal stimulus applied to the skin of different subjects can evoke varying patterns of thalamic and cortical activations. Although pain-related activations were located in >50% of our subjects, various combinations of cortical and thalamic activations were observed in individual subjects (e.g., insula only, S2 only, both insula and S2, etc.), and these patterns were typically different for the cold pain and heat pain tasks. The likelihood of finding a pain-related thalamic activation did not depend on the intensity of pain reported by the subject (see Table 3). The location of the heat pain and cold pain sites are consistent with the lateral and medial nuclei. Casey et al. (1996) Contributions to pain-related activations
Because a contact thermal stimulation device was used to deliver noxious thermal stimuli, potential contributions from nonnociceptive afferents must be considered. Low-threshold mechanoreceptors, in particular the slowly adapting receptors, would be excited by the maintained contact of the thermal probe with the skin. In this study, pain-related activation was determined by comparison of signal intensities during the pain and control tasks. Because contact with the skin was maintained throughout the control and pain task, it is unlikely that the large diameter afferents contribute to pain-related activations. Furthermore, the location of pain-related activations often did not coincide with tactile-related activations, especially in the insula and ipsilateral S2. Because a noxious thermal stimulus results in a complex sensation that has contributions from both the pain and thermoreception system and also because of possible coactivation of both thermoreceptors and nociceptors, each subject was tested with innocuous cool and warm stimuli in addition to the noxious cold and heat stimuli. However, the spatial segregation between innocuous thermal- and pain-related activations (e.g., insula, S2) argue against a major contribution from innocuous thermoreceptors to the pain responses. Furthermore, the signal intensities obtained during the innocuous thermal tasks served as the control for the determination of pain-related activations (i.e., were subtracted from the signal intensities during the pain task). One further consideration is the motor system that may be recruited during a painful stimulus if the subject has the urge to remove their hand from the stimulus. Although there was no overt movement associated with these stimuli, the basal ganglia activations in some subjects suggest they may have been preparing for a motor consequence to the stimulus or tensing their muscles (see Table 2). This is unlikely to be of major significance because there was no relation between the intensity of pain reported and the presence of basal ganglia activation (see Table 1) and because many subjects showed pain-related activations in the thalamus, S2, and insula in the absence of basal ganglia activation. Alternatively because the basal ganglia is connected with nociceptive systems (for review, see Chudler and Dong 1995 "Missing" activations and intersubject variability
Many subjects had cool- or warm-related activations in the thalamus or insula but not in both areas. This suggests that the innocuous thermal stimuli must have been robust enough to evoke a central response. Therefore the lack of insula or thalamic activations in these subjects may be due to a technical difficulty in observing the signal because of the spatial, temporal, or magnitude of response as reflected in an MRI signal.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
). Electrophysiological, anatomic, and lesion studies in the nonhuman primate suggest that the multidimensional nature of the human pain experience may involve several key structures, including the medial and lateral thalamus (Apkarian and Shi 1994; Bushnell and Duncan 1989; Casey and Morrow 1983; Chung et al. 1986; Craig 1987; Dougherty et al. 1997; Kenshalo et al. 1980), the insular cortex (Augustine 1996; Dostrovsky and Craig 1996), and the second somatosensory (S2) cortex (Berkley and Parmer 1974; Chudler et al. 1986; Dong et al. 1989, 1996; Robinson and Burton 1980; Stevens et al. 1993; Whitsel et al. 1969). The primate insula also has been shown to play a role in thermoreception and many other homeostatic functions (for reviews, see Augustine 1985, 1996).
, 1996; Coghill et al. 1994; Jones et al. 1991; Svensson et al. 1997; Talbot et al. 1991; Xu et al. 1997), consistent with animal findings. Although Craig et al. (1996) found that warm and cool stimuli can activate the insula and S2, another PET study found that innocuous thermal stimuli can activate the thalamus and insula but not S2 (Casey et al. 1996). Data obtained in the aforementioned PET studies have required data to be combined across a pool of subjects. Some of the discrepancies among studies concerning the exact location of these activations, especially in small structures such as the thalamus, are likely due to this averaging of group data and the spatial resolution of PET. Furthermore, little is known of the activations related to contact cold stimuli with the exception of a study by Craig et al. (1996). More recently, we have employed the technique of functional magnetic resonance imaging (fMRI) to study individual subject responses to a given painful stimulus (Davis et al. 1995b, 1997b). Indeed, our recent study of anterior cingulate (ACC) activation during painful median nerve stimulation (Davis et al. 1997b) revealed intersubject variability in the precise location of activations within the ACC. Intersubject variability can be a function of anatomic and functional differences across the population. For instance, there can be considerable variation in individual cingulate gyri patterns (Paus et al. 1996; Vogt et al. 1995). Microelectrode recordings in the human thalamus and pallidum also have revealed that physiological regions (e.g., tactile representation of various body regions) can vary somewhat in size and location, necessitating microelectrode mapping during certain surgical procedures (Tasker and Kiss 1995). Furthermore, although different subjects may rate the intensity of a stimulus similarly, their overall sensory-cognitive experience of that stimulus may vary. Therefore, a fMRI study of individual responses to noxious and innocuous thermal stimuli is warranted. The magnetic field environment in which fMRI are performed in the past has limited the type of stimuli that could be used to study pain and temperature. However, a MRI-compatible peltier-type contact thermal stimulator (Medoc, Ramat-Yishai, Israel) now allows for fMRI studies of heat- and cold-related activations. Therefore, we have used high-resolution fMRI to study the involvement of discrete thalamic and cortical sites during both painful cooling and heating of the skin in individual subjects. Our working hypothesis is that high resolution fMRI in individual subjects can reveal patterns of tactile-, thermal- and pain-related activations in discrete regions of the thalamus, insula, and S2 that likely vary among subjects.
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
; Meyer et al. 1992). Other parameters were: field of view = 22 × 22 cm, in plane resolution = 1.7 mm, TE = 40 ms, TR = 480 ms, 4 interleaves, 80-120 images/slice location/task. Therefore, the dimensions of each pixel (4 × 1.7 × 1.7 mm) result in a single pixel volume of 11.6 µl. Each temporal frame across all slices was acquired in 1.92 s. High-resolution T1-weighted gradient echo images of each slice were obtained to provide anatomic information on which the functional activation maps were later superimposed.
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FIG. 1.
Experimental tasks: each paradigm consisted of 4 repetitions of interleaved neutral and thermal or tactile tasks. A modified peltier-type thermal stimulator (Medoc) was used to deliver stimuli to the right thenar eminence and a wooden probe was used to deliver tactile stimuli to the right palm. A: cool-cold pain task included innocuous (20-28°C) and noxious (2°C) cold stimuli. B: warm-heat pain task included innocuous (40-43°C) and noxious (47.5°C) heat stimuli. Noxious heat stimuli were periodically interupted by a brief innocuous warm stimulus to avoid excessive skin damage. Thermal protocol shown in A and B were presented a total of 4 times. C: brush stimuli were applied to the palm at ~2 strokes/s for a duration of 60 s after a 60-s rest period. This protocol was repeated 4 times.
0.2 (Pearson's linear correlation coefficient). Pixels overlying vessels were not considered because it is not known with certainty whether the vessel drains the adjacent tissue or tissue at a distance from the slice location. An analysis then was performed on these "potential" task-related pixels to determined whether the time course of the signal intensity changes were related to the time course of the stimulus presentation. In this study, the term activation refers to task-related changes in signal intensity within a specific pixel or contiguous group of pixels (also termed region of interest, ROI). The AFNI software can calculate mean signal intensities for an ROI that consists of 1 pixel. ROIs that did not have consistent task-related changes in signal intensity (i.e., did not "sawtooth" reasonably well with the interleaved task and control periods) were considered false positives. Signal intensity profiles that did not show sawtooth task-related changes whereby the mean signal intensity of the task was greater than the signal intensity of the preceding and succeeding control tasks in at least three of four repetitions were considered false positives and were not classified as activations. Figure 2 shows examples of raw data that were inspected for activations with a task-related time course. Two of the study authors independently examined the time course of each ROI, and regions that were not deemed true positives by both authors were eliminated. Of a total of 338 potential activations that were inspected in this way, 223 (66%) were found to have an acceptable task-related time course and were considered true positive activations.
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FIG. 2.
Task-related and -unrelated activations. Examples of potential regions of activation identified in the initial stage of data analysis by the Analysis of Functional Neuroimages (AFNI) software during the cool (C)-cold pain (CP) task in subject 7. A: typical example of the signal intensity profile within the region of interest enclosed by the circle on the magnetic resonance imaging (MRI) image reliably "sawtoothed" during each stimulus compared with the control task (r > 0.31). Only profiles with this characteristic waveform was considered to be task related. B: example of a signal intensity profile of the region of interest within the circle on the MRI image that did not reliably sawtooth during the task (r > 0.26). These and other types of signal profiles that did not show task-related changes in 3 of 4 task repetitions were considered false positives and were not classified as activations.
2 test and activation data were analyzed with a one-way analysis of variance test. t-tests were used to assess differences in pain ratings during the cold and heat pain tasks.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
View this table:
TABLE 1.
Individual pain ratings and activations across all modalities
View this table:
TABLE 2.
Incidence of activations
View this table:
TABLE 3.
Mean pain ratings in subjects with and without pain-related activations
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FIG. 3.
Examples of task-related activations in individual subjects. Note the activations within regions of interest shown by the open circles. A: midsagittal section showing the typical locations of the 6 axial slices obtained for each subject. B and C: tactile-related responses in the contralateral thalamus and bilateral S2 in subject 3. D: cool-related activations in the contralateral thalamus in subject 9. E and F: cold-pain related activations in the ipsilateral caudate, and contralateral anterior insula and S2 in subject 9. G-I: warm and heat-pain related activations in the ipsilateral anterior insula and the contralateral S2 in subject 6. Note the different locations within the insula for the warm and heat pain tasks. Note that the right side of the image is the left side of the brain (contralateral to the stimuli). All regions of interest (ROIs) shown have r > 0.22.
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FIG. 4.
Tactile-related activations. Location of the innocuous tactile-related activations from all subjects are shown on representative line drawings according to the atlas of Talairach and Tournoux (1988) . Task-related activations were based on pixel by pixel analysis of MRI signal intensity during the application of the tactile stimuli compared with rest. Each symbol approximates the location of 1 activation in 1 subject based on activation criteria (see METHODS for further details). The upper and lower horizontal lines in each drawing represent the position of the anterior and posterior commissures (ac, pc) at the Talairach and Tournoux (1988) y coordinates of 0 mm and 
23 mm. sl, lateral sulcus; T, thalamus; vpl, ventroposterior lateral nucleus; dm, dorsal medial nucleus; I, insula; S2, second somatosensory area; C, caudate; P, putamen (note: globus pallidus is located medial to the putamen).
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FIG. 5.
Innocuous cool- and warm-related activations. Location of the innocuous tactile-related activations from all subjects are shown on representative line drawings as described in Fig. 4. Cool (or warm) activations were based on pixel by pixel analysis of MRI signal intensity during the cooling (or warming) stimuli compared with the MRI signal intensity during application of the neutral temperature stimuli. 
and 
, locations of the cool and warm-related activations, respectively.
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FIG. 6.
Cold and heat pain-related activations. Location of the painful thermal-related activations from all subjects are shown on representative line drawings as described in Fig. 4. Cold pain activations were based on pixel by pixel analysis of MRI signal intensity during the noxious cold stimuli compared with the MRI signal intensity during application of the innocuous cooling stimuli. Similarly, the heat pain activations were based on MRI signal intensity during the application of the noxious heat stimuli compared with the innocuous warm stimuli. 
and 
, locations of the cold pain and heat pain-related activations, respectively.
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FIG. 7.
Summary of tactile- and thermal-related activations. Location of all tactile- and thermal-related activations from all subjects as shown in Figs. 4-6 are combined onto a single set of representative line drawings to illustrate clustering of activations according to stimulus intensity (i.e., innocuous vs. noxious), and modality (cooling vs. heating, thermal vs. tactile). Activations are coded by the symbol shape and color to visually assist these comparisons (cool, blue circles; cold pain, dark blue triangles; warm, pink squares; heat pain, red inverted triangles; tactile, green diamonds).
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
; Lenz and Dougherty 1998; Lenz et al. 1993, 1994). Furthermore, our previous studies (Davis et al. 1995b, 1997b) revealed that pain-related ACC activations typically spanned only a few millimeters. Therefore, in this study, we have used 4-mm thick horizontal slices with an in-plane resolution of 1.7 mm to locate discrete areas of pain- and temperature-related activation within the thalamus, S2, and insula. This design precluded a simultaneous study of other potentially important regions such as the primary somatosensory cortex (SI) and the anterior cingulate. A parallel study of other "pain areas" will be reported as the focus of a future study.
; Lenz et al. 1988)]. Some activations may be within functional ventrocaudal nucleus but appear somewhat dorsal due to individual variations in anatomy and/or slight inconsistencies in slice locations. The posterior insula area of activation that we have found was predicted based on reports of tactile-responsive neurons in the posteriorly located granular insula (Ig) (Schneider et al. 1993) and increased cerebral blood flow in Ig during vibrotactile stimulation of the upper limb (Burton et al. 1993; Coghill et al. 1994). Our findings of reliable bilateral S2 activation during innocuous tactile stimulation of the hand are consistent with previous imaging studies (Burton et al. 1993; Coghill et al. 1994) and also were predicted according to the responses of primate S2 neurons to innocuous mechanical stimuli (Burton and Carlson 1986; Burton and Sinclair 1990, 1991; Robinson and Burton 1980).
) and S2 is part of a corticolimbic pathway, these activations may contribute to tactile recognition, learning and memory functions. Therefore activations associated with tactile stimuli may subserve a variety of sensory and cognitive functions.
; Bushnell et al. 1993) and cat (Martin and Manning 1971) and can adapt to prolonged stimuli. In humans, Casey et al. (1996) reported some medial thalamic PET activation during a warm task. However, only a small number of innocuous thermal neurons have been located in the human thalamus, and the location of these cells includes both the dorsal aspect of VPL (Lenz and Dougherty 1998) and the posterior part of the ventromedial nucleus (VMpo) (Craig et al. 1994; Davis et al. 1997a). Stimulation within VMpo also can evoke cool sensations (Davis et al. 1997a). Although we have found thalamic activations that may correspond to these regions in the present study, the spatial resolution cannot clearly identify these small thalamic regions.
, who also failed to find any S2 activation associated with warm stimuli applied with a similar size thermal probe as that used in the present study. Robinson and Burton (1980) also failed to locate any responses of primate S2 neurons to warm stimuli applied with a small probe. However, Craig et al. (1996) reported a strong S2 activation with cool stimuli but only a weak S2 activation during warm stimulation applied to a considerably larger region of the hand than the aforementioned studies. The difference in stimulus size may contribute to these variable findings across labs. Interestingly, Dong et al. (1996) and Greenspan and Winfield (1992) reported no change in innocuous thermosensitivity following experimental compression of the posterior parietal cortex (including S2). Therefore the precise role of S2 in innocuous thermoreception requires further study.
also has reported a somewhat medial thalamic activation associated with cold pain and heat pain. The different pain and temperature-related activations may help us understand the complexities of those sensory experiences and differences in human reports of pain and temperature sensations. Berkley (see Albe-Fessard et al. 1985) defined the role of three thalamic regions involved in the pain experience as follows: the posterior nuclei for designating stimuli as painful, the ventral posterior nuclei for localizing the painful stimulus, and the intralaminar nuclei for the affective-aversive nature of the stimulus. The spatial distribution of thalamic activations during the pain tasks in this study provide further evidence for a complex integration of signals from multiple sites that may help understand the experience of pain.
) and acute thermal pain (Casey et al. 1996; Coghill et al. 1994; Craig et al. 1996; Svensson et al. 1997) and are consistent with nociceptive neurons found in the monkey anterior insula (Dostrovsky and Craig 1996). These pain-related activations in the anterior insula are also congruent with the description of an agranular insular region (Ia), located anterior to Ig, that receives input from the thalamus and projects to the anterior cingulate cortex (area 24) (Augustine 1996). One particularly interesting finding across tasks was a concentration of tactile responses in the posterior insula in contrast to the predominantly anterior insula activation during painful tasks. This segregation of pain- and tactile-related activation in the anterior and posterior insula, respectively, is congruent with the findings of Coghill et al. (1994).
). Primate electrophysiological studies have localized a small number of neurons in S2 that respond to noxious mechanical stimulation (Dong et al. 1989; Robinson and Burton 1980; Whitsel et al. 1969). Involvement of S2 in pain processes also is suggested from studies of evoked potentials and behavioral responses to noxious stimuli (Chudler et al. 1986; Dong et al. 1996; Kitamura et al. 1997). Furthermore, the S2 has been activated consistently in PET studies of heat pain (Casey et al. 1996; Coghill et al. 1994; Craig et al. 1996; Talbot et al. 1991; Xu et al. 1997). Our findings of pain-related S2 activations are consistent with these previous studies. The small number of S2 nociceptive neurons and the spatial resolution of fMRI may have contributed to our findings of S2 activation in only half of our subjects during either a heat pain or cold pain task. The absence of cold pain S2 activations in some subjects may explain the lack of responses in previous studies of group responses to cold pain stimuli (Casey et al. 1996). One curious finding is that the pain-related S2 activations were confined to the contralateral side, unlike the bilateral tactile activations. This discrepancy suggests activation of different pathways with each stimulus modality.
), these activations may have other pain-related functional significance. The tactile stimulus, although not overtly painful or unpleasant, was somewhat annoying and "ticklish" in two subjects (subjects 5 and 7 in Table 1) and may have covertly triggered a preparatory motor response.
; Iadarola et al. 1995; Svensson et al. 1997; Vogt et al. 1996) and psychophysical studies (Davis 1998; Greenspan et al. 1993; Meh and Denislic 1994; Verdugo and Ochoa 1992) of pain and temperature perception have demonstrated intersubject variability. Therefore, negative findings may reflect real intersubject differences. For instance, variability in the vascular bed or the distribution of responsive neuronal clusters in the structures of interest could contribute to the intersubject variability of fMRI activations. Furthermore, differences in internal processing may be influenced by the individual's previous experiences. Recent electrophysiological studies reported that visceral pain could only be evoked during thalamic stimulation in patients with a prior history of that pain but not in patients who had never experienced that sensation (Davis et al. 1995a; Lenz et al. 1995). Intersubject differences in fMRI studies also may reflect the variable response to injury and the range of functional recovery. Recent imaging (Graveline and Hwang 1997) and psychophysical (Bernier et al. 1997) studies suggest that recruitment of ipsilateral pathways may account for some motor and sensory (touch, thermal, pain) function in hemispherectomized patients. Therefore, after an injury a patient's potential for sensory or motor rehabilitation in terms of plasticity may be in part due to their preexisting circuitry or ability to recruit other pathways.
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ACKNOWLEDGEMENTS |
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We thank Dr. R. Cox (Wisconsin) for Analysis of Functional NeuroImages software made available through the internet. The authors also thank Medoc Advanced Medical Systems and J. Lam for assistance in the modifications of the MRI-compatible thermal stimulator unit.
This study was funded by a Medical Research Council of Canada Operating Grant to K. D. Davis.
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FOOTNOTES |
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Address for reprint requests: K. D. Davis, Division of Neurosurgery, MP14-322, The Toronto Hospital (Western Division), 399 Bathurst St., Toronto, Ontario M5T 2S8, Canada.
Received 25 February 1998; accepted in final form 14 May 1998.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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