Abstract

Pain is an unpleasant sensation, and at the same time, it is always subjective and affective. Ten healthy subjects viewed 3 counterbalanced blocks of images from the International Affective Picture System: images showing painful events and those evoking emotions of fear and rest. They were instructed to imagine pain in their own body while viewing each image showing a painful event (the imagination of pain). Using functional magnetic resonance imaging, we compared cerebral hemodynamic responses during the imagination of pain with those to emotions of fear and rest. The results show that the imagination of pain is associated with increased activity in several brain regions involved in the pain-related neural network, notably the anterior cingulate cortex (ACC), right anterior insula, cerebellum, posterior parietal cortex, and secondary somatosensory cortex region, whereas increased activity in the ACC and amygdala is associated with the viewing of images evoking fear. Our results indicate that the imagination of pain even without physical injury engages the cortical representations of the pain-related neural network more specifically than emotions of fear and rest; it also engages the common representation (i.e., in ACC) between the imagination of pain and the emotion of fear.

Introduction

Pain is an unpleasant sensation, but at the same time, it is always subjective and emotional (Fields 1999). Individuals learn of “pain” through experiences related to injury in their life, and they are able to imagine pain from their past experiences even without physical injury.

Recently, from the viewpoint of “empathy,” some neuroimaging studies on pain processing have revealed a partial neural overlap between the experience of pain in self and the observation of pain in others (i.e., empathy for other's pain) (Singer and others 2004; Botvinick and others 2005; Jackson and others 2005). Although the actual experience of pain and the empathic feeling of the pain of other individuals involve similar brain regions such as the anterior cingulate cortex (ACC) and anterior insula, activations of the secondary somatosensory cortex (SII) and dorsal ACC were specifically attributable to receiving actual pain and were not detected from the observation of pain in others (Singer and others 2004). However, changing perspective taking, Jackson and others (2006) clearly differentiated the cerebral representation between the imagination of pain (i.e., a self-oriented aversive response that induces both empathy and distress) and imagining how others would feel pain (i.e., empathy for other's pain), showing that the imagination of pain activates the pain-related neural network (pain matrix) extensively including the SII, dorsal ACC (Brodmann Area [BA] 24), and insula. Furthermore, in a study of patients with phantom limb pain using a hypnotic suggestion that the missing limb was in a painful position, Willoch and others (2000) found a similar activation in the pain matrix including the SII, ACC, and insula in the absence of any noxious stimulation.

The aim of our functional magnetic resonance imaging (fMRI) study is to investigate the hemodynamic changes stemming from the inner experience of pain (imagination of pain) perceived from viewing images showing painful events in an intact body, in comparison with those stemming from another aversive emotion, that is, fear and rest emotion elicited by the International Affective Picture System (IAPS) (Lang and others 2005). This picture system includes images of several different emotional scenes; it is possible to use these images to elicit specific emotions. In a number of neuroimaging studies using the IAPS, various emotions, such as happiness, sadness (Lang and others 1998), and disgust (Schienle and others 2002), the anticipation of painful stimulation and aversive situations (Simmons and others 2004), the anticipation of aversion (Nitschke and others 2006), and their neural mechanisms have been shown. We focused on the emotions of pain and fear because these emotions have common features. Pain and fear belong to the category “negative affect,” which is associated with the withdrawal from the emotion elicitor serving to protect the organism from being harmed and are also part of different warning systems dealing with different types of threat.

Materials and Methods

Subjects

Ten healthy, right-handed volunteers (10 males; mean age 26.3 ± 4.7 years [range 22–37 years]) participated in the fMRI study. The subjects were all fMRI-experienced males. The subjects had no history of head injury, learning disability, or psychiatric illness, including substance abuse/dependence or taking regular medications. All the subjects gave their written informed consent after the explanation of the experimental protocol, as approved by the local Institutional Review Board.

Task Design

The stimulus materials consisted of 45 images belonging to 3 emotional categories: images showing painful events (pain condition), images evoking fear (fear condition), and images evoking rest (rest condition) (15 each). Trials were blocked by the emotional categories. The block order was counterbalanced. In each block, 5 images of the same emotional category were presented for every 6 s (a 5-s presentation with a 1-s interstimulus interval). One run consisted of nine 30-s blocks and lasted 270 s. All the subjects performed 2 runs. Each pain, fear, and rest image was presented twice in the experiment. The stimuli were displayed through a shielded liquid crystal display panel mounted on the head coil.

The images were taken from the IAPS of Lang and others (2005), which includes images that have already been rated as representative examples on different emotional dimensions: mainly valence and arousal or had been made by the authors (only for images showing painful events). Examples of images showing painful events made by authors are shown in Figure 1. Images showing painful events in Figure 1 depict arms and hands punctured by needles and syringes, using the author's arm and hand and red ink for simulating blood; a needle appears to have punctured the hand or arm in the images presented but actually it has not. The subjects were not informed of this setup. Other images showing painful events extracted from the IAPS included a man's face with a dental needle inserted into his tooth pulp, an arm wherein the cubital vein is punctured for taking blood samples, and a woman's face in agony caused by a severe headache. Images evoking fear from the IAPS included a hand holding a knife in a stabbing position, a gun pointed at the viewer, a giant shark attacking the viewer at any moment, and a man covered with a mask. Images evoking rest from the IAPS included beautiful landscapes. During the pain condition, the subjects were instructed specifically to feel their own pain as if they were in the same painful situation similar to the images presented showing painful events. That is, the subjects were instructed to imagine their own sharp acute pain as if it were their own arm while viewing images showing an arm punctured by needles, for example. Likewise, they were instructed to feel fear as if they were in the same fearful situation during the fear condition and to relax and feel free during the rest condition.

Figure 1.

Sample painful images. We used 15 images for each condition (pain, fear, and rest conditions). In addition to the “images showing painful events” taken from IAPS (Lang and others 2005), we used 8 pictures made by the authors in the pain condition to fill up the deficit of images showing painful events taken from IAPS. Images shown in Figure 1 are the examples of images showing painful events, which were made using the author's arm and hand punctured by needles and syringes and red ink for simulating blood; a needle appears to have punctured the hand or arm in the images presented, but actually it has not. The subjects were not informed of this setup.

Figure 1.

Sample painful images. We used 15 images for each condition (pain, fear, and rest conditions). In addition to the “images showing painful events” taken from IAPS (Lang and others 2005), we used 8 pictures made by the authors in the pain condition to fill up the deficit of images showing painful events taken from IAPS. Images shown in Figure 1 are the examples of images showing painful events, which were made using the author's arm and hand punctured by needles and syringes and red ink for simulating blood; a needle appears to have punctured the hand or arm in the images presented, but actually it has not. The subjects were not informed of this setup.

Following the scanning session, we ascertained verbally whether the subjects were able to imagine their own pain as they viewed the images showing painful events. The subjects provided ratings of their arousal level and the valence of each of the images showing painful events, images evoking fear, and images evoking rest presented during the experiment, using the self-assessment manikin (SAM), a 9-point visual analog scale (Bradley and Lang, 1994). The scale ranged from 1 (calm) to 9 (very excited) for the rating of emotional arousal and 1 (very negative/ unpleasant) to 9 (very positive or pleasant) for the rating of emotional valence. One-way ANOVA was used to compare valence and arousal ratings between the images used in the pain, fear, and rest conditions.

Magnetic Resonance Imaging Acquisition

Magnetic resonance imaging (MRI) was performed using a Shimadzu-Marconi's Magnex Eclipse 1.5-T PD250 (Kyoto, Japan) at the Advanced Telecommunications Research Institute International, Brain Activity Imaging Center (Kyoto, Japan). Functional T2-weighted images were acquired using a gradient echo-planar imaging (EPI) sequence (repetition time = 3000 ms, echo time = 49 ms, flip angle = 90°, field of view = 192 × 192 mm, and matrix size = 64 × 64 pixels). Thirty consecutive axial slices (thickness 5 mm) covering the entire cortex and cerebellum were acquired. T2-weighted anatomical images (voxel size = 0.75 × 0.75 × 5 mm) were acquired in the same plane. T1-weighted anatomical images (voxel size = 1 × 1 × 1 mm) were also acquired. Before the acquisition of functional images (voxel size = 3 × 3 × 5 mm), these 2 sets of anatomical images were used to improve spatial normalization (Seki and others 2004). First, T2-weighted image was coregistered to the mean EPI (functional) image. Second, T1-weighted image was coregistered to the T2-weighted image. Then, coregistered T1-weighted image was used to calculate parameters for spatial normalization, and the parameters were used to normalize EPI (functional) images (voxel size = 3 × 3 × 5 mm).

Image and Statistical Analyses

Image analysis was performed using SPM2 (Wellcome Institute of Cognitive Neurology, London, UK). Slice time was corrected, and reconstructed data were realigned, spatially normalized, high-pass filtered, and smoothed with a Gaussian filter (6 × 6 × 10 mm full width at half maximum) to minimize noise and residual differences in gyral anatomy (Friston and others 1995; Worsley and Friston 1995). Preprocessed MRI data were analyzed statistically on a voxel-by-voxel basis using SPM2. Serial correlations were corrected using an autoregressive model, and global signal changes were removed by scaling. Task-related neural activities were modeled using a boxcar function convolved with a hemodynamic response function.

To identify which cerebral networks were activated under the pain condition and fear condition, we analyzed the blood oxygenation level–dependent (BOLD) response under the different emotional conditions by calculating 3 contrasts: For each subject, a boxcar model convolved with the hemodynamic response function was applied to the fMRI time series at each voxel, and t-maps for the contrasts pain minus rest (contrast name: pain − rest contrast), fear minus rest (contrast name: fear − rest contrast), and pain minus fear (contrast name: pain − fear contrast) were computed. Then, the subject-specific contrast images of parameter estimates were used as inputs for the second (random effect) level analysis. At the second level, the 1-sample t-test was conducted and a threshold of P < 0.001 (uncorrected) was employed. To minimize false-positive activations, we only used activations exceeding 5 contiguous voxels as described by Phan and others (2003). The sites of activation for each contrast are listed in Table 2 with their number of voxels, corrected P at the cluster level, coordinates, and t-value at the voxel level. The coordinates and labels of anatomical localizations were defined in accordance with the macroscopic anatomical parcellation of the Montreal Neurological Institute MRI single-subject brain as described by Tzourio and others (2002).

Result

Subjective Self-Reports

All the subjects reported that they could imagine their own pain on their body as they viewed the images showing painful events in the MRI scanning set. Postscanning emotional ratings by the SAM method revealed that all the subjects reported comparable valence and arousal estimates among images showing painful events, evoking fear and rest (Table 1). ANOVA showed significant differences in both the valence and arousal ratings in rest versus pain, and rest versus fear conditions. On the other hand, for pain and fear conditions, no differences were found between valence and arousal ratings. Arousal and valence ratings were highly correlated (Pearson's correlation coefficient, r = 0.93, P < 0.001).

Table 1

Emotional ratings for image categories: images showing painful events (pain condition), images evoking fear (fear condition), and images evoking rest (rest condition)

 Pain (Mean ± SD) Fear (Mean ± SD) Rest (Mean ± SD) 
Postscan SAM valence (1–9) 2.25 ± 1.02* 2.33 ± 1.15* 7.52 ± 1.36 
Postscan SAM arousal (1–9) 7.21 ± 1.46* 7.48 ± 1.45* 2.10 ± 1.20 
 Pain (Mean ± SD) Fear (Mean ± SD) Rest (Mean ± SD) 
Postscan SAM valence (1–9) 2.25 ± 1.02* 2.33 ± 1.15* 7.52 ± 1.36 
Postscan SAM arousal (1–9) 7.21 ± 1.46* 7.48 ± 1.45* 2.10 ± 1.20 

Note: SD, standard deviation.

*

P < 0.01 versus rest using 1-way analysis of variance.

Representation of Imagination of Pain While Viewing Images Showing Painful Events

The pain – rest contrast revealed several increased activations in pain-related regions that are known to be activated during the perception of nociceptive stimulation (shown in the pain – rest contrast in Fig. 2 and Table 2), namely, the right upper bank of the Sylvian fissure, corresponding to the SII, right anterior insula, caudal portions of the bilateral ACC (BA 24), and the cerebellum. Additionally, an increased activation was located in the rostral part of the posterior parietal cortex (PPC) (right > left) in both hemispheres (BAs 5 and 7). The other peaks of increased changes in activity were found in the bilateral lateral occipitotemporal cortices around the fusiform gyrus corresponding to an extrastriate region, which is involved in the recognition of visual objects. At the subcortical level, in the thalamus as such, no activation was found in the pain – rest contrast.

Figure 2.

Brain activations in each contrast. Activated brain areas in each contrast: pain − rest, fear − rest, and pain − fear conditions. Pain − rest and pain − fear contrasts revealed activations in the SII region and PPC areas and in the affective components of the pain matrix such as the ACC, anterior insula, and cerebellum while viewing images showing painful events. The fear − rest contrast revealed activations in the left amygdala and ACC. The brain region is superimposed with orthogonal sections (sagittal, coronal, and axial) of a structural scan rendered in standard space, and the corresponding t-value is also shown in the color scale on the lower right side for each contrast. Uncorrected P < 0.001 was adopted as the height threshold, and the extent threshold of 5 voxels was adopted.

Figure 2.

Brain activations in each contrast. Activated brain areas in each contrast: pain − rest, fear − rest, and pain − fear conditions. Pain − rest and pain − fear contrasts revealed activations in the SII region and PPC areas and in the affective components of the pain matrix such as the ACC, anterior insula, and cerebellum while viewing images showing painful events. The fear − rest contrast revealed activations in the left amygdala and ACC. The brain region is superimposed with orthogonal sections (sagittal, coronal, and axial) of a structural scan rendered in standard space, and the corresponding t-value is also shown in the color scale on the lower right side for each contrast. Uncorrected P < 0.001 was adopted as the height threshold, and the extent threshold of 5 voxels was adopted.

Table 2

Local statistical maxima in activated brain regions in each contrast

   MNI coordinates (mm) 
Number of voxels Cluster level corrected P Brain region x y z t-Value 
Pain − rest 
57 0.001 (R) Anterior insula 40 −8 8.23 
18 0.309  36 −4 12 7.61 
117 0.000 (R) SII 64 −32 36 8.12 
27 0.081  52 7.02 
54 0.002 ACC (BA 24) 10 52 7.53 
26 0.093  14 32 9.06 
0.885  −6 48 6.19 
67 0.000 (R) PPC 34 −52 60 9.67 
26 0.093 (L) PPC −34 −50 52 7.44 
35 0.025 Cerebellum −24 −62 −56 7.23 
32 0.039  −12 −74 −48 5.62 
0.968  −64 −48 5.11 
193 0.000 (R) LOC 48 −70 −4 8.22 
91 0.000 (L) LOC −54 −66 −16 7.18 
Fear − rest 
30 0.129 (L) Amygdala −20 −16 6.98 
18 0.487 ACC (BA 24) −4 40 7.01 
0.940 Brain stem −32 −4 6.03 
24 0.254 Cerebellum −10 −74 −40 6.35 
443 0.000 (R) LOC 44 −80 −12 13.45 
61 0.005  42 −60 −24 7.69 
317 0.000 (L) LOC 52 −78 8.43 
Pain − fear 
283 0.000 (R) SII 58 −32 16 9.07 
13 0.657 (R) PPC 18 −48 72 6.68 
24 0.157 (L) SII −62 −26 20 7.59 
32 0.053 (L) PPC −58 −48 48 11.61 
0.997  −54 −34 52 8.27 
19 0.314 (R) Insula 42 −6 −12 8.90 
186 0.000  −54 −56 7.72 
24 0.157 Cerebellum −26 −50 −48 7.78 
17 0.409  −14 −56 −48 7.21 
   MNI coordinates (mm) 
Number of voxels Cluster level corrected P Brain region x y z t-Value 
Pain − rest 
57 0.001 (R) Anterior insula 40 −8 8.23 
18 0.309  36 −4 12 7.61 
117 0.000 (R) SII 64 −32 36 8.12 
27 0.081  52 7.02 
54 0.002 ACC (BA 24) 10 52 7.53 
26 0.093  14 32 9.06 
0.885  −6 48 6.19 
67 0.000 (R) PPC 34 −52 60 9.67 
26 0.093 (L) PPC −34 −50 52 7.44 
35 0.025 Cerebellum −24 −62 −56 7.23 
32 0.039  −12 −74 −48 5.62 
0.968  −64 −48 5.11 
193 0.000 (R) LOC 48 −70 −4 8.22 
91 0.000 (L) LOC −54 −66 −16 7.18 
Fear − rest 
30 0.129 (L) Amygdala −20 −16 6.98 
18 0.487 ACC (BA 24) −4 40 7.01 
0.940 Brain stem −32 −4 6.03 
24 0.254 Cerebellum −10 −74 −40 6.35 
443 0.000 (R) LOC 44 −80 −12 13.45 
61 0.005  42 −60 −24 7.69 
317 0.000 (L) LOC 52 −78 8.43 
Pain − fear 
283 0.000 (R) SII 58 −32 16 9.07 
13 0.657 (R) PPC 18 −48 72 6.68 
24 0.157 (L) SII −62 −26 20 7.59 
32 0.053 (L) PPC −58 −48 48 11.61 
0.997  −54 −34 52 8.27 
19 0.314 (R) Insula 42 −6 −12 8.90 
186 0.000  −54 −56 7.72 
24 0.157 Cerebellum −26 −50 −48 7.78 
17 0.409  −14 −56 −48 7.21 

Note: Results are superimposed on MNI coordinates. Coordinates refer to local cluster maxima. The voxel size is 3 × 3 × 5 mm. MNI, Montreal Neurological Institute; (R), right; (L), left; LOC, lateral occipital cortex. Uncorrected P < 0.001 was adopted as the height threshold, and the extent threshold of 5 voxels was adopted.

To determine cerebral activations specific to the pain condition, we compared cerebral activations during the viewing of images showing painful events with those during the viewing of images evoking fear (i.e., pain − fear contrast). This contrast revealed clear activations in the bilateral SII regions and posterior parietal cortices (PPCs), with stronger activations on the right side than on the left side (shown in the pain − fear contrast in Fig. 2 and Table 2). The other activations observed in this contrast were in the right insula and cerebellum. Activations in the bilateral lateral occipitotemporal cortices were not observed in the pain − fear contrast.

Representation of Viewing Images Evoking Fear

Different patterns of brain activation were found during the viewing of fearful images (fear − rest contrast) as compared with the viewing of painful images (pain − rest contrast) (shown in the fear − rest contrast in Fig. 2 and Table 2). There were activations in the left amygdala and the caudal portions of the ACC (BA 24), cerebellum, and bilateral lateral occipitotemporal cortices. The locations of the activation in ACC and lateral occipital cortices mostly overlapped with those of ACC and lateral occipital cortices activations noted in the pain − rest contrast.

Discussion

In this study, we investigated the cerebral hemodynamic response of the imagination of pain while viewing images showing painful events in comparison with those while viewing images evoking fear and rest. Our results show that the imagination of pain induced a different cortical representation and engage the brain region associated with pain-related neural network more extensively in comparison with the emotions of fear and rest, notably the ACC (BA 24), anterior insula, cerebellum, PPC, and the SII region.

Brain Regions Related to Subject Experience of Pain

Our general findings in imagination of pain are in agreement with the recent findings that Jackson and others (2006) have reported, in which they differentiated empathic responses to witnessed pain between imagining others versus imagining our own personal distress in similar painful situation. Recent functional imaging studies in humans have provided evidence that multiple regions of the brain are involved in pain perception (Treede and others 1999; Kakigi, Inui, and Tamura 2005; Qiu and others 2005). Despite their diversity, recent many studies have shown that the pain-related neural brain regions and network exhibit activation related to the subjective experience of pain. For example, we have shown, in a yoga master who claims not to feel pain during meditation, that BOLD signals of fMRI in these pain-related regions including the primary somatosensory cortex (SI) and SII were not increased while he received pain by applying a laser pulse (Kakigi, Nakata, and others 2005). Koyama and others (2005) showed that expectations of decreased pain strongly reduced both the subjective experience of pain and the activation of pain-related brain regions including the SI, SII, insula, prefrontal cortex, and ACC. In suggestion-prone subjects, Raij and others (2005) showed that the dorsal ACC and insula were activated during both physical and psychological induced pain, although the SII region and posterior insula were activated more strongly during physical than psychological induced pain. Seymour and others (2005) showed that prediction and expectation of pain relief is reflected by neural activities in the amygdala and midbrain and mirrored by activities in the lateral orbitofrontal cortex (OFC) and ACC. These findings, taken together with our results, suggest that the subjectivity of pain encompasses a widespread and functionally diverse set of brain regions.

Parasylvian Cortex and PPC Activations during Imagination of Pain While Viewing Images Showing Painful Events

The main findings of this study are activations in the SII region in the parasylvian cortex and PPC during the imagination of pain while viewing images showing painful events, in which activations in the SII region and PPC were considered to be relatively specific to the pain condition compared with fear and rest conditions. The SII region has been consistently shown as the main activity area in many pain imaging studies, suggesting that the SII region plays a major role in pain perception in humans (Treede and others 1999; Schnitzler and Ploner 2000; Kakigi, Inui, and Tamura 2005; Qiu and others 2005). However, the location of nociceptive cortical areas around the sylvian fissure is still a matter of controversy. It has been difficult to determine whether the nociceptive area is situated within the classic SII (parietal operculum) or within adjacent somatosensory areas such as the frontoparietal operculum or insula. Many previous studies have shown that noxious stimuli activate at least one cortical area around the sylvian region other than the SII. For example, fMRI (Brooks and others 2002, 2005; Bingel and others 2003; Iannetti and others 2005) and electroencephalographic (Lenz and others 2000; Frot and Mauguiere 2003) studies have shown activation in the posterior insula following noxious stimulation. Our previous studies also showed that activity from the insula may contribute to major magnetoencephalographic signals evoked by noxious stimuli (Inui and others 2003; Kakigi, Inui, and Tamura 2005). In this study, the pain − rest contrast showed activations in the right upper bank of the Sylvian fissure, and the pain − fear contrast showed activations in the same area bilaterally. Therefore, we consider that activations in the sylvian region in this study may be a summation of activities from the SII region and other adjacent areas, although the former appears to be the major contributor.

In spite of the constant finding of activation in the SII region following noxious stimuli among the fMRI, electroencephalographic, and magnetoencephalographic studies, the functional role of the SII region remains largely unknown. Using a nociceptive stimulus, some studies suggested that the SII region is associated more with the cognitive evaluative aspects of the painful nature of a stimulus than with the sensory discriminative aspects of pain (Treede and others 1999; Schnitzler and Ploner 2000; Timmermann and others 2001). Otherwise, attention to images showing painful events may also influence SII region activity; it is known that attention enhances SII region and PPC responses (Mauguiere and others 1997). Task-related responses to visual inputs suggest the role of the SII region in directing attention toward noxious stimuli (Dong and others 1994). Downar and others (2002) reported an interesting finding that activation in the temporoparietal junction, which is generally consistent with our observed activation in the SII region, showed sensitivity to stimulus salience across multiple sensory modalities, suggesting this region may play a general role in identifying salient stimuli. Therefore, activations in the SII region observed in this study may likewise functionally reflect attention capture or awareness entry in identifying salient features to the self, although they are situated within adjacent areas consistently showing activation following noxious stimuli.

Another main finding in this study is PPC activations during the imagination of pain. It is suggested that the role of the PPC is to integrate afferent information from multimodalities, such as vision, touch, and proprioception, and to convert it into common spatial representations (Andersen and others 1997). In this study, all the images showing painful events presented to the subjects (the examples are shown in Fig. 1) contain human body parts, and the bodies in the images are those of other individuals not those of the subjects themselves. The subjects were instructed to imagine pain on their own body as if they were the subjects in the images showing painful events, and we consider that such a task necessarily requires self-body image within the subjects. To project the pain imagined onto the self-body image, the transformation of spatial coordinates from the images of body parts of other individuals into the corresponding self-body coordinates is required. Therefore, PPC activation during the imagination of pain may reflect a transformation processing of the pain imagined to the self-body–centered coordinates. The role of the PPC in such a transformation is well established (Anderson 1995; Andersen and others 1997).

ACC and Right Anterior Insula Activation during imagination of Pain While Viewing Images Showing Painful Events

First, the activations in the ACC (BA 24) during imagination of pain are similar to those in previous imaging studies of pain perception, whether pain is actually experienced (Rainville and others 1997; Singer and others 2004), visually perceived from other's pain (Jackson and others 2005), hypnotically induced (Derbyshire and others 2004), imagined by self's perspective (Jackson and others 2006), or even induced by listening to pain-evoking words, compared with listening to nonsense syllables (Osaka and others 2004). This region is considered as a key cortical area involved in the regulation of subjective feelings of pain-related unpleasantness in humans and is particularly associated with the cognitive values of pain (Bush and others 2000; Rainville 2002). Also, note that neurons that respond specifically to painful stimulation have been identified using intracortical electrode recordings in a very similar region as the dorsal ACC (Hutchison and others 1999).

Second, we discuss whether anticipatory mechanisms were involved in our findings because viewing images showing painful events or evoking fear may prompt the anticipation of pain or fear in oneself. Our results showed that dorsal ACC activations during the fear condition mostly overlapped with ACC activations observed during the pain condition. It is well known that the prefrontal cortex, anterior insula, and rostral ACC are activated during the anticipation of pain (Ploghaus and others 1999; Petrovic and others 2002; Porro and others 2002). Furthermore, the anticipation of emotionally aversive visual stimuli activates the rostral ACC, anterior insula, dorsolateral prefrontal cortex, and medial OFC (Simmons and others 2004; Nitschke and others 2006); in particular, the medial OFC is uniquely associated with the anticipation of aversive pictures, on the other hand, the main areas activated both in anticipation and in response to aversive pictures were amygdala, anterior insula, and dorsal ACC (Nitschke and others 2006). In our results, we failed to observe activations in the dorsolateral prefrontal cortex and medial OFC in every contrast. Neither the subjects were actually inflicted with a pain stimulus nor were they led to believe that they will receive a pain stimulus during the course of our experiment. Therefore, we consider that activations in the dorsal ACC were positively associated with responses to aversive stimuli rather than an anticipatory mechanism.

Third, the pain − rest and pain − fear contrasts revealed right insula activation, particularly the anterior part, whereas the fear − rest contrast did not show any increased insula activation. Functional imaging studies consistently demonstrated pain-related activations in the insula, and most studies are in agreement that pain-related activations are located in the anterior parts of the insula, whereas tactile activations are distinctly located more posteriorly (Coghill and others 1994; Davis and others 1998; Inui and others 2003). The anterior insula activity was dependent on the attention of painful stimulation and was significantly attenuated when subjects were distracted from pain (Brooks and others 2002). The activation in the right anterior insula correlates with the subjective intensity rating of painful thermal stimulation, whereas posterior insula activation correlates with stimulus temperature (Craig and others 2000). The anticipation of pain activates more the anterior insular regions, whereas the actual experience of pain activates more the posterior insula, which suggests that the former is associated with affective dimensions, such as the anticipatory arousal and anxiety of pain, and the latter is associated with the actual sensory experience of pain (Ploghaus and others 1999). Anders and others (2004) reported that negative emotional valence varied with insular activity. Our psychological ratings (SAM method) showed that the imagination of pain induces a complete contrastive valence and arousal scores in comparison with rest emotion, suggesting that the imagination of pain places subjects in a significantly negative affective state.

Thus, our results support the model proposed by Craig (2000, 2003) that suggests the insula as an “interoceptive” cortex that reflects the internal condition of pain, similar to temperature, sensual touch, itch, hunger, or thirst. The activation in the right anterior insula during imagination of pain is in agreement with the finding that only the right insula would serve to compute a higher order “metarepresentation of the primary interoceptive activity,” which is related to the feeling of pain and its emotional awareness (Craig 2003). The activation in the right anterior insula is assumed to subserve subjective feelings of pain imagined while viewing images showing painful events. The activations of both the insula and ACC in this study may correspond to the simultaneous generation of a feeling and an emotional motivation because afferents also project to the ACC via the medial dorsal thalamic nucleus to produce behavioral drive (Craig 2000, 2003).

The insula as well as the PPC and SII activations in the pain condition tended to be stronger on the right side than on the left. Canli and others (1998) using IAPS showed that negative emotions are mostly represented in the right hemisphere, whereas positive emotions are lateralized to the left hemisphere. Brooks and others (2002) observed a right hemispheric lateralization of nociceptive processing in the anterior insula during a rating task of painful heat stimulation. Hari and others (1997) also showed that the unpleasant nature of a pain stimulus is associated with the right hemisphere predominance of SII responses, thereby suggesting the involvement of the right hemisphere in the emotional motivational aspects of pain processing. In contrast, Schlereth and others (2003) reported a left hemisphere predominance for the early sensory discriminative aspects of pain processing using brain electrical source analysis of laser-evoked potentials.

Amygdala Activation during Viewing Images Evoking Fear

The amygdala is suggested to play a crucial role in the processing of fear emotion (Calder and others 2001). The activation of the left amygdala during the fear condition in this study is consistent with its involvement in the processing of fear emotion found in most studies in which subjects were presented with images of human faces expressing fear (Breiter and others 1996; Morris and others 1998; Wright and others 2001). However, the notion that the amygdala is specific to fear-related emotions seems to be questionable; an alternative interpretation would be that unspecific negative emotional states such as fear, disgust, personal distress, and anxiety have a common neuronal circuitry. A number of studies have suggested that negative emotions are related to not only activation in the ACC but also activation in the amygdala (Irwin and others 1996; Davidson 2002; Stark and others 2003).

Conclusion

Imagination of pain while viewing images showing painful events involves activations in the ACC (BA 24), right anterior insula, cerebellum, SII region, and PPC. Activations in the SII region and PPC were detected specifically during the imagination of pain compared with emotions of fear and rest. These findings are in good agreement with the activation patterns associated with the perception of nociceptive stimulation. These results suggest that the activations during the imagination of pain elicited by viewing images showing painful events may be based on the cortical representations of the pain matrix in the human brain, which reflects the multidimensional nature of pain experience including sensory, affective, and cognitive components.

This research was supported in part by Grants-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), the 21st Century Centre of Excellence Program from MEXT, and Initiatives for Attractive Education in Graduate Schools from MEXT. We are grateful to Akiko Callan and Nobuo Masaki, PhD, of the Brain Activity Imaging Center, Advanced Telecommunications Research Institute International (Kyoto, Japan), for supporting this project. Conflict of Interest: None of the authors or participants have any financial interest in the subject matter, materials, or equipment.

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