Self-referential processing of negative stimuli within the ventral anterior cingulate gyrus and right amygdala

Brain and Cognition 69 (2009) 218–225

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Brain and Cognition journal homepage: www.elsevier.com/locate/b&c

Self-referential processing of negative stimuli within the ventral anterior cingulate gyrus and right amygdala Shinpei Yoshimura a, Kazutaka Ueda b, Shin-ichi Suzuki c, Keiichi Onoda a, Yasumasa Okamoto a, Shigeto Yamawaki a,* a

Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan b Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan c Faculty of Human Sciences, Waseda University, 2-579-15, Mikajima, Tokorozawa, Saitama 359-1192, Japan

a r t i c l e

i n f o

Article history: Accepted 14 July 2008 Available online 23 August 2008 Keywords: Emotion Self-reference effect Medial prefrontal gyrus fMRI

a b s t r a c t Neural activity associated with self-referential processing of emotional stimuli was investigated using whole brain functional magnetic resonance imaging (fMRI). Fifteen healthy subjects underwent fMRI scanning while making judgments about positive and negative trait words in four conditions (self-reference, other-reference, semantic processing, and letter processing). Significant activity was observed in the right ventral anterior cingulate gyrus and the right amygdala in the negative-word/self-reference condition, and in the left amygdala in the positive-word/self-reference condition. Compared with the semantic-processing condition, the self-reference conditions showed significantly more activity in the medial prefrontal and temporal gyri, posterior cingulate gyrus, and precuneus. These results suggest that the medial prefrontal gyrus, posterior cingulate gyrus, and precuneus are associated with a self-referential processing, and the ventral anterior cingulate gyrus is involved in self-referential processing of negative emotional stimuli. The results also suggest that the amygdala is associated with self-referential processing of both positive and negative emotional stimuli. Ó 2008 Elsevier Inc. All rights reserved.

1. Introduction Material processed with reference to oneself is more readily remembered, which is called the self-reference effect (Rogers, Kuiper, & Kirker, 1977; Symons & Johnson, 1997). The emotional content of the material may influence the self-reference effect. For example, depressed patients remember more negative emotional content than non-depressed patients, such as negative autobiographical memories (Barry, Naus, & Rehm, 2006) or negative emotional adjectives (Bradley & Mathews, 1983). Cognitive theories of depression suggest that depressed patients have a negative bias in their thinking (Beck, 1967). Other studies have found that cognitive processing of material congruent with mood is facilitated, and that there is more facilitation for self-referential processing than other-referential processing (for a review, see Forgas & Bower, 1988). Recent studies using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have suggested that the medial prefrontal gyrus is involved in self-referential processing (Craik et al., 1999; Fossati et al., 2003, 2004; Kelley * Corresponding author. Fax: +81 82 257 5209. E-mail address: [email protected] (S. Yamawaki). 0278-2626/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.bandc.2008.07.010

et al., 2002; Schmitz, Kawahara-Baccus, & Johnson, 2004). Brain scan studies indicate that the medial prefrontal and anterior cingulate gyri are involved in self-referential processing of emotional stimuli (Fossati et al., 2003, 2004; Gusnard, Akbudak, Shulman, & Raichle, 2001; Phan et al., 2004). There are some shared or exclusive brain regions of activation related to the emotional valence of stimuli being processed. Brain regions that have been shown to respond to negative emotional stimuli include the amygdala (Anderson, 1968; Irwin et al., 1996; Liberzon et al., 2000; Paradiso et al., 1999; Reiman et al., 1997; Siegle, Steinhauer, Thase, Stenger, & Carter, 2002; Siegle, Thompson, Carter, Steinhauer, & Thase, 2006; Taylor et al., 1998), the ventral anterior cingulate gyrus (Devinsky, Morrell, & Vogt, 1995; Lane, Fink, Chau, & Dolan, 1997; Lane et al., 1998; Taylor et al., 1998; Whalen et al., 1998), and the occipital cortex (Lang et al., 1998; Paradiso et al., 1999). Areas that have been shown to respond to positive emotional stimuli include the anterior cingulate gyrus (Lane et al., 1997), the medial, orbital and dorsolateral prefrontal gyri (Reiman et al., 1997), and the occipital cortex (Lang et al., 1998; Liberzon et al., 2000). Some studies reported that the anterior cingulate gyrus and medial prefrontal gyrus play a specific role in the cognitive processing of emotional stimuli (Lane et al., 1997, 1998).

S. Yoshimura et al. / Brain and Cognition 69 (2009) 218–225

However, little is known about brain activity during self-referential processing of emotional word stimuli. Fossati and colleagues (2003, 2004) used fMRI to investigate the interaction between selfreferential processing and emotional word stimuli. Their studies showed no distinctive activation in emotionally relevant regions, such as the amygdala and ventral anterior cingulate cortex, which had been previously reported in imaging studies (Elliott, Rubinsztein, Sahakian, & Dolan, 2002; Irwin et al., 1996; Lane et al., 1997, 1998; Liberzon et al., 2000; Paradiso et al., 1999; Phelps et al., 2001; Siegle et al., 2002; Zald, 2003). In our study, we focused not on differences between self-referential processing of emotional stimuli and neutral stimuli but on differences between self-referential processing of positive stimuli and negative stimuli, because the medial prefrontal gyrus activity to self-relevance is often confounded with emotional valence (Moran, Macrae, Heatherton, Wyland, & Kelley, 2006). To distinguish the effects of emotional stimuli during self-referential processing, we decided to exclude neutral words. In addition, the control condition in Fossati et al.’s studies was a letter recognition task in which participants decided whether words contained specific target letters. Possible semantic processing of the words in this condition may have affected activity levels in brain regions associated with emotional processing, such as the orbitofrontal gyrus, inferior frontal gyrus and amygdala (Kuchinke et al., 2005). To control for this possible confounding influence, in the present study we used two control conditions: one similar to that employed by Fossati et al., and a second condition involving a judgment about whether or not it was difficult to define the presented word. This second condition could be used to control for semantic processing of stimuli during self-referential processing of emotional stimuli. Using these separate control conditions we set out to determine which brain regions are associated with self-referential processing of emotional stimuli, and how these regions are influenced by the emotional valence of the stimuli.

2. Method 2.1. Participants We recruited 21 participants (12 males, 9 females; mean age = 23.5 years, SD = 3.0 years), and paid them for their participation. At the time of the initial screening, mood was assessed using the Japanese version of the Beck Depression Inventory. All participants were fluent in Japanese, right-handed as determined by the Edinburgh Handedness Inventory (Oldfield, 1971), and had normal or corrected-to-normal visual acuity. The study protocol was approved by the Ethics Committee of the Hiroshima University School of Medicine. All participants provided informed written consent. Six participants were excluded from the fMRI analyses due to either excessive movement artifacts (i.e., greater than 3 mm) or because they scored more than 20 on the BDI, and therefore were considered to have high levels of depression. The remaining 15 participants (7 males, 8 females; mean age = 23.3 years, SD = 2.7 years; mean BDI score = 5.54, SD = 4.2) were included in the study. 2.2. Stimuli Stimuli were selected from Anderson’s list of personality-trait words (Anderson, 1968) translated into Japanese by four judges (one of the authors and three graduate students). Fifty-seven university students (18 males, 39 females) rated the emotional valence and familiarity of the translated words. The rating scales went from 1 (negative or unfamiliar) to 7 (positive or familiar). Two hundred and eight trait words were selected that were within

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1.5 SD of the mean value for familiarity (mean value = 5.02, SD = 1.02). Hundred and sixty words were used in judgment tasks; these were the top 80 positive words and the bottom 80 negative words. Each word was presented only once during the judgment tasks, and each word was randomly assigned to each condition for each participant. Each participant viewed the words in random order. For the recognition task performed after the judgment tasks, the remaining 48 of the 208 words were used as distractors randomly presented with the 160 words used in judgment tasks. Stimuli were generated using a personal computer with Presentation software (Neurobehavioral Systems, Inc.; San Francisco, CA). Using an angled mirror, participants viewed the stimuli on a back projection screen mounted outside the scanner bore. 2.3. Experimental design The fMRI scans were performed while participants did the judgment tasks. Each participant did all the tasks in a factorial design with two factors. The first factor was type of judgment. Participants were instructed to make one of four judgments about the presented words. In the self-reference condition, participants judged whether or not each trait word described themselves. In the other-reference condition, participants judged whether or not each trait word described the Prime Minister of Japan, Jun-ichiro Koizumi. In the semantic-processing condition, participants judged whether or not it was difficult to define each trait word. In the letter-processing condition, participants judged whether or not each trait word contained a specific target letter. The semantic-processing and letter-processing conditions were used to control for extraneous variables such as the visual and motor processing of stimuli, and language processing. The second factor was type of word stimuli: positive or negative emotional valence. The four judgment conditions each included both positive and negative-word stimuli, resulting in eight conditions. For all conditions, participants made a ‘‘yes” or ‘‘no” response by pressing a button with the right-hand index or middle finger, respectively, to indicate their decision. Button presses were recorded using an MRI-compatible keypad (Lumitouch, Lightwave Technologies; Richmond, BC, Canada). Participants were not asked to remember the words. Participants performed each condition four times. At the onset of each condition, a fixation cross was displayed for 1000 ms followed by an instruction cue presented for 3000 ms (e.g., ‘‘self-reference condition”). Then there were five trials consisting of a fixation cross displayed for 1000 ms followed by an adjective displayed for 3000 ms and the participant’s response. Next a fixation point was displayed for 4000 ms, and then the instruction cue was presented for the next block of five trials. Each condition contained four blocks. The duration of each block was 28 s. To control for order effects, blocks within a run were presented in pseudo-random order, with no two consecutive blocks with the same instructions. The total time for our self-reference task was 896 s. Both responses and reaction times were recorded using Presentation software. Outside of the scanner, participants were immediately given an unexpected recognition task. Participants were instructed to discriminate between words presented (n = 160) or not presented (n = 48) in the earlier judgment task. Words were presented in random order on the back projection screen, used in the previous task. Participants responded ‘‘yes” (presented) or ‘‘no” (not presented) with the right-hand index or middle finger button press, as in the previous task. Responses and reaction times were recorded. 2.4. Functional imaging The fMRI was performed using a Magnex Eclipse 1.5 T Power Drive 250 MR scanner (Shimazu Medical Systems; Kyoto, Japan).

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A time series of 227 scans (the first three scans were discarded because the MR signal had not reached steady state, and a total of 224 scans were analyzed) was acquired with a T2*-weighted, gradient echo, echo planar imaging (EPI) sequence. Each volume consisted of 38 slices, with a slice thickness of 4 mm with no gap, and covered the entire cerebral and cerebellar cortices. The interval between two successive acquisitions of the same image (TR) was 4000 ms, the echo time (TE) was 55 ms, and the flip angle was 90°. The field of view (FOV) was 256 mm, and the matrix size was 64  64, giving voxel dimensions of 4  4  4 mm. Scan acquisition was synchronized to the onset of the trial. After fMRI, structural scans were acquired using a Tl-weighted gradient echo pulse sequence (TR = 12 ms; TE = 4.5 ms; flip angle = 20°; FOV = 256 mm; voxel dimensions of 2  2  2 mm) for anatomical registration of the fMRI data. 2.5. Statistical analysis Image processing and statistical analyses were carried out using Statistical Parametric Mapping (SPM2) software (Wellcome Department of Cognitive Neurology; London, UK). The first three volumes of each fMRI run were discarded because the MR signal had not reached steady state. All EPI images were spatially registered to the Montreal Neurological Institute (MNI) T1 template for group analysis. Imaging data were corrected for motion and smoothed with an 8-mm full-width, half-maximum Gaussian filter. A general linear model analysis was then used to create contrast images for each participant, summarizing differences between conditions. Using a group analysis according to a random effects model, we identified regions that exhibited significant responses (to reduce the probability of accepting false positives, we report only those clusters that reached a p < .001 uncorrected voxel level, and a p < .05 corrected cluster level, following Ueda et al. (2003) and Miceli et al. (2002)) during (1) the self-reference condition compared to the semantic-processing condition; (2) the self-reference condition compared to the other-referential condition; and (3) the other-reference condition compared to the semantic-processing condition. These three contrasts were performed for both positive and negative valence words. We performed a small volume correction for the amygdala (p < .05 corrected for multiple comparisons), because we hypothesized that the amygdala would play an important role in emotional processing during the self-reference processing based on previous studies (Siegle et al., 2002, 2006). The spatial coordinates provided by SPM2, which are in MNI brain space, were converted to spatial coordinates of Talairach and Tournoux’s brain space (Talairach & Tournoux, 1988). Labels for brain activation foci were obtained in Talairach coordinates using Talairach Deamon software (Lancaster et al., 2000). The areas identified as labeled areas by this software were then confirmed by comparison with activation maps overlaid on MNI-normalized structural MRI images.

3. Results 3.1. Behavioral results Table 1 shows the mean reaction times for responses in each condition for the positive and negative emotional valence words. A repeated-measures ANOVA with judgment condition (self-reference, other-reference, semantic, letter) and valence (positive, negative) as the within-participant factors showed a main effect of condition (F(3, 12) = 37.62, p < .001, e = 0.79). Post hoc analyses showed that the mean reaction time for the letter-processing condition was shorter than for the other conditions (all p < .001). Be-

Table 1 Reaction time and recognition memory accuracy for self-referential, other-referential, and semantic processing of positive and negative words (N = 15) Condition and emotional valence of words presented to participants

Reaction time (ms)

Proportion of correct recognition (hit rate false alarm rate)

Mean

SD

Mean

SD

Self-reference condition Positive Negative

1530.1 1517.0

255.6 262.4

0.68 0.57

0.15 0.19

Other-reference condition Positive Negative

1560.6 1558.6

259.9 233.2

0.46 0.43

0.17 0.22

Semantic-processing condition Positive Negative

1615.8 1673.1

190.7 163.0

0.53 0.50

0.13 0.18

Letter-processing condition Positive Negative

1065.5 1117.7

173.5 155.3

— —

— —

cause differences in reaction times between conditions may be responsible for detectable differences in brain activity, the letterprocessing condition was deemed unsuitable as a control condition, and was excluded from further analyses. The mean recognition accuracy, expressed as the hit rate minus the false alarm rate (HR-FA), for each trial type is shown in Table 1. A repeated-measures ANOVA with judgment condition (self-reference, other-reference, semantic) and valence (positive, negative) as within-participant factors and (HR-FA) as the dependent variable yielded significant main effects of both condition (F(2, 13) = 15.59, p < .001, e = 0.89), and valence (F(1, 14) = 4.71, p < .05, e = 1). Recognition accuracy was significantly higher for words judged in the self-reference condition than for those judged in the semantic-processing condition (p < .05). Words judged in the self-reference condition were better recognized than words judged in the other-reference condition (p < .001). In addition, positive words were better recognized than negative words regardless of judgment condition (p < .05). 3.2. fMRI results: Analysis without valence Brain regions exhibiting activity associated with self-referential processing and other-referential processing, irrespective of word valence, are summarized in Table 2. The self-reference vs. semantic contrast included the bilateral medial prefrontal gyrus (BA 9, 10, and 11), left superior frontal gyrus (BA 9), left superior temporal gyrus (BA 22), bilateral middle temporal gyrus (BA 21), bilateral inferior temporal gyrus (BA 21), right anterior cingulate gyrus (BA 24 and 32), and bilateral precuneus (BA 7 and 31). The other-reference vs. semantic contrast included the right medial frontal gyrus (BA 9 and 11), right superior frontal gyrus (BA 9), bilateral superior temporal gyrus (BA 22 and 38), bilateral middle temporal gyrus (BA 21 and 39), right inferior temporal gyrus (BA 21), bilateral cingulate gyrus (BA 31), right posterior cingulate gyrus (BA 33), and left precuneus (BA 19). The self-reference vs. other-reference contrast exhibited only left parahippocampal gyrus activity (x = 18, y = 20, z = 14 mm). The other-reference vs. self-reference contrast included the right middle temporal gyrus (BA 39) and right precuneus (BA 19). 3.3. fMRI Results: Analysis of judgment and valence Brain regions exhibiting activity associated with the interaction between judgment condition and valence are summarized

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S. Yoshimura et al. / Brain and Cognition 69 (2009) 218–225 Table 2 Brain regions exhibiting significant activity during self- and other-referential processing of emotional words Condition, area

BA

Side

794

7 31

L L R

7.67 5.99 7.04

8 8 8

52 61 49

41 23 28

Medial prefrontal gyrus Anterior cingulate gyrus

401

11 24 32

L R R

6.63 6.13 5.56

4 2 6

44 37 36

12 2 10

Medial prefrontal gyrus Superior frontal gyrus

368

9 9

R L

6.73 6.3

4 2

55 52

16 29

Middle temporal gyrus Inferior temporal gyrus

298 21

L L

5.46 6.75

55 57

5 10

24 18

Middle temporal gyrus Inferior temporal gyrus

223

21 21

R R

6.37 4.76

51 59

3 8

25 13

Superior temporal gyrus

180

22

L

6.62

59

55

19

Other-reference condition Cingulate gyrus

1823

31

8.35 11.16 9.02

12 6 10

55 43 47

29 28 23

Self-reference condition Precuneus

Cluster extent

t-score

x

y

z

33

L R R

Superior temporal gyrus Middle temporal gyrus

646

38 21

L L

7.5 9.45

44 57

23 1

33 22

Precuneus Middle temporal gyrus

425

19 39

L L

7.87 7.03

40 50

72 67

40 25

Superior temporal gyrus Middle temporal gyrus

319

22 39

R R

4.48 9.86

53 53

58 65

14 24

Middle temporal gyrus Inferior temporal gyrus

268

21 21

R R

6.65 5.96

53 61

12 5

16 15

Medial frontal gyrus

224

11 9

R R

6.11 4.76

4 8

55 58

17 27

Medial frontal gyrus

135

9

R

6.74

2

42

14

Self-reference vs. other-reference Parahippocampal gyrus

131

L

5.79

18

20

14

R R

5.09 6.56

50 42

65 70

24 37

Posterior cingulate gyrus

Other-reference vs. self-reference Middle temporal gyrus Precuneus

117

39 19

in Table 3. The self-reference/positive vs. semantic/positive contrast (Fig. 1a) included the right medial prefrontal gyrus (BA 10), right posterior cingulate gyrus (BA 31), left precuneus (BAs 7 and 31), and left amygdala (x = 24, y = 1, z = 15 mm). The self-reference/negative vs. semantic/negative contrast (Fig. 1b) included the left medial frontal gyrus (BA 10 and 11), left superior temporal gyrus (BA 22), bilateral middle temporal gyrus (BA 21), left inferior temporal gyrus (BA 20), right anterior cingulate gyrus (BA 24), right posterior cingulate gyrus (BA 23), left precuneus (BA 7 and 31), and right amygdala (x = 24, y = 10, z = 11 mm). The other-reference/positive vs. semantic/ positive contrast included the right medial prefrontal gyrus (BA 10), right superior frontal gyrus (BA 9), bilateral superior temporal gyrus (BA 38 and 39), bilateral middle temporal gyrus (BA 21 and 39), right cingulate gyrus (BA 31), right posterior cingulate gyrus (BA 30), and bilateral precuneus (BAs 7 and 19). The other-reference/negative vs. semantic/negative contrast included the bilateral middle temporal gyrus (BAs 21 and 39), left inferior temporal gyrus (BA 21), and bilateral precuneus (BA 31). The self-reference/positive vs. other-reference/positive contrast showed no significantly activated brain regions. The selfreference/negative vs. other-reference/negative contrast (Fig. 1c) revealed activation in the right anterior cingulate gyrus (BA 24).

4. Discussion The primary purpose of the present study was to identify brain regions associated with self-referential processing of positive and negative valence trait words. Because we used a semantic-processing condition to control for brain activity concerned with self-referential processing without semantic processing. Several studies (Fossati et al., 2004; Symons & Johnson, 1997) have showed that the self-reference effect involves processes both at the encoding and retrieval phase. Our behavioral results showed that recognition accuracy in self-reference condition was higher than in the other conditions. This result is consistent with a number of behavioral studies that have demonstrated a self-reference superiority effect in memory at the retrieval phase. The results can be attributed to the self-reference effect, thereby replicating Rogers et al. (1977) (Table 1). The main findings are that self-referential processing of negative trait words was associated with activity within the right ventral anterior cingulate gyrus and the right amygdala. In the selfreference/negative condition, activity was observed in the left ventral medial prefrontal gyrus (BA 11) and the right ventral anterior cingulate gyrus (BA 24), suggesting these regions play an important role in self-referential processing of negative stimuli. The medial prefrontal region is associated with emotional cognitive processing. Several studies suggest that the ventral medial prefron-

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Table 3 Brain regions exhibiting significant activity associated with the interaction of processing condition (self-reference, other-reference, semantic) and valence of emotional stimuli (positive, negative) Condition/emotion, area

BA

Side

t-score

447

31 7 31

R L L

6.55 4.51 7.07

8 4 4

54 58 47

25 43 30

300

10

R L

6.37 7.28

2 24

55 1

17 15

605

7 31 23

L L R

6.57 8.25 6.88

8 8 8

54 61 47

40 21 24

Superior temporal gyrus Middle temporal gyrus Inferior temporal gyrus

538

22 21 20

L L L

6.09 6.61 6.45

42 51 51

24 16 9

6 9 20

Anterior cingulate cortex Medial prefrontal gyrus

503

24 10 11

R L L

7.72 6.58 6.95

2 0 4

35 51 42

2 12 12

Middle temporal gyrus Amygdala*

147

21

R R

4.92 5.69

53 24

14 10

13 11

1157

30 31 7

R R R

8.66 8.62 5.92

10 2 6

47 45 60

23 32 36

Middle temporal gyrus

292

21

L

9.27

58

1

22

Superior temporal gyrus Middle temporal gyrus

291

38 21

R R

6.61 5.10

48 56

18 12

29 18

Medial prefrontal gyrus Superior frontal gyrus

240

10 9

R R

4.90 4.88

2 6

59 58

17 28

Self/positive vs. semantic/positive Posterior cingulate gyrus Precuneus Medial prefrontal gyrus Amygdala* Self/negative vs. semantic/negative Precuneus

Cluster extent

Posterior cingulate cortex

Other/positive vs. semantic/positive Posterior cingulate gyrus Cingulate gyrus Precuneus

x

y

z

Middle temporal gyrus

183

39

R

6.80

44

63

22

Precuneus Superior temporal gyrus

167

19 39

L L

5.34 4.43

40 50

74 57

37 23

Superior temporal gyrus

122

38

L

7.13

44

14

30

1137

31

L R

8.15 7.97

12 10

53 47

30 30

389

21 21

L L

7.84 6.87

55 63

5 12

25 16

Other/negative vs. semantic/negative Precuneus Middle temporal gyrus Inferior temporal gyrus Middle temporal gyrus

172

39

R

7.51

53

65

25

Middle temporal gyrus

141

39

L

7.20

51

63

29

135

24

R

6.78

2

23

3

Self/positive vs. other/positive No significant activity Self/negative vs. other/negative Anterior cingulate cortex *

A small volume correction was performed for the amygdala (p < .05).

tal region is related to general emotional processing and evaluative judgment (Damasio et al., 2000; Elliott et al., 2002; Gusnard et al., 2001; Zysset, Huber, Ferstl, & von Cramon, 2002). Anatomical studies have revealed that the anterior cingulate gyrus has neural connections to the prefrontal gyrus and is divided into dorsal cognitive and ventral affective regions (Bush, Luu, & Posner, 2000). The ventral affective division is connected to the amygdala, hippocampus, orbitofrontal cortex, and insula, and has outflow to sub-cortical autonomic visceromotor systems. This ventral affective division has been shown to be activated by induced negative mood or processing of negative emotions (Habel, Klein, Kellermann, Shah, & Schneider, 2005; Mayberg et al., 1999; Phan, Wager, Taylor, & Liberzon, 2002). Thus, the ventral affective division evaluates the importance of emotional information and regulates emotional response. Hence, the ventral medial prefrontal gyrus and the ventral

anterior cingulate gyrus were considered to underlay self-referential processing in the emotional domain (Northoff et al., 2006) (see Fig. 2). Our results showed significant activity in the left amygdala for the self-reference/positive condition and in the right amygdala for the self-reference/negative condition (see Fig. 3). Some studies have suggested that the amygdala is involved in the processing of negative emotions (Phan et al., 2002, 2004; Siegle et al., 2002, 2006), whereas other studies have reported that the amygdala is activated during the processing of positive emotions (Canli, Sivers, Whitfield, Gotlib, & Gabrieli, 2002; Tabert et al., 2001; Williams, Morris, McGlone, Abbott, & Mattingley, 2004). Our results show that the amygdala is associated with self-referential processing of both negative and positive emotional stimuli. Functional differences between the left and right amygdala

S. Yoshimura et al. / Brain and Cognition 69 (2009) 218–225

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Fig. 1. Statistical activation maps for each conditions (N = 15). Picture (a) shows the activated regions during self-referential processing, compared with semantic processing. Picture (b) shows the activated regions during self-referential processing of positive words compared with semantic processing of positive words. Picture (c) shows the activated regions during self-referential processing of negative words compared with semantic processing of negative words. Picture (d) shows the activated regions during other-referential processing compared with semantic processing. Picture (e) is the activated regions during other-referential processing of positive words compared with semantic processing of positive words. Picture (f) is the activated regions during other-referential processing of negative words compared with semantic processing of negative words. All regions are displayed at p < .001 uncorrected at voxel level and p < .05 corrected at cluster level.

Fig. 2. Statistical parametric maps of brain regions showing significant increases in activity associated with self-referential processing compared to semantic processing of (a) positive and (b) negative words, and (c) self-referential processing compared to other-referential processing of negative words (p < .001, uncorrected, at the single voxel level and p < .05, corrected, at the cluster level). Clusters of activity are overlaid on T1-weighted anatomical images. In (a), the blue-cross line indicates the right medial prefrontal gyrus and the white arrow indicates the right precuneus. In (b), the blue-cross line indicates the left medial prefrontal gyrus, the white arrow indicates the left precuneus, and the green arrow indicates the left medial prefrontal gyrus (ventral area) and the right anterior cingulate cortex (ventral area). In (c), the blue-cross line indicates the right anterior cingulate cortex (ventral area).

during self-reference/positive and self-reference/negative processing were unclear. However, studies have suggested that the right amygdala responds to unanticipated or unconscious processing of emotional stimuli (Morris, Ohman, & Dolan, 1998; Phelps et al., 2001; Zald, 2003). In addition, the temporal gyrus has neural connections to the amygdala (Goldin et al., 2005), which may enhance the processing of negative trait words during emotional episodic memory retrieval. Activity in the parahippocampal gyrus (x = 18, y = 24, z = 14) was found in the self versus other condition. Gardini, Cornoldi, De Beni, and Venneri (2006) found activity in the parahippocampal gyrus during the retrieval of autobiographical memory. This result means that

self-referential processing might be associated with the retrieval of autobiographical memory. In the self versus semantic contrast, however, tactivation of the parahippocampal gyrus was not found, and we thus considere it difficult to conclude that activation of the parahippocampal gyrus is associated with autobiographical memory retrieval in self-referential processing. Our findings of activity in the medial prefrontal gyrus, temporal gyrus, precuneus, and posterior cingulate gyrus associated with self-referential processing are similar to Fossati et al. (2003). These regions are associated with emotion-related cognitive processing such as self-referential processing, self-generated emotional feelings, autobiographical memory, and evaluative judgment (Damasio

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References

Fig. 3. The activation of the left amygdala (a) in the self-positive vs. semanticpositive condition and the right amygdala (b) in the self-negative vs. semanticnegative condition (figure threshold was small volume correction FWE corrected p < .05).

et al., 2000; Elliott et al., 2002; Gusnard et al., 2001; Markowitsch, Vandekerckhove, Lanfermann, & Russ, 2003; Zysset et al., 2002). In our study, however, self-referential and other-referential processing exhibited similar levels of activity within the medial prefrontal gyrus, temporal gyrus and precuneus. In addition, the self-reference vs. other-reference contrast did not reveal activity within these regions. Kelley et al. (2002) also found that other-referential processing activates the medial prefrontal gyrus. Gillihan and Farah (2005) suggest that it is difficult to conclude that special processing underlies self-referential processing due to methodological problems in studies, such as different manipulations of conditions. Therefore, our findings of brain activation associated with self-referential processing may not solely be due to the self-reference effect, or indicate that self-reference and other-reference includes similar emotional processing. Activations of the medial prefrontal gyrus and precuneus were found in the self vs. semantic contrast across both positive and negative valences. In addition, activations of the middle temporal gyrus and precunes in the other vs. semantic contrast also occurred across positive and negative valences. Regrettably, it was unclear whether the activations in these regions were due to a main effect of self- and other-reference or to an interaction of self-reference and valence, because we did not perform an ANOVA. A final limitation in the fMRI results stems from the lack of use neutral stimuli during the self-reference task. As a result of this it is unclear that the results are specific to self-referential processing of emotional stimuli. In conclusion, this study examined brain activity associated with self-referential processing, using a control condition different from that used by Fossati et al. (2003, 2004). Our findings provide support for the involvement of different brain regions during selfreferential processing of emotional information. Positive words processed in the self-reference condition were associated with activity in the right medial prefrontal gyrus and left amygdala; negative words processed in the self-reference condition were associated with activity in the left ventral medial prefrontal gyrus, bilateral ventral anterior cingulate gyrus, and right amygdala. We found that the medial prefrontal gyrus is involved not only during self-referential processing, but also during other-referential processing. This result suggests that self-reference and other-reference involve similar emotional processing. Our findings are also consistent with other research demonstrating that dysfunction of the medial prefrontal gyrus, ventral anterior cingulate gyrus, and amygdala is related to the bias of emotional processing in depression (Mayberg, 2003).

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