- Email: [email protected]
Reciprocal activation of the orbitofrontal cortex and the ventrolateral prefrontal cortex in processing ambivalent stimuli
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –14 3
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Research Report
Reciprocal activation of the orbitofrontal cortex and the ventrolateral prefrontal cortex in processing ambivalent stimuli Young-Chul Jung a,b , Hae-Jeong Park c,d , Jae-Jin Kim a,b,c,⁎, Ji Won Chun b,c , Hye Sun Kim b , Nam Wook Kim a , Sang Jun Son a , Maeng-Gun Oh d , Jong Doo Lee c,d a
Department of Psychiatry, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemeun-gu, Seoul 120-752, Republic of Korea Institute of Behavioral Science in Medicine, Severance Mental Health Hospital, Yonsei University College of Medicine, 696-6 Tanbul-dong, Gwangju-si, Gyeonggi-do 464-100, Republic of Korea c Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemeun-gu, Seoul 120-752, Republic of Korea d Department of Diagnostic Radiology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemeun-gu, Seoul 120-752, Republic of Korea b
A R T I C LE I N FO
AB S T R A C T
Article history:
The neural basis of ambivalence has not yet been identified. We investigated the prefrontal
Accepted 24 September 2008
cortical activations implicated in evaluative processing of ambivalent stimuli under the
Available online 11 October 2008
forced and non-forced response conditions. Cerebral blood flow was measured using H15 2 O positron emission tomography in twelve normal volunteers during a modified word-stem
Keywords:
completion task that was designed to evoke different conditions of ambivalence. The
Ambivalence
prefrontal cortical activations were restricted to the orbitofrontal cortex during the non-
Evaluative processing
forced ambivalent condition, whereas the ventrolateral prefrontal cortex and the
Orbitofrontal cortex
frontopolar cortex were activated in addition to the orbitofrontal cortex during the forced
Ventrolateral prefrontal cortex
ambivalent condition. It is remarkable that the orbitofrontal cortex and the ventrolateral prefrontal cortex demonstrated a reciprocal activation pattern, which might be linked to the evaluative attitude toward the ambivalent stimuli. © 2008 Elsevier B.V. All rights reserved.
1.
Introduction
Ambivalence is defined as a state of simultaneous and antithetical emotional tone and action tendency (Raulin and Brenner, 1993). It happens to be the underlying cause of everyday dilemmas and contributes to apparent inconsistency and hesitation (Billig et al., 1988). Despite there being a long history of conceptual issues of ambivalence, empirical
research has remained limited and no meaningful construct has been fully elaborated because of the problems inherent in measuring ambivalence. Traditionally, ambivalence has been investigated by assessing the subjective feeling of ambivalence through self-reporting measures or combining separately measured positive and negative evaluations. However, correlations between subjectively reported ambivalence and conflicting evaluations have not been clearly identified
⁎ Corresponding author. Department of Psychiatry, Yongdong Severance Hospital, 612 Eonjuro, Gangnam-gu, Seoul 135-720, Republic of Korea. Fax: +2 3462 4304. E-mail address: [email protected] (J.-J. Kim). 0006-8993/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2008.09.081
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –1 43
(Priester and Petty, 2001; Newby-Clark et al., 2002). Considering this issue, Albertson et al. (2004) insisted that the simultaneous presence of positive and negative evaluations does not connote subjective ambivalence, in that contradictory evaluations can be held separately and thus a state of mind, which creates difficulty in evaluating the object, should be required for ambivalence. Little is known of the brain activity involved in the evaluative processing of ambivalent stimuli. Growing evidence suggests that the prefrontal cortex underlies conscious, controlled evaluative processes that are sensitive to the complexity of information, whereas the amygdala is assumed to be involved in nonconscious, automatic evaluative processes (Nomura et al., 2004; Dolcos et al., 2004). Although positive and negative evaluation are separable and can occur simultaneously, physical constraints generally restrict behavioral manifestations to bivalent actions (approach or avoidance) (Cacioppo et al., 1999). In this context, a recent neuroimaging study proposed that ambivalence is a state that arises during prefrontal cortical processing, which should be necessary to arrive at an evaluative judgment of complex emotional information (Cunningham et al., 2003, 2004). Meanwhile, previous studies
137
(Keightley et al, 2003) have indicated that brain activity during processing of emotional content was dependent on not only the type of stimuli but also the manner in which the stimuli are processed. These findings indicate that the role of the prefrontal cortex in processing ambivalent stimuli might be affected by the response condition. The purpose of this study was to investigate the functional organization of the prefrontal cortex involved in evaluative processing of ambivalent stimuli. We attempted to verify the viewpoint that the simultaneous presence of positive and negative emotional evaluation does not connote subjective ambivalence. We hypothesized that the prefrontal cortical activity involved in evaluative processing of ambivalent stimuli would be influenced by the response condition, especially when forced to make a dichotomous evaluative judgment. The forced choice conditions were designed in order to ensure that subjects made efforts to solve the contradictory emotional information and induced internalized conflict. We assumed that ambivalent stimuli would elicit different cortical activity patterns under different response conditions. To address this issue, we took advantage of the wordstem completion paradigm. The word-stem completion task
Fig. 1 – Modified word-stem completion paradigm. During the study phase, visual stimuli were presented for 2700 ms at 300 ms intervals and the subjects responded as “good” or “bad.” During the test phase, monosyllabic word stems were presented on a black background and subjects were instructed to respond according to the subjective feeling elicited when trying to complete each word-stem with a word from the preceding study phase. For an example, two different words of opposite emotional valence – “love” [sa-lang] (positive) and “death” [sa-mang] (negative) – could be recalled by the word-stem [sa]. In the forced ambivalent conditions, the subjects had to make a dichotomous choice between only “good” or “bad.” In the non-forced ambivalent condition, the subject could response as “good,” “bad,” or “neither good nor bad.”
138
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –14 3
Table 1 – Behavioral measures according to block conditions Condition
Response percentage (%) Missing
Good
Bad
Univalent Positive stimulus Negative stimulus
0.6 ± 1.4 0 ± 0.0
99.4 ± 1.5 b 0.3 ± 1.2
0.0 ± 1.0 99.7 ± 1.2 b
Non-forced ambivalent Positive stimulus Negative stimulus Ambivalent stimulus
1.3 ± 4.4 1.3 ± 3.0 1.0 ± 1.9
93.6 ± 10.8 b 6.4 ± 11.3 15.3 ± 23.7
1.3 ± 4.4 90.4 ± 18.0 b 6.3 ± 12.8
Forced ambivalent Positive stimulus Negative stimulus Ambivalent stimulus
0.7 ± 2.4 0.0 ± 0.0 0.7 ± 1.6
99.3 ± 2.4 b 3.8 ± 6.1 61.3 ± 16.0 b
0.0 ± 0.0 96.2 ± 6.1 b 35.3 ± 16.7
Compromise
a
Reaction time (ms) 787.5 ± 78.2 794.3 ± 87.3 780.1 ± 103.6
3.8 ± 7.7 1.9 ± 6.7 77.4 ± 36.8 b
1102.2 ± 234.0 c 1036.4 ± 275.9 971.7 ± 282.7 1207.6 ± 255.5 996.6 ± 232.2 c 898.6 ± 248.6 891.1 ± 197.8 1107.3 ± 264.4
a
The compromise response (“neither good nor bad”) was allowed only in non-forced ambivalent blocks. Analysis of variance revealed a significant effect of stimulus valence on the mean response percentage. c Analysis of variance revealed a significant difference of reaction time between conditions (p < 0.001). Post-hoc analysis revealed a significant difference between the univalent and non-forced ambivalent conditions (p < 0.001), and between the univalent and forced ambivalent conditions (p = 0.045). However, there was no significant difference between the non-forced ambivalent and forced ambivalent conditions (p = 0.118). b
was primarily regarded as an example of perceptual priming. However, several component processes can be manipulated by varying the instructions (Henson, 2003). We modified the task by defining three conditions — univalent (U), non-forced ambivalent (nFA) and forced ambivalent (FA) (Fig. 1). Meanwhile, previous studies have deliberated the problem of how to segregate affective processes from cognitive processes associated with emotion induction methods, which are confounding factors (Phan et al., 2002; Grim et al., 2006). Cognitive processes associated with the word-stem completion task – retrieving and maintaining words from the study phase – have been well-studied (Buckner et al., 1995) and were taken into consideration in interpreting our findings.
2.
Results
2.1.
Behavioral observation
The mean percentages of responses in each condition are summarized in Table 1. It is remarkable that the response pattern toward ambivalent word stems differed according to the response condition. During the nFA conditions, the compromise response (“neither good nor bad”) was the major response (77.4%). In contrast, during FA condition blocks, in which a dichotomous choice was forced, the subjects preferred to respond as “good” (61.3%) rather than “bad” (35.3%) to the ambivalent word stem (p < 0.001).
Fig. 2 – Correlation between the delayed reaction time and the orbitofrontal activations. The regions of interest corresponded to the clusters of significant contiguous vowels identified in the contrast nFA > U. The mean reaction time (a) was prolonged in both the non-forced (nFA) and forced ambivalent (FA) conditions in contrast to the univalent (U) conditions (nFA: p < 0.001; FA: p = 0.045). There was a significant correlation between the delayed reaction time and the orbitofrontal activations in both the non-forced ambivalent condition (Pearson correlation coefficient = 0.686, p = 0.014) and the forced ambivalent condition (Pearson correlation coefficient = 0.760, p = 0.004).
139
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –1 43
Table 2 – Response condition effect on ambivalent stimuli-related brain activities a Region
Non-forced ambivalent > univalent Orbitofrontal cortex Medial dorsal thalamus Cerebellum Cerebellum (vermis) Forced ambivalent > univalent Orbitofrontal cortex Frontopolar cortex Ventrolateral prefrontal cortex Medial dorsal thalamus Cerebellum Cerebellum (vermis) Forced ambivalent > non-forced ambivalent Insular cortex Superior temporal sulcus
Brodmann area
Voxels
Right Left Left Right
11 – – –
24 94 95 64
Right Right Right Left Right Left Right
11 10 44 – – – –
651
Left Right
– 22
Z max
Coordinates x
y
z
3.32 3.59 4.42 3.59
20 −12 −52 2
50 − 22 − 58 − 72
−8 6 − 48 − 40
103 162 44 26 324
4.58 3.57 3.94 3.97 3.37 3.60 4.37
22 30 46 −14 4 −50 2
50 52 14 − 12 − 20 − 60 − 72
−8 0 14 8 6 − 50 − 40
27 45
3.44 3.54
−26 70
20 − 36
− 12 2
a The threshold of significance for the clusters was defined as exceeding an uncorrected p-level of 0.001 and containing at least 20 contiguous voxels.
The mean reaction time significantly differed between block conditions (p < 0.001) (Fig. 2). The mean reaction time of ambivalent conditions was significantly prolonged compared to the univalent condition (FA: p = 0.045; nFA: p < 0.001). However, the difference between the FA condition and nFA conditions was not significant (p = 0.118).
2.2. Response condition effect on ambivalent-related activations As summarized in Table 2, we explored the response condition effect on ambivalent stimuli-related cortical activities accord-
ing to the response instruction. The contrast nFA-minus-U (nFA > U) revealed activities in the orbitofrontal cortex, the medial dorsal thalamus, and the cerebellum. The contrast FAminus-U (FA > U) revealed activities in the orbitofrontal cortex, the frontopolar cortex, the ventrolateral prefrontal cortex, the medial dorsal thalamus, and the cerebellum. Interestingly, the prefrontal cortical activities showed laterality to the right hemisphere. In order to investigate cortical areas selectively implicated in the FA condition, we used the contrast FA-minus-nFA (FA > nFA), which revealed activities in the superior temporal sulcus and the insula.
Fig. 3 – Reciprocal activations of the ventrolateral prefrontal cortex* and the orbitofrontal cortex*. The regions of interest corresponded to the clusters of significant contiguous vowels identified in the contrast FA > U. When we estimated the mean adjusted activity change of forced ambivalent (FA) minus univalent (U) conditions, there was a reverse correlation between the ventrolateral prefrontal cortex (a) and the orbitofrontal cortex (b) (e; Pearson correlation coefficient = −0.629, p = 0.028).
140
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –14 3
2.3. Correlation between the prolonged reaction time and the orbitofrontal activities When compared to the U conditions, the mean activity change of the orbitofrontal cortex showed correlations with the prolonged reaction time in both the nFA conditions (Pearson correlation coefficient = 0.686, p = 0.014) and the FA conditions (Pearson correlation coefficient = 0.760, p = 0.004) (Fig. 2).
2.4. Reciprocal correlation between the ventrolateral prefrontal activities and the orbitofrontal activities The mean adjusted activity change of the ventrolateral prefrontal cortex and the orbitofrontal cortex showed reciprocal correlation in the FA conditions (Pearson correlation coefficient = − 0.629, p = 0.028) (Fig. 3).
3.
Discussion
The aim of this exploratory study was to investigate the prefrontal cortical regions that were implicated in the evaluative judgment of ambivalent stimuli. Our findings supported the hypothesis that the prefrontal cortical activations implicated in processing ambivalent stimuli would demonstrate different patterns according to the response condition. The orbitofrontal cortex was activated in ambivalent conditions, regardless of the response conditions. Correlations with reaction time provide strong evidence that the orbitofrontal cortex played a key role in evaluating processing of ambivalent stimuli. The orbitofrontal cortex has been suggested to be involved in evaluating affective valence of stimuli and mediating subjective experience (Dehaene et al., 1998; Rolls et al., 1999; Kringelbach, 2005). In addition, it has been reported that the orbitofrontal cortex is more activated when there is insufficient information available to determine the appropriate response (Elliott et al., 2000). Considering that the medial dorsal thalamus has pronounced connections with the orbitofrontal cortex (Ongür and Price, 2000), it would be more reasonable to assume that the orbitofrontal cortex, together with the medial dorsal thalamus and the cerebellum, were recruited as a functional circuit rather than a single region in order to make evaluative judgments in the ambivalent conditions. As we hypothesized, the prefrontal cortical activities were restricted to the orbitofrontal region during the nFA condition, whereas the ventrolateral prefrontal cortex and the frontopolar cortex were activated in addition to the orbitofrontal cortex during the FA condition. The right ventrolateral prefrontal cortex is implicated in control processes while making explicit judgments, including cognitive control of emotional intensity (Petrides et al., 2002; Ochsner et al., 2002; Grim et al., 2006). Consistent with our findings, the ventrolateral prefrontal cortex has been proposed to be associated with control processes in order to provide more accurate judgments in ambivalent situations (Cunningham et al., 2004). In addition, the frontopolar cortex is also implicated in explicit processing of internal mental states (Christoff and Gabrieli, 2000). Taken together, the activations of the ventrolateral prefrontal cortex and the frontopolar cortex seem to reflect the high-level
cognitive control required to make a dichotomous evaluative judgment during the FA condition. It is also noteworthy that the ventrolateral prefrontal cortex and the frontopolar cortex demonstrated lateralization to the right hemisphere. There are mixed findings on right hemisphere dominance in emotion processing and some studies have proposed that the regional activations might differ according to the emotional valence (Wager et al., 2003). However, our findings support that the right hemisphere is predominantly involved in processing emotional stimuli with ambivalence. Although both the frontopolar–orbitofrontal cortex and the ventrolateral prefrontal cortex were implicated in explicit processing of ambivalent stimuli, it is remarkable that these two regions demonstrated a reciprocal activation pattern. There is a growing interest in understanding the functional specialization of the prefrontal cortex, and converging evidence supports the dissociable pattern between the role of the orbitofrontal cortex in affectively laden “hot” processes and the lateral prefrontal cortex in purely “cool” cognitive processes (Zelazo and Muller, 2002; Krain et al., 2006). From this perspective, it is possible to suggest that the orbitofrontal cortex and the ventrolateral prefrontal cortex played complementary roles in the evaluative judgment of ambivalent stimuli, and that the activation pattern was largely attributed to the evaluative attitude toward ambivalent stimuli. However, the statistical power of our correlation analysis is limited due to the small sample size, and further replication and elaboration should follow. The contrast of the FA condition-minus-nFA condition revealed activations in the insular cortex. The insula has been linked to the assessment of emotionally aversive states (Phillips et al., 1998) and emotional distress with action planning in order to avoid aversive stimuli (Paulus et al., 2003; Simmons et al., 2006). Recently, connections with the limbic structures and the orbitofrontal areas have been proposed to subserve the role of the insula as a critical structure for the integration of emotion and behavior (Dupont et al., 2003; Reynold and Zahm, 2005). As mentioned above, it would be feasible to assume that the insula has been implicated in evaluative processing through bidirectional connections with the orbitofrontal cortex. On the other hand, considering that the simultaneous existence of conflicting emotions toward an object might be better characterized as a bittersweet feeling (Albertson et al., 2004), the insular activations might reflect the emotional distress induced by the FA condition. The response percentages give further accounts of the role of the cortical activities in evaluating processing of ambivalent stimuli. It is noteworthy that subjects preferred to assign positive rather than negative valence to ambivalent wordstem cues when dichotomous responses were forced. One plausible explanation concerning this finding is the positivity offset. The positivity offset refers to a tendency for the positive affective system to respond more than the negative affective system when evaluative input is weak or absent (Cacioppo et al., 1999). It should be stressed that we induced emotion indirectly by retrieving emotional words and pictures rather than directly presenting them and thus the substantial emotional input was initially weak. Therefore, when subjects tried to make evaluative judgments according to subjective
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –1 43
feelings, the behavioral responses probably followed a pattern of the positivity offset. Within this context, our findings might be associated with previous studies that have proposed that the orbitofrontal cortex is a part of the baseline default mode of the human brain (Gusnard et al., 2001; Kringelbach, 2005). On the other hand, these findings complement our previous study (Jung et al., 2006), in which emotion was induced by directly presenting emotional words or pictures and thus subjects' responses followed a negativity bias pattern, i.e., subjects preferred to assign negative valence when positive and negative emotional inputs were strong. The results of this study must be addressed within the context of several considerations. First, many Korean word stems are derived from Chinese, and we could not rule out the possibility that subjects might have well-established connotations attached to certain word stems based on their natural occurrence or self-containing Chinese meaning. We tried to minimize these effects by repeating the target words continuously during the preceding study phase in order to manipulate the immediate emotional context of our word stems. Second, the mean reaction time was more prolonged in the nFA condition than the FA condition although it fell short of statistical significance. The prolonged reaction time did not represent simply the internalized conflict induced by contradictory information but also the elaborative processes due to an additional response option. Third, the key to the validity of our study lies in the fact that images were obtained using a positron emission tomography/computerized tomography scanner. In most previous functional magnetic resonance imaging (fMRI) studies without a special consideration for the orbitofrontal cortex, the characteristic activations in the region would have been prone to signal dropout and susceptible to artifacts due to its close proximity to the air-filled sinuses (Wilson et al., 2002; Deichmann et al., 2002). In conclusion, our findings demonstrated that the prefrontal regions – including the orbitofrontal cortex, the frontopolar cortex and the ventrolateral prefrontal cortex – are crucially implicated in processing ambivalent stimuli. Most of these cortical activations were recruited especially when a dichotomous evaluative judgment was required. It is remarkable that the orbitofrontal cortex and the ventrolateral prefrontal cortex demonstrated a reciprocal activation pattern, which indicates a functional dissociation of the prefrontal regions in processing ambivalent stimuli.
4.
Experimental procedures
4.1.
Participants
Twelve healthy right-handed volunteers (seven men, five women) were included in our study. The mean age and mean educational achievement was 24.8 years (SD = 2.3) and 15.5 years (SD = 1.9) respectively. All participants were screened for past or present history of medical, neurological and psychiatric illnesses during an interview using the Structured Clinical Interview for DSM-IV (First et al., 1995). After a complete description of the study was provided to participants, written informed consent was obtained. Our study was carried out under the guidelines for the use of
141
human subjects established by the Institutional Review Board of Severance Mental Health Hospital.
4.2.
Modified word-stem completion test and procedure
We modified the word-stem competition task by pairing two disyllabic words with one monosyllabic word stem. In the Korean language, the majority of nouns are disyllabic words, and it is a common occurrence for disyllabic words to share an identical monosyllabic word stem. We used 16 monosyllabic word-stems that had no semantic meaning by themselves that corresponded to 16 Korean word pairs. All disyllabic words were all chosen from the 100 emotional words frequently used in Korea (Lee, 1998). The pair of disyllabic words held either identical or antithetical emotional valence and were categorized into three groups: positive–positive word pair (e.g., “kindness [chin-jul]” and “friend [chin-gu]”), negative–negative word pair (e.g., “suffering [go-nan]” and “torture [go-mun]”), and positive–negative word pair (e.g., “love [sa-lang]” and “death [sa-mang]”). Monosyllabic word-stem cues that corresponded to a positive–positive or negative– negative word pair were referred to as a univalent positive (e.g., [chin]) or univalent negative stimulus (e.g., [go]). In contrast, monosyllabic word-stem cues that corresponded to a positive–negative word pair were referred to as an ambivalent stimulus (e.g., [sa]). The modified word-stem completion task consisted of two phases, a study phase and a test phase. In the study phase, subjects responded by pressing one of two buttons –“good” or “bad” – according to their subjective feelings. Each word was presented with an emotionally congruent background picture that was manipulated to strengthen the subjective feeling elicited by the visual stimuli. We developed the background pictures by modifying photographs from the International Affective Picture System (IAPS) (Lang et al., 1998). Each visual stimulus was presented for 2700 ms at 300-ms intervals, and this was repeated four times during the study phase. In the test phase, a monosyllabic word stem was presented on a black background and subjects were instructed to respond according to the subjective feeling elicited when trying to complete each word stem with a word from the preceding study phase. The test phase included three blocks: 1) the U condition, 2) the nFA condition and 3) the FA condition. Each block was composed of eight monosyllabic word-stem cues. The U condition was composed of four positive univalent word stems and four negative univalent word-stems. In contrast, the ambivalent conditions were composed of four ambivalent word-stems together with two positive word stems and two negative word-stems. During the nFA conditions, subjects could respond as “good,” “bad,” or “neither good nor bad.” In contrast, during the FA conditions, subjects had to make a dichotomous choice between only “good” or “bad.” Considering the FA condition, two words of contradictory valence were recalled by the ambivalent word-stem cue, and subjects had to confront an ambivalent situation. However, during the nFA condition, subjects could make use of the compromise response (“neither good nor bad”). The sequence of the blocks was randomized. Each monosyllabic word-stem cue was presented for 2700 ms at 300-ms intervals and was repeated six times. All responses were automatically transferred to a
142
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –14 3
computer file. We analyzed the behavioral data in terms of response percentage and reaction time. Before the word-stem completion test, the valence of each stimulus (disyllabic words and monosyllabic word stems) was determined by asking subjects to rate the valence on a fivepoint Likert scale: 1 (strong negative), 2 (weak negative), 3 (neutral), 4 (weak positive) and 5 (strong positive). Subjects rated 4.3 ± 0.2 for positive words and 1.5 ± 0.5 for negative words. Meanwhile, subjects assigned a weak positive valence of 3.3 ± 0.1 for monosyllabic word stems.
4.3.
Imaging data acquisition and data processing
Scans were obtained using a Philips GEMINI PET/CT scanner (Cleveland, OH, USA), which had an intrinsic resolution of 4.96 mm full width at half maximum (FWHM) and simultaneously imaged 90 contiguous transverse planes with a thickness of 2 mm for a longitudinal field of view of 18 cm. In each block, an intravenous bolus injection of about 370 MBq of [15O]H2O was given in the antecubital vein in the left forearm through an indwelling catheter. Correction for tissue attenuation was based on data from low dose computed tomography transmission measurements, performed with a 140-kV, 40-mAs/slice. List data acquisition was started at the same time that the tracer IV bolus was administered. PET data were acquired over a 120-s time period. During the test phase, four scans were acquired per subject and a 15-min interval between successive scans was used to allow radioactive levels to return to baseline. The acquired images were attenuationcorrected and reconstructed using the row-action maximum likelihood algorithm (3D-RAMLA). List-mode data were binned into sinograms, allowing frame durations to be determined after acquisition. Images were reconstructed based on a time– activity curve using 20- to 120-s intervals. Spatial preprocessing and statistical analysis were performed using Statistical Parametric Mapping 2 (Department of Neurology, University College of London, UK). All reconstructed images were realigned and transformed into a standard stereotactic anatomical space (Talairach and Tournoux, 1988) using affine and nonlinear transformation to remove participant anatomical variability. Spatially normalized images were smoothed by convolution with an isotropic Gaussian kernel with 10 mm FWHM in order to increase the signal-to-noise ratio and accommodate subtle variations in the anatomical structures.
4.4.
Statistical analysis
A voxel-based comparison of the adjusted mean activities obtained under different conditions was performed in each group using paired t-statistics. The resulting t-values were transformed into Z scores, and regions were considered to be activated when showing increased regional cerebral blood flow. First, contrasts were generated to test for voxel-wise effects of differences between blocks: a) nFA > U, b) FA > U, c) FA > nFA. The threshold of significance for the clusters was defined as exceeding an uncorrected p-level of 0.001 and containing at least 20 contiguous voxels. Second, post-hoc analysis was performed to investigate the correlation between behavioral measures and subregional mean activities. Regions
of interest corresponded to the clusters of significant contiguous voxels identified in the previous three contrasts. The adjusted mean activity (Kim et al., 2005) was calculated as the average of the estimated intensity value of all of voxels, which corresponded to the clusters of significant contiguous voxels identified in the above contrasts. The significance of the correlations was accepted when p < 0.05.
Acknowledgments This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A050495). REFERENCES
Albertson, B., Brehm, J., Alvarez, R.M., 2004. Ambivalence as experienced conflict. In: Craig, S., Martinez, M.D. (Eds.), Ambivalence and the Structure of Political Opinion. Palgrave Macmillan, New York. Billig, M., Condor, S., Edwards, D., Gane, M., Middleton, D., Radley, A., 1988. Ideological Dilemmas: A Social Psychology of Everyday Thinking. Sage, London. Buckner, R.L., Raichle, M.E., Petersen, S.E., 1995. Dissociation of human prefrontal cortical areas across different speech production tasks and gender groups. J. Neurophysiol. 74, 2163–2173. Cacioppo, J.T., Gardner, W.L., Berntson, G.G., 1999. The affect system has parallel and integrative processing components form follows function. J. Pers. Soc. Psychol. 76, 839–855. Christoff, K., Gabrieli, J.D.E., 2000. The frontopolar cortex and human cognition: evidence for a rostrocaudal hierarchical organization within the human prefrontal cortex. Psychobiology 28, 168–186. Cunningham, W.A., Johnson, M.K., Gatenby, J.C., Gore, J.C., Banaji, M.R., 2003. Neural components of social evaluation. J. Pers. Soc. Psychol. 85, 639–649. Cunningham, W.A., Raye, C.L., Johnson, M.K., 2004. Implicit and explicit evaluation: fMRI correlates of valence, emotional intensity, and control in the processing of attitudes. J. Cogn. Neurosci. 16, 1717–1729. Dehaene, S., Kerszberg, M., Changeuz, J.P., 1998. A neuronal model of global workspace in effortful cognitive tasks. Proc. Natl. Acad. Sci. U. S. A. 95, 14529–14534. Deichmann, R., Josephs, O., Hutton, C., Corfield, D.R., Turner, R., 2002. Compensation of susceptibility-induced BOLD sensitivity losses in echo-planar fMRI imaging. NeuroImage 15, 120–135. Dolcos, F., LaBar, K.S., Cabeza, R., 2004. Dissociable effects of arousal and valence on prefrontal activity indexing emotional evaluation and subsequent memory: an event-related fMRI study. NeuroImage 23, 64–74. Dupont, S., Bouilleret, V., Hasboun, D., Semah, F., Baulac, M., 2003. Functional anatomy of the insula: new insights from imaging. Surg. Radiol. Anat. 25, 113–119. Elliott, R., Dolan, R.J., Frith, C.D., 2000. Dissociable functions in the medial and lateral orbitofrontal cortex: evidence from human neuroimaging studies. Cereb. Cortex 10, 308–317. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1995. Structured Clinical Interview for DSM-IV Axis I Disorders. New York State Psychiatric Institute Biometrics Research, New York. Grim, S., Schmidt, C.F., Bermpohl, F., Heinzel, A., Dahlem, Y., Wyss, M., Hell, D., Boesiger, P., Boeker, H., Northoff, G., 2006. Segregated neural representation of distinct emotion
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –1 43
dimensions in the prefrontal cortex-an fMRI study. NeuroImage 30, 325–340. Gusnard, D.A., Raichle, M.E., Raichle, M.E., 2001. Searching for a baseline: functional imaging and the resting human brain. Nat. Rev. Neurosci. 2, 685–694. Henson, R.N.A., 2003. Neuroimaging studies of priming. Prog. Neurobiol. 70, 53–81. Jung, Y.C., An, S.K., Seok, J.H., Kim, J.S., Oh, S.J., Moon, D.H., Kim, J.J., 2006. Neural substrates associated with evaluative processing during co-activation of positivity and negativity: a PET investigation. Biol. Psychol. 73, 253–261. Keightley, M.L., Winocur, G., Graham, S.J., Mayberg, H.S., Hevenor, S.J., Grady, C.L., 2003. An fMRI study investigating cognitive modulation of brain regions associated with emotional processing of visual stimuli. Neuropsychologia 41, 585–596. Kim, J.J., Seok, J.H., Park, H.J., Lee, D.S., Lee, M.C., Kwon, J.S., 2005. Functional disconnection of the semantic networks in schizophrenia. Neuroreport 16, 355–359. Krain, A.L., Wilson, A.M., Arbuckle, R., Castellanos, F.X., Milham, M.P., 2006. Distinct neural mechanisms of risk and ambiguity: a meta-analysis of decision-making. Neuroimage 32, 477–484. Kringelbach, M.L., 2005. The human orbitofrontal cortex: linking reward to hedonic experience. Nat. Rev. Neurosci. 6, 691–702. Lang, P.J., Bradley, M.M., Cuthbert, B.N., 1998. International Affective Picture System (IAPS): Photographic Slides. Center for Research in Psychophysiology University of Florida, Gainsville. Lee, S.J., 1998. Conscious/Nonconscious processing of affective information: affective primacy effect in priming paradigm. The graduate school of Yonsei University, Seoul. Newby-Clark, I.R., McGregor, I., Zanna, M.P., 2002. Thinking and caring about cognitive inconsistency: when and for whom does attitudinal ambivalence feel uncomfortable? J. Pers. Soc. Psychol. 82, 157–166. Nomura, M., Ohira, H., Haneda, K., Iidaka, T., Sadato, N., Okada, T., Yonekura, Y., 2004. Functional association of the amygdala and ventral prefrontal cortex during cognitive evaluation of facial expressions primed by masked angry faces: an event-related fMRI study. Neuroimage 21, 352–363. Ochsner, K.N., Bunge, S.A., Gross, J.J., Gabrieli, J.D., 2002. Rethinking feelings: an fMRI study of the cognitive regulation of emotion. J. Cogn. Neurosci. 15, 1215–1229. Ongür, D., Price, J.L., 2000. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb. Cortex 10, 206–219.
143
Paulus, M.P., Rogalsky, C., Simmons, A., Feinstein, J.S., Stein, M.B., 2003. Increased activation in the right insula during risk-taking decision making is related to harm avoidance and neuroticism. Neuroimage 19, 1439–1448. Petrides, M., Alivisatos, B., Frey, S., 2002. Differential activation of the human orbital, mid-ventrolateral and mid-dorsolateral prefrontal cortex during processing of visual stimuli. Proc. Natl. Acad. Sci. U. S. A. 98, 5649–5654. Phan, K.L., Wager, T., Taylor, S.F., Liberzon, I., 2002. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 16, 331–348. Phillips, M.L., Young, A.W., Scott, S.K., Calder, A.J., Andrew, C., Giampietro, V., Williams, S.C., Bullmore, E.T., Brammer, M., Gray, J.A., 1998. Neural responses to facial and vocal expressions of fear and disgust. Proc. Biol. Sci. 265, 1809–1817. Priester, J.R., Petty, R.E., 2001. Extending the bases of subjective attitudinal ambivalence: interpersonal and intrapersonal antecedents of evaluative tension. J. Pers. Soc. Psychol. 80, 19–34. Raulin, M.L., Brenner, V., 1993. Ambivalence. In: Costello, C.G. (Ed.), Symptoms of Schizophrenia. Wiley, New York, pp. 201–226. Reynolds, S.M., Zahm, D.S., 2005. Specificity in the projections of prefrontal and insular cortex to ventral striatopallidum and the extended amygdala. J. Neurosci. 25, 11757–11767. Rolls, E.T., Crichley, H.D., Browning, A.S., Hemadi, I., Lenard, L., 1999. Responses to the sensory properties of fat of neurons in the primate orbitofrontal cortex. J. Neurosci. 19, 1532–1540. Simmons, A., Strigo, I., Matthews, S.C., Paulus, M.P., Stein, M.A., 2006. Anticipation of aversive visual stimuli in associated with increased insula activation in anxiety prone subjects. Biol. Psychiatry 60, 402–409. Talairach, J., Tournoux, P., 1988. Co-planar stereotaxic atlas of the human brain. Thieme, New York. Wager, T.D., Phan, K.L., Liberzon, I., Taylor, S.F., 2003. Valence, gender, and lateralization of functional brain anatomy in emotion: a meta-analysis of findings from neuroimaging. Neuroimage 19, 513–531. Wilson, J.L., Jenkinson, M., de Araujo, I., Kringelbach, M.L., Rolls, E.T., Jezzard, P., 2002. Fast, fully automated global and local magnetic field optimization for fMRI of the human brain. Neuroimage 17, 967–976. Zelazo, P.D., Muller, U., 2002. Executive function in typical and atypical development. In: Goswami, U. (Ed.), Handbook of Childhood Cognitive Development. Blackwell, Oxford.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Research Report
Reciprocal activation of the orbitofrontal cortex and the ventrolateral prefrontal cortex in processing ambivalent stimuli Young-Chul Jung a,b , Hae-Jeong Park c,d , Jae-Jin Kim a,b,c,⁎, Ji Won Chun b,c , Hye Sun Kim b , Nam Wook Kim a , Sang Jun Son a , Maeng-Gun Oh d , Jong Doo Lee c,d a
Department of Psychiatry, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemeun-gu, Seoul 120-752, Republic of Korea Institute of Behavioral Science in Medicine, Severance Mental Health Hospital, Yonsei University College of Medicine, 696-6 Tanbul-dong, Gwangju-si, Gyeonggi-do 464-100, Republic of Korea c Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemeun-gu, Seoul 120-752, Republic of Korea d Department of Diagnostic Radiology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemeun-gu, Seoul 120-752, Republic of Korea b
A R T I C LE I N FO
AB S T R A C T
Article history:
The neural basis of ambivalence has not yet been identified. We investigated the prefrontal
Accepted 24 September 2008
cortical activations implicated in evaluative processing of ambivalent stimuli under the
Available online 11 October 2008
forced and non-forced response conditions. Cerebral blood flow was measured using H15 2 O positron emission tomography in twelve normal volunteers during a modified word-stem
Keywords:
completion task that was designed to evoke different conditions of ambivalence. The
Ambivalence
prefrontal cortical activations were restricted to the orbitofrontal cortex during the non-
Evaluative processing
forced ambivalent condition, whereas the ventrolateral prefrontal cortex and the
Orbitofrontal cortex
frontopolar cortex were activated in addition to the orbitofrontal cortex during the forced
Ventrolateral prefrontal cortex
ambivalent condition. It is remarkable that the orbitofrontal cortex and the ventrolateral prefrontal cortex demonstrated a reciprocal activation pattern, which might be linked to the evaluative attitude toward the ambivalent stimuli. © 2008 Elsevier B.V. All rights reserved.
1.
Introduction
Ambivalence is defined as a state of simultaneous and antithetical emotional tone and action tendency (Raulin and Brenner, 1993). It happens to be the underlying cause of everyday dilemmas and contributes to apparent inconsistency and hesitation (Billig et al., 1988). Despite there being a long history of conceptual issues of ambivalence, empirical
research has remained limited and no meaningful construct has been fully elaborated because of the problems inherent in measuring ambivalence. Traditionally, ambivalence has been investigated by assessing the subjective feeling of ambivalence through self-reporting measures or combining separately measured positive and negative evaluations. However, correlations between subjectively reported ambivalence and conflicting evaluations have not been clearly identified
⁎ Corresponding author. Department of Psychiatry, Yongdong Severance Hospital, 612 Eonjuro, Gangnam-gu, Seoul 135-720, Republic of Korea. Fax: +2 3462 4304. E-mail address: [email protected] (J.-J. Kim). 0006-8993/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2008.09.081
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –1 43
(Priester and Petty, 2001; Newby-Clark et al., 2002). Considering this issue, Albertson et al. (2004) insisted that the simultaneous presence of positive and negative evaluations does not connote subjective ambivalence, in that contradictory evaluations can be held separately and thus a state of mind, which creates difficulty in evaluating the object, should be required for ambivalence. Little is known of the brain activity involved in the evaluative processing of ambivalent stimuli. Growing evidence suggests that the prefrontal cortex underlies conscious, controlled evaluative processes that are sensitive to the complexity of information, whereas the amygdala is assumed to be involved in nonconscious, automatic evaluative processes (Nomura et al., 2004; Dolcos et al., 2004). Although positive and negative evaluation are separable and can occur simultaneously, physical constraints generally restrict behavioral manifestations to bivalent actions (approach or avoidance) (Cacioppo et al., 1999). In this context, a recent neuroimaging study proposed that ambivalence is a state that arises during prefrontal cortical processing, which should be necessary to arrive at an evaluative judgment of complex emotional information (Cunningham et al., 2003, 2004). Meanwhile, previous studies
137
(Keightley et al, 2003) have indicated that brain activity during processing of emotional content was dependent on not only the type of stimuli but also the manner in which the stimuli are processed. These findings indicate that the role of the prefrontal cortex in processing ambivalent stimuli might be affected by the response condition. The purpose of this study was to investigate the functional organization of the prefrontal cortex involved in evaluative processing of ambivalent stimuli. We attempted to verify the viewpoint that the simultaneous presence of positive and negative emotional evaluation does not connote subjective ambivalence. We hypothesized that the prefrontal cortical activity involved in evaluative processing of ambivalent stimuli would be influenced by the response condition, especially when forced to make a dichotomous evaluative judgment. The forced choice conditions were designed in order to ensure that subjects made efforts to solve the contradictory emotional information and induced internalized conflict. We assumed that ambivalent stimuli would elicit different cortical activity patterns under different response conditions. To address this issue, we took advantage of the wordstem completion paradigm. The word-stem completion task
Fig. 1 – Modified word-stem completion paradigm. During the study phase, visual stimuli were presented for 2700 ms at 300 ms intervals and the subjects responded as “good” or “bad.” During the test phase, monosyllabic word stems were presented on a black background and subjects were instructed to respond according to the subjective feeling elicited when trying to complete each word-stem with a word from the preceding study phase. For an example, two different words of opposite emotional valence – “love” [sa-lang] (positive) and “death” [sa-mang] (negative) – could be recalled by the word-stem [sa]. In the forced ambivalent conditions, the subjects had to make a dichotomous choice between only “good” or “bad.” In the non-forced ambivalent condition, the subject could response as “good,” “bad,” or “neither good nor bad.”
138
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –14 3
Table 1 – Behavioral measures according to block conditions Condition
Response percentage (%) Missing
Good
Bad
Univalent Positive stimulus Negative stimulus
0.6 ± 1.4 0 ± 0.0
99.4 ± 1.5 b 0.3 ± 1.2
0.0 ± 1.0 99.7 ± 1.2 b
Non-forced ambivalent Positive stimulus Negative stimulus Ambivalent stimulus
1.3 ± 4.4 1.3 ± 3.0 1.0 ± 1.9
93.6 ± 10.8 b 6.4 ± 11.3 15.3 ± 23.7
1.3 ± 4.4 90.4 ± 18.0 b 6.3 ± 12.8
Forced ambivalent Positive stimulus Negative stimulus Ambivalent stimulus
0.7 ± 2.4 0.0 ± 0.0 0.7 ± 1.6
99.3 ± 2.4 b 3.8 ± 6.1 61.3 ± 16.0 b
0.0 ± 0.0 96.2 ± 6.1 b 35.3 ± 16.7
Compromise
a
Reaction time (ms) 787.5 ± 78.2 794.3 ± 87.3 780.1 ± 103.6
3.8 ± 7.7 1.9 ± 6.7 77.4 ± 36.8 b
1102.2 ± 234.0 c 1036.4 ± 275.9 971.7 ± 282.7 1207.6 ± 255.5 996.6 ± 232.2 c 898.6 ± 248.6 891.1 ± 197.8 1107.3 ± 264.4
a
The compromise response (“neither good nor bad”) was allowed only in non-forced ambivalent blocks. Analysis of variance revealed a significant effect of stimulus valence on the mean response percentage. c Analysis of variance revealed a significant difference of reaction time between conditions (p < 0.001). Post-hoc analysis revealed a significant difference between the univalent and non-forced ambivalent conditions (p < 0.001), and between the univalent and forced ambivalent conditions (p = 0.045). However, there was no significant difference between the non-forced ambivalent and forced ambivalent conditions (p = 0.118). b
was primarily regarded as an example of perceptual priming. However, several component processes can be manipulated by varying the instructions (Henson, 2003). We modified the task by defining three conditions — univalent (U), non-forced ambivalent (nFA) and forced ambivalent (FA) (Fig. 1). Meanwhile, previous studies have deliberated the problem of how to segregate affective processes from cognitive processes associated with emotion induction methods, which are confounding factors (Phan et al., 2002; Grim et al., 2006). Cognitive processes associated with the word-stem completion task – retrieving and maintaining words from the study phase – have been well-studied (Buckner et al., 1995) and were taken into consideration in interpreting our findings.
2.
Results
2.1.
Behavioral observation
The mean percentages of responses in each condition are summarized in Table 1. It is remarkable that the response pattern toward ambivalent word stems differed according to the response condition. During the nFA conditions, the compromise response (“neither good nor bad”) was the major response (77.4%). In contrast, during FA condition blocks, in which a dichotomous choice was forced, the subjects preferred to respond as “good” (61.3%) rather than “bad” (35.3%) to the ambivalent word stem (p < 0.001).
Fig. 2 – Correlation between the delayed reaction time and the orbitofrontal activations. The regions of interest corresponded to the clusters of significant contiguous vowels identified in the contrast nFA > U. The mean reaction time (a) was prolonged in both the non-forced (nFA) and forced ambivalent (FA) conditions in contrast to the univalent (U) conditions (nFA: p < 0.001; FA: p = 0.045). There was a significant correlation between the delayed reaction time and the orbitofrontal activations in both the non-forced ambivalent condition (Pearson correlation coefficient = 0.686, p = 0.014) and the forced ambivalent condition (Pearson correlation coefficient = 0.760, p = 0.004).
139
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –1 43
Table 2 – Response condition effect on ambivalent stimuli-related brain activities a Region
Non-forced ambivalent > univalent Orbitofrontal cortex Medial dorsal thalamus Cerebellum Cerebellum (vermis) Forced ambivalent > univalent Orbitofrontal cortex Frontopolar cortex Ventrolateral prefrontal cortex Medial dorsal thalamus Cerebellum Cerebellum (vermis) Forced ambivalent > non-forced ambivalent Insular cortex Superior temporal sulcus
Brodmann area
Voxels
Right Left Left Right
11 – – –
24 94 95 64
Right Right Right Left Right Left Right
11 10 44 – – – –
651
Left Right
– 22
Z max
Coordinates x
y
z
3.32 3.59 4.42 3.59
20 −12 −52 2
50 − 22 − 58 − 72
−8 6 − 48 − 40
103 162 44 26 324
4.58 3.57 3.94 3.97 3.37 3.60 4.37
22 30 46 −14 4 −50 2
50 52 14 − 12 − 20 − 60 − 72
−8 0 14 8 6 − 50 − 40
27 45
3.44 3.54
−26 70
20 − 36
− 12 2
a The threshold of significance for the clusters was defined as exceeding an uncorrected p-level of 0.001 and containing at least 20 contiguous voxels.
The mean reaction time significantly differed between block conditions (p < 0.001) (Fig. 2). The mean reaction time of ambivalent conditions was significantly prolonged compared to the univalent condition (FA: p = 0.045; nFA: p < 0.001). However, the difference between the FA condition and nFA conditions was not significant (p = 0.118).
2.2. Response condition effect on ambivalent-related activations As summarized in Table 2, we explored the response condition effect on ambivalent stimuli-related cortical activities accord-
ing to the response instruction. The contrast nFA-minus-U (nFA > U) revealed activities in the orbitofrontal cortex, the medial dorsal thalamus, and the cerebellum. The contrast FAminus-U (FA > U) revealed activities in the orbitofrontal cortex, the frontopolar cortex, the ventrolateral prefrontal cortex, the medial dorsal thalamus, and the cerebellum. Interestingly, the prefrontal cortical activities showed laterality to the right hemisphere. In order to investigate cortical areas selectively implicated in the FA condition, we used the contrast FA-minus-nFA (FA > nFA), which revealed activities in the superior temporal sulcus and the insula.
Fig. 3 – Reciprocal activations of the ventrolateral prefrontal cortex* and the orbitofrontal cortex*. The regions of interest corresponded to the clusters of significant contiguous vowels identified in the contrast FA > U. When we estimated the mean adjusted activity change of forced ambivalent (FA) minus univalent (U) conditions, there was a reverse correlation between the ventrolateral prefrontal cortex (a) and the orbitofrontal cortex (b) (e; Pearson correlation coefficient = −0.629, p = 0.028).
140
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –14 3
2.3. Correlation between the prolonged reaction time and the orbitofrontal activities When compared to the U conditions, the mean activity change of the orbitofrontal cortex showed correlations with the prolonged reaction time in both the nFA conditions (Pearson correlation coefficient = 0.686, p = 0.014) and the FA conditions (Pearson correlation coefficient = 0.760, p = 0.004) (Fig. 2).
2.4. Reciprocal correlation between the ventrolateral prefrontal activities and the orbitofrontal activities The mean adjusted activity change of the ventrolateral prefrontal cortex and the orbitofrontal cortex showed reciprocal correlation in the FA conditions (Pearson correlation coefficient = − 0.629, p = 0.028) (Fig. 3).
3.
Discussion
The aim of this exploratory study was to investigate the prefrontal cortical regions that were implicated in the evaluative judgment of ambivalent stimuli. Our findings supported the hypothesis that the prefrontal cortical activations implicated in processing ambivalent stimuli would demonstrate different patterns according to the response condition. The orbitofrontal cortex was activated in ambivalent conditions, regardless of the response conditions. Correlations with reaction time provide strong evidence that the orbitofrontal cortex played a key role in evaluating processing of ambivalent stimuli. The orbitofrontal cortex has been suggested to be involved in evaluating affective valence of stimuli and mediating subjective experience (Dehaene et al., 1998; Rolls et al., 1999; Kringelbach, 2005). In addition, it has been reported that the orbitofrontal cortex is more activated when there is insufficient information available to determine the appropriate response (Elliott et al., 2000). Considering that the medial dorsal thalamus has pronounced connections with the orbitofrontal cortex (Ongür and Price, 2000), it would be more reasonable to assume that the orbitofrontal cortex, together with the medial dorsal thalamus and the cerebellum, were recruited as a functional circuit rather than a single region in order to make evaluative judgments in the ambivalent conditions. As we hypothesized, the prefrontal cortical activities were restricted to the orbitofrontal region during the nFA condition, whereas the ventrolateral prefrontal cortex and the frontopolar cortex were activated in addition to the orbitofrontal cortex during the FA condition. The right ventrolateral prefrontal cortex is implicated in control processes while making explicit judgments, including cognitive control of emotional intensity (Petrides et al., 2002; Ochsner et al., 2002; Grim et al., 2006). Consistent with our findings, the ventrolateral prefrontal cortex has been proposed to be associated with control processes in order to provide more accurate judgments in ambivalent situations (Cunningham et al., 2004). In addition, the frontopolar cortex is also implicated in explicit processing of internal mental states (Christoff and Gabrieli, 2000). Taken together, the activations of the ventrolateral prefrontal cortex and the frontopolar cortex seem to reflect the high-level
cognitive control required to make a dichotomous evaluative judgment during the FA condition. It is also noteworthy that the ventrolateral prefrontal cortex and the frontopolar cortex demonstrated lateralization to the right hemisphere. There are mixed findings on right hemisphere dominance in emotion processing and some studies have proposed that the regional activations might differ according to the emotional valence (Wager et al., 2003). However, our findings support that the right hemisphere is predominantly involved in processing emotional stimuli with ambivalence. Although both the frontopolar–orbitofrontal cortex and the ventrolateral prefrontal cortex were implicated in explicit processing of ambivalent stimuli, it is remarkable that these two regions demonstrated a reciprocal activation pattern. There is a growing interest in understanding the functional specialization of the prefrontal cortex, and converging evidence supports the dissociable pattern between the role of the orbitofrontal cortex in affectively laden “hot” processes and the lateral prefrontal cortex in purely “cool” cognitive processes (Zelazo and Muller, 2002; Krain et al., 2006). From this perspective, it is possible to suggest that the orbitofrontal cortex and the ventrolateral prefrontal cortex played complementary roles in the evaluative judgment of ambivalent stimuli, and that the activation pattern was largely attributed to the evaluative attitude toward ambivalent stimuli. However, the statistical power of our correlation analysis is limited due to the small sample size, and further replication and elaboration should follow. The contrast of the FA condition-minus-nFA condition revealed activations in the insular cortex. The insula has been linked to the assessment of emotionally aversive states (Phillips et al., 1998) and emotional distress with action planning in order to avoid aversive stimuli (Paulus et al., 2003; Simmons et al., 2006). Recently, connections with the limbic structures and the orbitofrontal areas have been proposed to subserve the role of the insula as a critical structure for the integration of emotion and behavior (Dupont et al., 2003; Reynold and Zahm, 2005). As mentioned above, it would be feasible to assume that the insula has been implicated in evaluative processing through bidirectional connections with the orbitofrontal cortex. On the other hand, considering that the simultaneous existence of conflicting emotions toward an object might be better characterized as a bittersweet feeling (Albertson et al., 2004), the insular activations might reflect the emotional distress induced by the FA condition. The response percentages give further accounts of the role of the cortical activities in evaluating processing of ambivalent stimuli. It is noteworthy that subjects preferred to assign positive rather than negative valence to ambivalent wordstem cues when dichotomous responses were forced. One plausible explanation concerning this finding is the positivity offset. The positivity offset refers to a tendency for the positive affective system to respond more than the negative affective system when evaluative input is weak or absent (Cacioppo et al., 1999). It should be stressed that we induced emotion indirectly by retrieving emotional words and pictures rather than directly presenting them and thus the substantial emotional input was initially weak. Therefore, when subjects tried to make evaluative judgments according to subjective
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –1 43
feelings, the behavioral responses probably followed a pattern of the positivity offset. Within this context, our findings might be associated with previous studies that have proposed that the orbitofrontal cortex is a part of the baseline default mode of the human brain (Gusnard et al., 2001; Kringelbach, 2005). On the other hand, these findings complement our previous study (Jung et al., 2006), in which emotion was induced by directly presenting emotional words or pictures and thus subjects' responses followed a negativity bias pattern, i.e., subjects preferred to assign negative valence when positive and negative emotional inputs were strong. The results of this study must be addressed within the context of several considerations. First, many Korean word stems are derived from Chinese, and we could not rule out the possibility that subjects might have well-established connotations attached to certain word stems based on their natural occurrence or self-containing Chinese meaning. We tried to minimize these effects by repeating the target words continuously during the preceding study phase in order to manipulate the immediate emotional context of our word stems. Second, the mean reaction time was more prolonged in the nFA condition than the FA condition although it fell short of statistical significance. The prolonged reaction time did not represent simply the internalized conflict induced by contradictory information but also the elaborative processes due to an additional response option. Third, the key to the validity of our study lies in the fact that images were obtained using a positron emission tomography/computerized tomography scanner. In most previous functional magnetic resonance imaging (fMRI) studies without a special consideration for the orbitofrontal cortex, the characteristic activations in the region would have been prone to signal dropout and susceptible to artifacts due to its close proximity to the air-filled sinuses (Wilson et al., 2002; Deichmann et al., 2002). In conclusion, our findings demonstrated that the prefrontal regions – including the orbitofrontal cortex, the frontopolar cortex and the ventrolateral prefrontal cortex – are crucially implicated in processing ambivalent stimuli. Most of these cortical activations were recruited especially when a dichotomous evaluative judgment was required. It is remarkable that the orbitofrontal cortex and the ventrolateral prefrontal cortex demonstrated a reciprocal activation pattern, which indicates a functional dissociation of the prefrontal regions in processing ambivalent stimuli.
4.
Experimental procedures
4.1.
Participants
Twelve healthy right-handed volunteers (seven men, five women) were included in our study. The mean age and mean educational achievement was 24.8 years (SD = 2.3) and 15.5 years (SD = 1.9) respectively. All participants were screened for past or present history of medical, neurological and psychiatric illnesses during an interview using the Structured Clinical Interview for DSM-IV (First et al., 1995). After a complete description of the study was provided to participants, written informed consent was obtained. Our study was carried out under the guidelines for the use of
141
human subjects established by the Institutional Review Board of Severance Mental Health Hospital.
4.2.
Modified word-stem completion test and procedure
We modified the word-stem competition task by pairing two disyllabic words with one monosyllabic word stem. In the Korean language, the majority of nouns are disyllabic words, and it is a common occurrence for disyllabic words to share an identical monosyllabic word stem. We used 16 monosyllabic word-stems that had no semantic meaning by themselves that corresponded to 16 Korean word pairs. All disyllabic words were all chosen from the 100 emotional words frequently used in Korea (Lee, 1998). The pair of disyllabic words held either identical or antithetical emotional valence and were categorized into three groups: positive–positive word pair (e.g., “kindness [chin-jul]” and “friend [chin-gu]”), negative–negative word pair (e.g., “suffering [go-nan]” and “torture [go-mun]”), and positive–negative word pair (e.g., “love [sa-lang]” and “death [sa-mang]”). Monosyllabic word-stem cues that corresponded to a positive–positive or negative– negative word pair were referred to as a univalent positive (e.g., [chin]) or univalent negative stimulus (e.g., [go]). In contrast, monosyllabic word-stem cues that corresponded to a positive–negative word pair were referred to as an ambivalent stimulus (e.g., [sa]). The modified word-stem completion task consisted of two phases, a study phase and a test phase. In the study phase, subjects responded by pressing one of two buttons –“good” or “bad” – according to their subjective feelings. Each word was presented with an emotionally congruent background picture that was manipulated to strengthen the subjective feeling elicited by the visual stimuli. We developed the background pictures by modifying photographs from the International Affective Picture System (IAPS) (Lang et al., 1998). Each visual stimulus was presented for 2700 ms at 300-ms intervals, and this was repeated four times during the study phase. In the test phase, a monosyllabic word stem was presented on a black background and subjects were instructed to respond according to the subjective feeling elicited when trying to complete each word stem with a word from the preceding study phase. The test phase included three blocks: 1) the U condition, 2) the nFA condition and 3) the FA condition. Each block was composed of eight monosyllabic word-stem cues. The U condition was composed of four positive univalent word stems and four negative univalent word-stems. In contrast, the ambivalent conditions were composed of four ambivalent word-stems together with two positive word stems and two negative word-stems. During the nFA conditions, subjects could respond as “good,” “bad,” or “neither good nor bad.” In contrast, during the FA conditions, subjects had to make a dichotomous choice between only “good” or “bad.” Considering the FA condition, two words of contradictory valence were recalled by the ambivalent word-stem cue, and subjects had to confront an ambivalent situation. However, during the nFA condition, subjects could make use of the compromise response (“neither good nor bad”). The sequence of the blocks was randomized. Each monosyllabic word-stem cue was presented for 2700 ms at 300-ms intervals and was repeated six times. All responses were automatically transferred to a
142
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –14 3
computer file. We analyzed the behavioral data in terms of response percentage and reaction time. Before the word-stem completion test, the valence of each stimulus (disyllabic words and monosyllabic word stems) was determined by asking subjects to rate the valence on a fivepoint Likert scale: 1 (strong negative), 2 (weak negative), 3 (neutral), 4 (weak positive) and 5 (strong positive). Subjects rated 4.3 ± 0.2 for positive words and 1.5 ± 0.5 for negative words. Meanwhile, subjects assigned a weak positive valence of 3.3 ± 0.1 for monosyllabic word stems.
4.3.
Imaging data acquisition and data processing
Scans were obtained using a Philips GEMINI PET/CT scanner (Cleveland, OH, USA), which had an intrinsic resolution of 4.96 mm full width at half maximum (FWHM) and simultaneously imaged 90 contiguous transverse planes with a thickness of 2 mm for a longitudinal field of view of 18 cm. In each block, an intravenous bolus injection of about 370 MBq of [15O]H2O was given in the antecubital vein in the left forearm through an indwelling catheter. Correction for tissue attenuation was based on data from low dose computed tomography transmission measurements, performed with a 140-kV, 40-mAs/slice. List data acquisition was started at the same time that the tracer IV bolus was administered. PET data were acquired over a 120-s time period. During the test phase, four scans were acquired per subject and a 15-min interval between successive scans was used to allow radioactive levels to return to baseline. The acquired images were attenuationcorrected and reconstructed using the row-action maximum likelihood algorithm (3D-RAMLA). List-mode data were binned into sinograms, allowing frame durations to be determined after acquisition. Images were reconstructed based on a time– activity curve using 20- to 120-s intervals. Spatial preprocessing and statistical analysis were performed using Statistical Parametric Mapping 2 (Department of Neurology, University College of London, UK). All reconstructed images were realigned and transformed into a standard stereotactic anatomical space (Talairach and Tournoux, 1988) using affine and nonlinear transformation to remove participant anatomical variability. Spatially normalized images were smoothed by convolution with an isotropic Gaussian kernel with 10 mm FWHM in order to increase the signal-to-noise ratio and accommodate subtle variations in the anatomical structures.
4.4.
Statistical analysis
A voxel-based comparison of the adjusted mean activities obtained under different conditions was performed in each group using paired t-statistics. The resulting t-values were transformed into Z scores, and regions were considered to be activated when showing increased regional cerebral blood flow. First, contrasts were generated to test for voxel-wise effects of differences between blocks: a) nFA > U, b) FA > U, c) FA > nFA. The threshold of significance for the clusters was defined as exceeding an uncorrected p-level of 0.001 and containing at least 20 contiguous voxels. Second, post-hoc analysis was performed to investigate the correlation between behavioral measures and subregional mean activities. Regions
of interest corresponded to the clusters of significant contiguous voxels identified in the previous three contrasts. The adjusted mean activity (Kim et al., 2005) was calculated as the average of the estimated intensity value of all of voxels, which corresponded to the clusters of significant contiguous voxels identified in the above contrasts. The significance of the correlations was accepted when p < 0.05.
Acknowledgments This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A050495). REFERENCES
Albertson, B., Brehm, J., Alvarez, R.M., 2004. Ambivalence as experienced conflict. In: Craig, S., Martinez, M.D. (Eds.), Ambivalence and the Structure of Political Opinion. Palgrave Macmillan, New York. Billig, M., Condor, S., Edwards, D., Gane, M., Middleton, D., Radley, A., 1988. Ideological Dilemmas: A Social Psychology of Everyday Thinking. Sage, London. Buckner, R.L., Raichle, M.E., Petersen, S.E., 1995. Dissociation of human prefrontal cortical areas across different speech production tasks and gender groups. J. Neurophysiol. 74, 2163–2173. Cacioppo, J.T., Gardner, W.L., Berntson, G.G., 1999. The affect system has parallel and integrative processing components form follows function. J. Pers. Soc. Psychol. 76, 839–855. Christoff, K., Gabrieli, J.D.E., 2000. The frontopolar cortex and human cognition: evidence for a rostrocaudal hierarchical organization within the human prefrontal cortex. Psychobiology 28, 168–186. Cunningham, W.A., Johnson, M.K., Gatenby, J.C., Gore, J.C., Banaji, M.R., 2003. Neural components of social evaluation. J. Pers. Soc. Psychol. 85, 639–649. Cunningham, W.A., Raye, C.L., Johnson, M.K., 2004. Implicit and explicit evaluation: fMRI correlates of valence, emotional intensity, and control in the processing of attitudes. J. Cogn. Neurosci. 16, 1717–1729. Dehaene, S., Kerszberg, M., Changeuz, J.P., 1998. A neuronal model of global workspace in effortful cognitive tasks. Proc. Natl. Acad. Sci. U. S. A. 95, 14529–14534. Deichmann, R., Josephs, O., Hutton, C., Corfield, D.R., Turner, R., 2002. Compensation of susceptibility-induced BOLD sensitivity losses in echo-planar fMRI imaging. NeuroImage 15, 120–135. Dolcos, F., LaBar, K.S., Cabeza, R., 2004. Dissociable effects of arousal and valence on prefrontal activity indexing emotional evaluation and subsequent memory: an event-related fMRI study. NeuroImage 23, 64–74. Dupont, S., Bouilleret, V., Hasboun, D., Semah, F., Baulac, M., 2003. Functional anatomy of the insula: new insights from imaging. Surg. Radiol. Anat. 25, 113–119. Elliott, R., Dolan, R.J., Frith, C.D., 2000. Dissociable functions in the medial and lateral orbitofrontal cortex: evidence from human neuroimaging studies. Cereb. Cortex 10, 308–317. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1995. Structured Clinical Interview for DSM-IV Axis I Disorders. New York State Psychiatric Institute Biometrics Research, New York. Grim, S., Schmidt, C.F., Bermpohl, F., Heinzel, A., Dahlem, Y., Wyss, M., Hell, D., Boesiger, P., Boeker, H., Northoff, G., 2006. Segregated neural representation of distinct emotion
BR A I N R ES E A RC H 1 2 4 6 ( 2 00 8 ) 1 3 6 –1 43
dimensions in the prefrontal cortex-an fMRI study. NeuroImage 30, 325–340. Gusnard, D.A., Raichle, M.E., Raichle, M.E., 2001. Searching for a baseline: functional imaging and the resting human brain. Nat. Rev. Neurosci. 2, 685–694. Henson, R.N.A., 2003. Neuroimaging studies of priming. Prog. Neurobiol. 70, 53–81. Jung, Y.C., An, S.K., Seok, J.H., Kim, J.S., Oh, S.J., Moon, D.H., Kim, J.J., 2006. Neural substrates associated with evaluative processing during co-activation of positivity and negativity: a PET investigation. Biol. Psychol. 73, 253–261. Keightley, M.L., Winocur, G., Graham, S.J., Mayberg, H.S., Hevenor, S.J., Grady, C.L., 2003. An fMRI study investigating cognitive modulation of brain regions associated with emotional processing of visual stimuli. Neuropsychologia 41, 585–596. Kim, J.J., Seok, J.H., Park, H.J., Lee, D.S., Lee, M.C., Kwon, J.S., 2005. Functional disconnection of the semantic networks in schizophrenia. Neuroreport 16, 355–359. Krain, A.L., Wilson, A.M., Arbuckle, R., Castellanos, F.X., Milham, M.P., 2006. Distinct neural mechanisms of risk and ambiguity: a meta-analysis of decision-making. Neuroimage 32, 477–484. Kringelbach, M.L., 2005. The human orbitofrontal cortex: linking reward to hedonic experience. Nat. Rev. Neurosci. 6, 691–702. Lang, P.J., Bradley, M.M., Cuthbert, B.N., 1998. International Affective Picture System (IAPS): Photographic Slides. Center for Research in Psychophysiology University of Florida, Gainsville. Lee, S.J., 1998. Conscious/Nonconscious processing of affective information: affective primacy effect in priming paradigm. The graduate school of Yonsei University, Seoul. Newby-Clark, I.R., McGregor, I., Zanna, M.P., 2002. Thinking and caring about cognitive inconsistency: when and for whom does attitudinal ambivalence feel uncomfortable? J. Pers. Soc. Psychol. 82, 157–166. Nomura, M., Ohira, H., Haneda, K., Iidaka, T., Sadato, N., Okada, T., Yonekura, Y., 2004. Functional association of the amygdala and ventral prefrontal cortex during cognitive evaluation of facial expressions primed by masked angry faces: an event-related fMRI study. Neuroimage 21, 352–363. Ochsner, K.N., Bunge, S.A., Gross, J.J., Gabrieli, J.D., 2002. Rethinking feelings: an fMRI study of the cognitive regulation of emotion. J. Cogn. Neurosci. 15, 1215–1229. Ongür, D., Price, J.L., 2000. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb. Cortex 10, 206–219.
143
Paulus, M.P., Rogalsky, C., Simmons, A., Feinstein, J.S., Stein, M.B., 2003. Increased activation in the right insula during risk-taking decision making is related to harm avoidance and neuroticism. Neuroimage 19, 1439–1448. Petrides, M., Alivisatos, B., Frey, S., 2002. Differential activation of the human orbital, mid-ventrolateral and mid-dorsolateral prefrontal cortex during processing of visual stimuli. Proc. Natl. Acad. Sci. U. S. A. 98, 5649–5654. Phan, K.L., Wager, T., Taylor, S.F., Liberzon, I., 2002. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 16, 331–348. Phillips, M.L., Young, A.W., Scott, S.K., Calder, A.J., Andrew, C., Giampietro, V., Williams, S.C., Bullmore, E.T., Brammer, M., Gray, J.A., 1998. Neural responses to facial and vocal expressions of fear and disgust. Proc. Biol. Sci. 265, 1809–1817. Priester, J.R., Petty, R.E., 2001. Extending the bases of subjective attitudinal ambivalence: interpersonal and intrapersonal antecedents of evaluative tension. J. Pers. Soc. Psychol. 80, 19–34. Raulin, M.L., Brenner, V., 1993. Ambivalence. In: Costello, C.G. (Ed.), Symptoms of Schizophrenia. Wiley, New York, pp. 201–226. Reynolds, S.M., Zahm, D.S., 2005. Specificity in the projections of prefrontal and insular cortex to ventral striatopallidum and the extended amygdala. J. Neurosci. 25, 11757–11767. Rolls, E.T., Crichley, H.D., Browning, A.S., Hemadi, I., Lenard, L., 1999. Responses to the sensory properties of fat of neurons in the primate orbitofrontal cortex. J. Neurosci. 19, 1532–1540. Simmons, A., Strigo, I., Matthews, S.C., Paulus, M.P., Stein, M.A., 2006. Anticipation of aversive visual stimuli in associated with increased insula activation in anxiety prone subjects. Biol. Psychiatry 60, 402–409. Talairach, J., Tournoux, P., 1988. Co-planar stereotaxic atlas of the human brain. Thieme, New York. Wager, T.D., Phan, K.L., Liberzon, I., Taylor, S.F., 2003. Valence, gender, and lateralization of functional brain anatomy in emotion: a meta-analysis of findings from neuroimaging. Neuroimage 19, 513–531. Wilson, J.L., Jenkinson, M., de Araujo, I., Kringelbach, M.L., Rolls, E.T., Jezzard, P., 2002. Fast, fully automated global and local magnetic field optimization for fMRI of the human brain. Neuroimage 17, 967–976. Zelazo, P.D., Muller, U., 2002. Executive function in typical and atypical development. In: Goswami, U. (Ed.), Handbook of Childhood Cognitive Development. Blackwell, Oxford.