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Research Report

Reciprocal activation of the orbitofrontal cortex and theventrolateral prefrontal cortex in processingambivalent stimuli

Young-Chul Junga,b, Hae-Jeong Parkc,d, Jae-Jin Kima,b,c,⁎, Ji Won Chunb,c, Hye Sun Kimb,Nam Wook Kima, Sang Jun Sona, Maeng-Gun Ohd, Jong Doo Leec,d

aDepartment of Psychiatry, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemeun-gu, Seoul 120-752, Republic of KoreabInstitute 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 KoreacBrain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemeun-gu, Seoul 120-752,Republic of KoreadDepartment of Diagnostic Radiology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemeun-gu, Seoul 120-752,Republic of Korea

A R T I C L E I N F O

⁎ Corresponding author. Department of PsychKorea. Fax: +2 3462 4304.

E-mail address: jaejkim@yonsei.ac.kr (J.-J.

0006-8993/$ – see front matter © 2008 Elsevidoi:10.1016/j.brainres.2008.09.081

A B S T R A C T

Article history:Accepted 24 September 2008Available online 11 October 2008

The neural basis of ambivalence has not yet been identified. We investigated the prefrontalcortical activations implicated in evaluative processing of ambivalent stimuli under theforced and non-forced response conditions. Cerebral blood flow was measured using H2

15Opositron emission tomography in twelve normal volunteers during a modified word-stemcompletion task that was designed to evoke different conditions of ambivalence. Theprefrontal cortical activations were restricted to the orbitofrontal cortex during the non-forced ambivalent condition, whereas the ventrolateral prefrontal cortex and thefrontopolar cortex were activated in addition to the orbitofrontal cortex during the forcedambivalent condition. It is remarkable that the orbitofrontal cortex and the ventrolateralprefrontal cortex demonstrated a reciprocal activation pattern, whichmight be linked to theevaluative attitude toward the ambivalent stimuli.

© 2008 Elsevier B.V. All rights reserved.

Keywords:AmbivalenceEvaluative processingOrbitofrontal cortexVentrolateral prefrontal cortex

1. Introduction

Ambivalence is defined as a state of simultaneous andantithetical emotional tone and action tendency (Raulin andBrenner, 1993). It happens to be the underlying cause ofeveryday dilemmas and contributes to apparent inconsistencyand hesitation (Billig et al., 1988). Despite there being a longhistory of conceptual issues of ambivalence, empirical

iatry, Yongdong Severan

Kim).

er B.V. All rights reserved

research has remained limited and no meaningful constructhas been fully elaborated because of the problems inherent inmeasuring ambivalence. Traditionally, ambivalence has beeninvestigated by assessing the subjective feeling of ambiva-lence through self-reporting measures or combining sepa-rately measured positive and negative evaluations. However,correlations between subjectively reported ambivalence andconflicting evaluations have not been clearly identified

ce Hospital, 612 Eonjuro, Gangnam-gu, Seoul 135-720, Republic of

.

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(Priester and Petty, 2001; Newby-Clark et al., 2002). Consideringthis issue, Albertson et al. (2004) insisted that the simulta-neous presence of positive and negative evaluations does notconnote subjective ambivalence, in that contradictory evalua-tions can be held separately and thus a state of mind, whichcreates difficulty in evaluating the object, should be requiredfor ambivalence.

Little is known of the brain activity involved in theevaluative processing of ambivalent stimuli. Growing evi-dence suggests that the prefrontal cortex underlies con-scious, controlled evaluative processes that are sensitive tothe complexity of information, whereas the amygdala isassumed to be involved in nonconscious, automatic evalua-tive processes (Nomura et al., 2004; Dolcos et al., 2004).Although positive and negative evaluation are separable andcan occur simultaneously, physical constraints generallyrestrict behavioral manifestations to bivalent actions(approach or avoidance) (Cacioppo et al., 1999). In thiscontext, a recent neuroimaging study proposed that ambiva-lence is a state that arises during prefrontal corticalprocessing, which should be necessary to arrive at anevaluative judgment of complex emotional information(Cunningham et al., 2003, 2004). Meanwhile, previous studies

Fig. 1 – Modifiedword-stem completion paradigm. During the stuintervals and the subjects responded as “good” or “bad.” During tblack background and subjects were instructed to respond accordeach word-stem with a word from the preceding study phase. Fovalence – “love” [sa-lang] (positive) and “death” [sa-mang] (negatambivalent conditions, the subjects had to make a dichotomousambivalent condition, the subject could response as “good,” “ba

(Keightley et al, 2003) have indicated that brain activityduring processing of emotional content was dependent onnot only the type of stimuli but also the manner in whichthe stimuli are processed. These findings indicate that therole of the prefrontal cortex in processing ambivalent stimulimight be affected by the response condition.

The purpose of this study was to investigate the functionalorganization of the prefrontal cortex involved in evaluativeprocessing of ambivalent stimuli. We attempted to verify theviewpoint that the simultaneous presence of positive andnegative emotional evaluation does not connote subjectiveambivalence. We hypothesized that the prefrontal corticalactivity involved in evaluative processing of ambivalentstimuli would be influenced by the response condition,especially when forced to make a dichotomous evaluativejudgment. The forced choice conditions were designed inorder to ensure that subjects made efforts to solve thecontradictory emotional information and induced interna-lized conflict. We assumed that ambivalent stimuli wouldelicit different cortical activity patterns under differentresponse conditions.

To address this issue, we took advantage of the word-stem completion paradigm. The word-stem completion task

dy phase, visual stimuliwere presented for 2700ms at 300mshe test phase, monosyllabic word stems were presented on aing to the subjective feeling elicited when trying to completer an example, two different words of opposite emotionalive) – could be recalled by the word-stem [sa]. In the forcedchoice between only “good” or “bad.” In the non-forcedd,” or “neither good nor bad.”

Table 1 – Behavioral measures according to block conditions

Condition Response percentage (%) Reactiontime (ms)

Missing Good Bad Compromisea

Univalent 787.5±78.2Positive stimulus 0.6±1.4 99.4±1.5b 0.0±1.0 794.3±87.3Negative stimulus 0±0.0 0.3±1.2 99.7±1.2b 780.1±103.6

Non-forced ambivalent 1102.2±234.0c

Positive stimulus 1.3±4.4 93.6±10.8b 1.3±4.4 3.8±7.7 1036.4±275.9Negative stimulus 1.3±3.0 6.4±11.3 90.4±18.0b 1.9±6.7 971.7±282.7Ambivalent stimulus 1.0±1.9 15.3±23.7 6.3±12.8 77.4±36.8b 1207.6±255.5

Forced ambivalent 996.6±232.2c

Positive stimulus 0.7±2.4 99.3±2.4b 0.0±0.0 898.6±248.6Negative stimulus 0.0±0.0 3.8±6.1 96.2±6.1b 891.1±197.8Ambivalent stimulus 0.7±1.6 61.3±16.0b 35.3±16.7 1107.3±264.4

a The compromise response (“neither good nor bad”) was allowed only in non-forced ambivalent blocks.b 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 significantdifference 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).

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was primarily regarded as an example of perceptual prim-ing. However, several component processes can be manipu-lated by varying the instructions (Henson, 2003). Wemodified the task by defining three conditions — univalent(U), non-forced ambivalent (nFA) and forced ambivalent (FA)(Fig. 1). Meanwhile, previous studies have deliberated theproblem of how to segregate affective processes fromcognitive processes associated with emotion inductionmethods, which are confounding factors (Phan et al., 2002;Grim et al., 2006). Cognitive processes associated with theword-stem completion task – retrieving and maintainingwords from the study phase – have been well-studied(Buckner et al., 1995) and were taken into consideration ininterpreting our findings.

Fig. 2 – Correlation between the delayed reaction time and the oto the clusters of significant contiguous vowels identified in the cboth the non-forced (nFA) and forced ambivalent (FA) conditionsFA: p=0.045). There was a significant correlation between the dethe non-forced ambivalent condition (Pearson correlation coeffic(Pearson correlation coefficient=0.760, p=0.004).

2. Results

2.1. Behavioral observation

The mean percentages of responses in each condition aresummarized in Table 1. It is remarkable that the responsepattern toward ambivalent word stems differed according tothe response condition. During the nFA conditions, thecompromise response (“neither good nor bad”) was themajor response (77.4%). In contrast, during FA conditionblocks, in which a dichotomous choice was forced, thesubjects preferred to respond as “good” (61.3%) rather than“bad” (35.3%) to the ambivalent word stem (p<0.001).

rbitofrontal activations. The regions of interest correspondedontrast nFA > U. The mean reaction time (a) was prolonged inin contrast to the univalent (U) conditions (nFA: p<0.001;layed reaction time and the orbitofrontal activations in bothient=0.686, p=0.014) and the forced ambivalent condition

Table 2 – Response condition effect on ambivalent stimuli-related brain activities a

Region Brodmannarea

Voxels Zmax

Coordinates

x y z

Non-forced ambivalent>univalentOrbitofrontal cortex Right 11 24 3.32 20 50 −8Medial dorsal thalamus Left – 94 3.59 −12 −22 6Cerebellum Left – 95 4.42 −52 −58 −48Cerebellum (vermis) Right – 64 3.59 2 −72 −40

Forced ambivalent>univalentOrbitofrontal cortex Right 11 651 4.58 22 50 −8Frontopolar cortex Right 10 3.57 30 52 0Ventrolateral prefrontal cortex Right 44 103 3.94 46 14 14Medial dorsal thalamus Left – 162 3.97 −14 −12 8

Right – 44 3.37 4 −20 6Cerebellum Left – 26 3.60 −50 −60 −50Cerebellum (vermis) Right – 324 4.37 2 −72 −40

Forced ambivalent>non-forced ambivalentInsular cortex Left – 27 3.44 −26 20 −12Superior temporal sulcus Right 22 45 3.54 70 −36 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 contiguousvoxels.

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The mean reaction time significantly differed betweenblock conditions (p<0.001) (Fig. 2). The mean reaction time ofambivalent conditions was significantly prolonged comparedto the univalent condition (FA: p=0.045; nFA: p<0.001).However, the difference between the FA condition and nFAconditions was not significant (p=0.118).

2.2. Response condition effect on ambivalent-relatedactivations

As summarized in Table 2, we explored the response conditioneffect on ambivalent stimuli-related cortical activities accord-

Fig. 3 – Reciprocal activations of the ventrolateral prefrontal cortcorresponded to the clusters of significant contiguous vowels ideadjusted activity change of forced ambivalent (FA) minus univaleventrolateral prefrontal cortex (a) and the orbitofrontal cortex (b)

ing to the response instruction. The contrast nFA-minus-U(nFA>U) revealed activities in the orbitofrontal cortex, themedial dorsal thalamus, and the cerebellum. The contrast FA-minus-U (FA>U) revealed activities in the orbitofrontal cortex,the frontopolar cortex, the ventrolateral prefrontal cortex, themedial dorsal thalamus, and the cerebellum. Interestingly, theprefrontal cortical activities showed laterality to the righthemisphere.

In order to investigate cortical areas selectively implicatedin the FA condition, we used the contrast FA-minus-nFA(FA>nFA), which revealed activities in the superior temporalsulcus and the insula.

ex* and the orbitofrontal cortex*. The regions of interestntified in the contrast FA > U. When we estimated the meannt (U) conditions, there was a reverse correlation between the(e; Pearson correlation coefficient=−0.629, p=0.028).

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2.3. Correlation between the prolonged reaction time andthe orbitofrontal activities

When compared to the U conditions, themean activity changeof the orbitofrontal cortex showed correlations with theprolonged reaction time in both the nFA conditions (Pearsoncorrelation 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 ventrolateralprefrontal activities and the orbitofrontal activities

The mean adjusted activity change of the ventrolateralprefrontal cortex and the orbitofrontal cortex showed recipro-cal correlation in the FA conditions (Pearson correlationcoefficient=−0.629, p=0.028) (Fig. 3).

3. Discussion

The aim of this exploratory study was to investigate theprefrontal cortical regions that were implicated in the evalua-tive judgment of ambivalent stimuli. Our findings supportedthe hypothesis that the prefrontal cortical activations impli-cated in processing ambivalent stimuli would demonstratedifferent patterns according to the response condition.

The orbitofrontal cortex was activated in ambivalentconditions, regardless of the response conditions. Correlationswith reaction time provide strong evidence that the orbito-frontal cortex played a key role in evaluating processing ofambivalent stimuli. The orbitofrontal cortex has been sug-gested to be involved in evaluating affective valence of stimuliand mediating subjective experience (Dehaene et al., 1998;Rolls et al., 1999; Kringelbach, 2005). In addition, it has beenreported that the orbitofrontal cortex is more activated whenthere is insufficient information available to determine theappropriate response (Elliott et al., 2000). Considering that themedial dorsal thalamus has pronounced connections with theorbitofrontal cortex (Ongür and Price, 2000), it would be morereasonable to assume that the orbitofrontal cortex, togetherwith the medial dorsal thalamus and the cerebellum, wererecruited as a functional circuit rather than a single region inorder to make evaluative judgments in the ambivalentconditions.

As we hypothesized, the prefrontal cortical activities wererestricted to the orbitofrontal region during the nFA condition,whereas the ventrolateral prefrontal cortex and the frontopo-lar cortex were activated in addition to the orbitofrontal cortexduring the FA condition. The right ventrolateral prefrontalcortex is implicated in control processes while making explicitjudgments, including cognitive control of emotional intensity(Petrides et al., 2002; Ochsner et al., 2002; Grim et al., 2006).Consistent with our findings, the ventrolateral prefrontalcortex has been proposed to be associated with controlprocesses in order to provide more accurate judgments inambivalent situations (Cunningham et al., 2004). In addition,the frontopolar cortex is also implicated in explicit processingof internal mental states (Christoff and Gabrieli, 2000). Takentogether, the activations of the ventrolateral prefrontal cortexand the frontopolar cortex seem to reflect the high-level

cognitive control required to make a dichotomous evaluativejudgment during the FA condition. It is also noteworthy thatthe ventrolateral prefrontal cortex and the frontopolar cortexdemonstrated lateralization to the right hemisphere. Thereare mixed findings on right hemisphere dominance inemotion processing and some studies have proposed thatthe regional activations might differ according to the emo-tional valence (Wager et al., 2003). However, our findingssupport that the right hemisphere is predominantly involvedin processing emotional stimuli with ambivalence.

Although both the frontopolar–orbitofrontal cortex and theventrolateral prefrontal cortex were implicated in explicitprocessing of ambivalent stimuli, it is remarkable that thesetwo regions demonstrated a reciprocal activation pattern.There is a growing interest in understanding the functionalspecialization of the prefrontal cortex, and converging evi-dence supports the dissociable pattern between the role of theorbitofrontal cortex in affectively laden “hot” processes andthe lateral prefrontal cortex in purely “cool” cognitive pro-cesses (Zelazo and Muller, 2002; Krain et al., 2006). From thisperspective, it is possible to suggest that the orbitofrontalcortex and the ventrolateral prefrontal cortex played comple-mentary roles in the evaluative judgment of ambivalentstimuli, and that the activation pattern was largely attributedto the evaluative attitude toward ambivalent stimuli. How-ever, the statistical power of our correlation analysis is limiteddue to the small sample size, and further replication andelaboration should follow.

The contrast of the FA condition-minus-nFA conditionrevealed activations in the insular cortex. The insula has beenlinked to the assessment of emotionally aversive states(Phillips et al., 1998) and emotional distress with actionplanning in order to avoid aversive stimuli (Paulus et al.,2003; Simmons et al., 2006). Recently, connections with thelimbic structures and the orbitofrontal areas have beenproposed to subserve the role of the insula as a criticalstructure for the integration of emotion and behavior (Dupontet al., 2003; Reynold and Zahm, 2005). As mentioned above, itwould be feasible to assume that the insula has beenimplicated in evaluative processing through bidirectionalconnections with the orbitofrontal cortex. On the otherhand, considering that the simultaneous existence of con-flicting emotions toward an object might be better character-ized as a bittersweet feeling (Albertson et al., 2004), the insularactivationsmight reflect the emotional distress induced by theFA condition.

The response percentages give further accounts of the roleof the cortical activities in evaluating processing of ambivalentstimuli. It is noteworthy that subjects preferred to assignpositive rather than negative valence to ambivalent word-stem cues when dichotomous responses were forced. Oneplausible explanation concerning this finding is the positivityoffset. The positivity offset refers to a tendency for the positiveaffective system to respond more than the negative affectivesystem when evaluative input is weak or absent (Cacioppoet al., 1999). It should be stressed that we induced emotionindirectly by retrieving emotional words and pictures ratherthan directly presenting them and thus the substantialemotional input was initially weak. Therefore, when subjectstried to make evaluative judgments according to subjective

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feelings, the behavioral responses probably followed a patternof the positivity offset. Within this context, our findings mightbe associated with previous studies that have proposed thatthe orbitofrontal cortex is a part of the baseline default modeof the human brain (Gusnard et al., 2001; Kringelbach, 2005).On the other hand, these findings complement our previousstudy (Jung et al., 2006), in which emotion was induced bydirectly presenting emotional words or pictures and thussubjects' responses followed a negativity bias pattern, i.e.,subjects preferred to assign negative valence when positiveand negative emotional inputs were strong.

The results of this study must be addressed within thecontext of several considerations. First, many Korean wordstems are derived from Chinese, and we could not rule out thepossibility that subjects might have well-established connota-tions attached to certain word stems based on their naturaloccurrence or self-containing Chinese meaning. We tried tominimize these effects by repeating the target words con-tinuously during the preceding study phase in order tomanipulate the immediate emotional context of our wordstems. Second, themean reaction timewasmore prolonged inthe nFA condition than the FA condition although it fell shortof statistical significance. The prolonged reaction time did notrepresent simply the internalized conflict induced by contra-dictory information but also the elaborative processes due toan additional response option. Third, the key to the validity ofour study lies in the fact that images were obtained using apositron emission tomography/computerized tomographyscanner. In most previous functional magnetic resonanceimaging (fMRI) studies without a special consideration for theorbitofrontal cortex, the characteristic activations in theregion would have been prone to signal dropout and suscep-tible to artifacts due to its close proximity to the air-filledsinuses (Wilson et al., 2002; Deichmann et al., 2002).

In conclusion, our findings demonstrated that the pre-frontal regions – including the orbitofrontal cortex, thefrontopolar cortex and the ventrolateral prefrontal cortex –are crucially implicated in processing ambivalent stimuli.Most of these cortical activations were recruited especiallywhen a dichotomous evaluative judgment was required. It isremarkable that the orbitofrontal cortex and the ventrolateralprefrontal cortex demonstrated a reciprocal activation pat-tern, which indicates a functional dissociation of the pre-frontal regions in processing ambivalent stimuli.

4. Experimental procedures

4.1. Participants

Twelve healthy right-handed volunteers (seven men, fivewomen) were included in our study. The mean age and meaneducational achievement was 24.8 years (SD=2.3) and15.5 years (SD=1.9) respectively. All participants werescreened for past or present history of medical, neurologicaland psychiatric illnesses during an interview using theStructured Clinical Interview for DSM-IV (First et al., 1995).After a complete description of the study was provided toparticipants, written informed consent was obtained. Ourstudy was carried out under the guidelines for the use of

human subjects established by the Institutional Review Boardof Severance Mental Health Hospital.

4.2. Modified word-stem completion test and procedure

We modified the word-stem competition task by pairing twodisyllabic words with one monosyllabic word stem. In theKorean language, the majority of nouns are disyllabic words,and it is a common occurrence for disyllabic words to share anidentical monosyllabic word stem. We used 16 monosyllabicword-stems that had no semantic meaning by themselvesthat corresponded to 16 Korean word pairs. All disyllabicwords were all chosen from the 100 emotional wordsfrequently used in Korea (Lee, 1998). The pair of disyllabicwords held either identical or antithetical emotional valenceand were categorized into three groups: positive–positiveword 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-stemcues 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]). Incontrast, monosyllabic word-stem cues that corresponded toa positive–negative word pair were referred to as an ambiva-lent stimulus (e.g., [sa]).

The modified word-stem completion task consisted of twophases, 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 waspresented with an emotionally congruent background picturethat was manipulated to strengthen the subjective feelingelicited by the visual stimuli. We developed the backgroundpictures by modifying photographs from the InternationalAffective Picture System (IAPS) (Lang et al., 1998). Each visualstimulus was presented for 2700 ms at 300-ms intervals, andthis was repeated four times during the study phase. In thetest phase, a monosyllabic word stem was presented on ablack background and subjects were instructed to respondaccording to the subjective feeling elicited when trying tocomplete each word stem with a word from the precedingstudy phase. The test phase included three blocks: 1) the Ucondition, 2) the nFA condition and 3) the FA condition. Eachblock was composed of eight monosyllabic word-stem cues.TheU conditionwas composed of four positive univalentwordstems and four negative univalent word-stems. In contrast,the ambivalent conditions were composed of four ambivalentword-stems together with two positive word stems and twonegative word-stems. During the nFA conditions, subjectscould respond as “good,” “bad,” or “neither good nor bad.” Incontrast, during the FA conditions, subjects had to make adichotomous choice between only “good” or “bad.” Consider-ing the FA condition, two words of contradictory valence wererecalled by the ambivalent word-stem cue, and subjects had toconfront an ambivalent situation. However, during the nFAcondition, subjects could make use of the compromiseresponse (“neither good nor bad”). The sequence of the blockswas randomized. Each monosyllabic word-stem cue waspresented for 2700 ms at 300-ms intervals and was repeatedsix times. All responses were automatically transferred to a

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computer file. We analyzed the behavioral data in terms ofresponse percentage and reaction time.

Before the word-stem completion test, the valence of eachstimulus (disyllabic words and monosyllabic word stems) wasdetermined by asking subjects to rate the valence on a five-point Likert scale: 1 (strong negative), 2 (weak negative), 3(neutral), 4 (weak positive) and 5 (strong positive). Subjectsrated 4.3±0.2 for positive words and 1.5±0.5 for negativewords. Meanwhile, subjects assigned a weak positive valenceof 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 of4.96 mm full width at half maximum (FWHM) and simulta-neously imaged 90 contiguous transverse planes with athickness of 2 mm for a longitudinal field of view of 18 cm.In each block, an intravenous bolus injection of about 370 MBqof [15O]H2O was given in the antecubital vein in the leftforearm through an indwelling catheter. Correction for tissueattenuation was based on data from low dose computedtomography transmission measurements, performed with a140-kV, 40-mAs/slice. List data acquisition was started at thesame time that the tracer IV bolus was administered. PET datawere acquired over a 120-s time period. During the test phase,four scans were acquired per subject and a 15-min intervalbetween successive scans was used to allow radioactive levelsto return to baseline. The acquired images were attenuation-corrected and reconstructed using the row-action maximumlikelihood algorithm (3D-RAMLA). List-mode data were binnedinto sinograms, allowing frame durations to be determinedafter acquisition. Images were reconstructed based on a time–activity curve using 20- to 120-s intervals.

Spatial preprocessing and statistical analysis were per-formed using Statistical Parametric Mapping 2 (Department ofNeurology, University College of London, UK). All recon-structed images were realigned and transformed into astandard stereotactic anatomical space (Talairach and Tour-noux, 1988) using affine and nonlinear transformation toremove participant anatomical variability. Spatially normal-ized images were smoothed by convolution with an isotropicGaussian kernel with 10 mm FWHM in order to increase thesignal-to-noise ratio and accommodate subtle variations inthe anatomical structures.

4.4. Statistical analysis

A voxel-based comparison of the adjusted mean activitiesobtained under different conditions was performed in eachgroup using paired t-statistics. The resulting t-values weretransformed into Z scores, and regions were considered to beactivated when showing increased regional cerebral bloodflow. First, contrasts were generated to test for voxel-wiseeffects of differences between blocks: a) nFA>U, b) FA>U, c)FA>nFA. The threshold of significance for the clusters wasdefined as exceeding an uncorrected p-level of 0.001 andcontaining at least 20 contiguous voxels. Second, post-hocanalysis was performed to investigate the correlation betweenbehavioralmeasures and subregional mean activities. Regions

of interest corresponded to the clusters of significant con-tiguous voxels identified in the previous three contrasts. Theadjusted mean activity (Kim et al., 2005) was calculated as theaverage of the estimated intensity value of all of voxels, whichcorresponded to the clusters of significant contiguous voxelsidentified in the above contrasts. The significance of thecorrelations was accepted when p<0.05.

Acknowledgments

This study was supported by a grant from the Korea Health 21R&D Project, Ministry of Health andWelfare, Republic of Korea(A050495).

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