Activation of the Caudal Anterior Cingulate Cortex Due to Task-Related Interference in an Auditory Stroop Paradigm

Transcription

1 Human Bain Mapping 30: (2009) Activation of the Caudal Anteio Cingulate Cotex Due to Task-Related Intefeence in an Auditoy Stoop Paadigm Sven Haupt, 1 Nikolai Axmache, 1,2 * Michael X. Cohen, 1,2 Chistian E. Elge, 1,2 and Juegen Fell 1 1 Depatment of Epileptology, Univesity of Bonn, Bonn, Gemany 2 Life and Bain Cente of Academic Reseach, Univesity of Bonn, Bonn, Gemany Abstact: Successful infomation pocessing equies the focusing of attention on a cetain stimulus popety and the simultaneous suppession of ielevant infomation. The Stoop task is a useful paadigm to study such attentional top-down contol in the pesence of intefeence. Hee, we investigated the neual coelates of an auditoy Stoop task using fmri. Subjects focused eithe on tone pitch (elatively high o low; phonetic task) o on the meaning of a spoken wod (high/low/good; semantic task), while ignoing the othe stimulus featue. We diffeentiated between task-elated (phonetic inconguent vs. semantic inconguent) and sensoy-level intefeence (phonetic inconguent vs. phonetic conguent). Task-elated intefeence activated simila egions as in visual Stoop tasks, including the anteio cingulate cotex (ACC) and the pesupplementay moto-aea (pe-sma). Moe specifically, we obseved that the vey caudal/posteio pat of the ACC was activated and not the dosal/anteio egion. Because identical stimuli but diffeent task demands ae compaed in this contast, it eflects conflict at a elatively high pocessing level. A moe conventional contast between inconguent and conguent phonetic tials was associated with a diffeent cluste in the pe-sma/acc which was obseved in a lage numbe of pevious studies. Finally, functional connectivity analysis evealed that activity within the egions activated in the phonetic inconguent vs. semantic inconguent contast was moe stongly inteelated duing semantically vs. phonetically inconguent tials. Taken togethe, we found (besides activation of egions well-known fom visual Stoop tasks) activation of the vey caudal and posteio pat of the ACC due to task-elated intefeence in an auditoy Stoop task. Hum Bain Mapp 30: , VC 2009 Wiley-Liss, Inc. Key wods: Stoop task; attention; intefeence; cognitive contol; inhibition; anteio cingulate; pefontal cotex; functional connectivity Contact gant sponso: Volkswagen Foundation; Contact gant numbe: I/ *Coespondence to: Nikolai Axmache, Depatment of Epileptology, Univesity of Bonn, Sigmund-Feud-St. 25, D Bonn, Gemany. nikolai.axmache@ukb.uni-bonn.de Received fo publication 21 Febuay 2008; Revised 3 Decembe 2008; Accepted 8 Decembe 2008 DOI: /hbm Published online 29 Januay 2009 in Wiley InteScience (www. intescience.wiley.com). INTRODUCTION Since the Stoop effect was fist descibed moe than 70 yeas ago [Stoop, 1935], it became one of the most intensively studied phenomena in cognitive neuoscience and still has a key ole in the study of attentional top-down mechanisms [fo eviews see Dye and Seveance, 1973; MacLeod, 1991]. In spite of many vaiations of the Stoop task, the basic pinciple of wod eading and colo detection has not changed ove the decades and is still widely VC 2009 Wiley-Liss, Inc.

2 Haupt et al. used. In the standad Stoop task, subjects ae asked to name the colos of compatible and incompatible colowods and of contol patches, e.g., solid colo squaes. Stoop intefeence coesponds to the diffeence between the eaction times in the inconguent and the contol condition. The intefeence effect and significant eaction time incease duing the inconguent tials is accompanied by a facilitation effect fo the conguent tials, eflected by a decease in eaction times, although facilitation is consideed to be a somewhat weake phenomenon than intefeence [MacLeod, 1991]. Duing the last two decades, the Stoop task was implemented using neuoimaging techniques, such as PET and fmri, and evealed functional neual netwoks involved in the contol of Stoop intefeence [e.g., Cate et al., 1995; Leung et al., 2000; Pado et al., 1990; Peteson et al., 1999]. The Stoop intefeence task seems to pincipally ely on the activity of a limited numbe of key egions, in spite of the fact that the expeimental designs evolved to numeous specializations. Accoding to the standad theoy, the anteio cingulate cotex (ACC) signals fontal egions, such as the dosolateal pefontal cotex (DLPFC), to futhe incease the attentional bias towad task-elevant pocessing when distacting stimulus popeties cause a task-elated conflict. Consequently, ecent studies showed a majo inteest in the ACC and DLPFC, which emeged as the two anatomical egions playing the most impotant ole in the contol of conflict management [e.g., Banich et al., 2001; MacDonald et al., 2000; Milham et al., 2001]. Seveal studies have addessed theoies of ACC functions elated to diffeent cognitive abilities, such as, fo example, conflict monitoing [Botvinick et al., 1999, 2001; Cate et al., 2000; Kens et al., 2004; MacDonald et al., 2000], eo detection [see eviews Bush et al., 2002; Gehing and Knight, 2000], and esponse selection [Eickson et al., 2004; Milham et al., 2003; Paus, 2001]. In addition, the DLPFC has been shown to contibute to cognitive contol function [MacDonald et al., 2000; Mille and Cohen, 2001]. In this study, we implemented an auditoy Stoop intefeence task using fmri. Seveal studies demonstated the applicability of the Stoop intefeence task in the auditoy domain behavioally [Leboe and Mondo, 2007; McClain, 1983; Sho, 1975]. In one vesion, not only wee stimuli pesented in auditoy modality, but subjects wee also eithe equied to espond by naming a wod o poducing a hum with diffeent pitch [McClain, 1983]. This paadigm indicated that intefeence was at least patially attibutable to esponse inconsistency, as suggested by the esponse incompatibility theoy [Teisman and Feanley, 1969]. In ou paadigm, howeve, esponses wee neithe given by spoken wods no by hummed tones, but by button pesses. In this context, anothe souce of intefeence is moe elevant: Stoop conflict aises if esponses have to be given accoding to that one of two contasting item featues, which is pocessed slowe and less automatic, such as colo o pitch naming, in the pesence of inconsistent semantic infomation. Conflict is smalle o absent if esponses ae given accoding to the faste and moe automatically pocessed item featue, such as wod meaning in the pesence of inconsistent colo o pitch infomation. This asymmety pedicts that in ou task, intefeence should be lage if subjects ae equied to espond to a pitch in the pesence of inconguent semantic infomation when compaed with when they ae equied to espond to the meaning of a wod in the pesence of inconguent pitch infomation. Ou motivation fo implementing the auditoy Stoop appoach with functional imaging was foufold as follows: Selective attention might be diffeent in the auditoy when compaed with the visual domain. Most applications of the Stoop intefeence task wee designed using visual stimuli and evealed vaiations of activity in the anteio ACC and DLPFC. We addessed the question of whethe the functional netwok activated by conflict pocessing epesents a common system o whethe thee ae specific alteations egading the sensoy modality. We expected the behavioal esults and the conflict netwok activations to geneally follow the common Stoop findings, but hypothesized pominent diffeences due to the new sensoy modality fo two easons. Fistly, because the visual and the auditoy pathways include fundamentally diffeent pocessing steps fo sensoy input [Hendee and Wells, 1997; Handel, 1989]. Secondly, because alteations of activations in ACC due to diffeent cognitive pocesses ae well descibed in the fmri liteatue, e.g., in the context of conflict pocessing and movement execution [Picad and Stick, 2001], attention and stimulus detection [Posne and Petesen, 1990], and emotional pocessing [Bush et al., 2000; Devinsky et al., 1995]. To futhe investigate the integation of activity within the conflict netwok and to eveal its adjustments due to the auditoy modality, we additionally pefomed a functional connectivity analysis using the psychophysiological inteaction appoach [Fiston et al., 1997]. In most investigations of the Stoop effect, intefeence effects ae being analyzed by the contast between inconguent and conguent (o neutal) stimuli in a colo-naming task (whee the pocessing of semantic infomation has to be suppessed). This contast involves intefeence aleady at the sensoy level of pocessing as well as at highe levels. The contast between inconguent items in the colo naming and inconguent items in the colo eading task has aely been investigated. Howeve, this latte contast does not involve intefeence at a sensoy level, because stimuli ae exactly identical in the two conditions and only task demands diffe (in othe wods, conflict at the level of sensoy pocessing is substacted out ). Because this contast eveals moe diectly intefeence at highe pocessing levels, we aimed at compaing it with the moe conventional inconguent > conguent contast. Thee is an ongoing discussion egading the ole of piming in the Stoop task. A cente of debate in ecent stud- 3044

3 Modality Specific Activity in Auditoy Stoop ies involving conflict-adaptation is the contovesy of the conflict theoy vesus piming-effects. It is still unclea if eaction time deceases elated to epetitions of equal stimuli duing a conflict task ae actually caused by the geate ecuitment of top-down conflict monitoing o should athe be attibuted to episodic memoy o stimulus-specific epetition piming as shown fo Flanke-tasks [May et al., 2003; Nieuwenhuis et al., 2006]. An auditoy Stoop appoach could be useful fo clinical puposes. Abnomal conflict management was evidenced fo seveal bain disodes, e.g., attention-deficit/hypeactivity disode [fo eview see Lansbegen et al., 2007] o in paanoid schizophenia [Nodahl et al., 2001]. An auditoy appoach to the common Stoop intefeence task seems of paticula inteest since the auditoy sense is especially affected in psychiatic disodes such as schizophenia [Veuillet et al., 2001]. Recently, it has been epoted that an inceased Stoop effect can seve as a make fo a genetic vulneability to schizophenia [e.g., Becke et al., 2008; Filbey et al., 2008]. Because schizophenic patients have deficits in both auditoy pocessing and conflict monitoing, an auditoy vesion of the Stoop task might povide an even moe sensitive tait make fo schizophenia. METHODS Paticipants A total of 29 healthy subjects (14 women; age 18 34, mean age 6 s.d.: yeas; and handedness: 22 ight, 7 left) paticipated in the study. They wee ecuited fom the Univesity of Bonn as well as via newspape. The study was appoved by the local medical ethics committee, and all subjects povided witten infomed consent. Expeimental Pocedues We used an auditoy vesion of the Stoop task [Stoop, 1935], whee subjects wee pesented the Geman equivalents of the wods high and low (Geman: Hoch, Tief ) in eithe a high o low tone pitch. In each of the two identical blocks of the paadigm, subjects pefomed fist the semantic condition, whee they indicated via button pess whethe the wod high o low was pesented, egadless of the tone pitch. In the consecutive phonetic condition, the subjects wee asked to decide if the wod was pesented in a high o low tone pitch, egadless of the wod meaning. As an additional contol, we pesented the wod good (Geman: Gut ) eithe in a high o in a low tone pitch in both conditions. In the semantic condition, subjects wee instucted not to pess a button in these tials. These tials did not ente futhe analysis. Only the contol tials in the phonetic condition wee subsequently analyzed. Only tials with coect esponses enteed into the contasts of the second level Figue 1. Oveview of the paadigm. geneal linea model. An oveview of the paadigm is depicted in Figue 1. The sound files wee spoken and digitalized by one of the expeimentes, and tansposed to a high o low tone pitch (tone diffeence of a quint), espectively, aligned in fequency using the Entopic Timescale Modification (ETSM TM ) as included in the Goldwave audio editing softwae ( This tansfomation guaanteed equal length of all sound files (500 ms). Test Session Subjects completed a total of 480 tials while they wee being scanned in fmri. Pio to the stat of the expeiment, subjects went though at least 10 pactice tials o moe, if necessay. The expeiment was divided into two pats of 240 tials each to ascetain a stable level of attention duing the entie length of the paadigm. Subjects wee allowed to leave the scanne between the two pats. Evey pat was subdivided into two blocks, each with 120 tials fo the semantic block and 120 tials fo the phonetic block. Evey block contained all thee sound files ( high, low, and good ) in eithe a high o low tone pitch. Each of these six conditions was pesented in 20 tials. The wods wod meaning and tone pitch wee pesented on the sceen in all tials fo the sake of claity. Wods wee pesented fo 500 ms, and the subjects wee asked to answe as fast as possible duing the consecutive 2,000 ms inteval. All tials with esponse delays longe than 2,500 ms wee discaded. Tials wee administeed in a andomized, countebalanced ode acoss subjects. The 2,500 ms tial was followed by a pause of 2,000 5,000 ms length, duing which a fixation coss was shown. Stimuli wee 3045

4 Haupt et al. pesented using Pesentation 1 softwae (Vesion 0.71; Neuobehavioal Systems; Albany, CA) via MRI-compatible liquid-cystal display (LCD) goggles and MRI-compatible electostatic headphones (both NodicNeuoLab, Begen, Noway), and esponses wee obtained though a fibe optic magnetic esonance-compatible contol pad. MRI Data Acquisition Thity-eight axial slices wee collected in a 1.5T scanne (Avanto, Siemens, Elangen, Gemany). We collected 1160 T2*-weighted, gadient echo (EPI) scans (slice thickness: 3 mm; inteslice gap: 0.48 mm; matix size: ; field of view: 222 mm; echo time: 35 ms; and epetition time: 2,500 ms). Theeafte, we acquied a sagittal T1-weighted MPRAGE sequence fo each subject fo anatomical localization (numbe of slices: 160; slice thickness: 1 mm; inte-slice gap: 0.5 mm; matix size: ; field of view: 256 mm; echo time: 3.09 ms; and epetition time: 1,660 ms). fmri Analysis Analysis was caied out using FEAT (FMRI Expet Analysis Tool) Vesion 5.63, pat of FSL softwae (FMRIB s Softwae Libay, using standad pocedues. The following pestatistics pocessing was applied: motion coection using MCFLIRT [Jenkinson et al., 2002]; slice-timing coection using Fouie-space time-seies phase-shifting; nonbain emoval using BET [Smith, 2002]; spatial smoothing using a Gaussian kenel of FWHM 6 mm; mean-based intensity nomalization of all volumes by the same facto; and highpass tempoal filteing (Gaussian-weighted least-squaes staight line fitting, with sigma s). Time-seies statistical analysis was caied out using FILM [Woolich et al., 2001]. Registation to high esolution and/o standad images was caied out using FLIRT [Jenkinson et al., 2002]. Pepocessed data wee fitted by the convolution of multiple egessos with a canonical hemodynamic esponse function to obtain paamete estimates fo each condition covaiate. The fmri-analysis used a set of seven egessos, each of 1,000 ms duation. Fou egessos wee used fo the conguent (pitch: high /meaning: high o low/low ), and inconguent ( high/low o low/high ) tials in the semantic and phonetic blocks of the paadigm (i.e., (1) conguent semantic; (2) inconguent semantic; (3) conguent phonetic; and (4) inconguent phonetic). Two egessos wee used fo the contol-condition ( good ) in the semantic and phonetic block, and one egesso fo the tials with incoect esponses. Incoect esponses wee modeled because othewise vaiance of the associated BOLD esponses would contibute to the implicit baseline activity and deteioate the estimation of the othe egessos beta values. To contol fo epetition effects, the fmri analysis was caied out a second time with the same set of egessos, with the only exception that each epetition of a tial in the same categoy (conguent conguent o inconguent inconguent) was modeled with the same egesso as the incoect tials, theefoe, excluding them fom the elevant contasts. A thid analysis was caied out, whee instead of excluding epeating tials fo evey subject, the same amount of andomly chosen tials was excluded fom the elevant contasts of the second level geneal linea model, by moving them to the egesso fo incoect tials. The compaison of activations was caied out by extacting activation values fom, e.g., the inconguent phonetic > inconguent semantic contast fo all thee analyses. We used an inclusion mask defined by the activated egions of the fist analysis on significance level (Z 5 3.1; P ) to specify activations enteing the othe two analyses. P values in the ANOVAs wee Huynh-Feldt coected fo inhomogenities of covaiance when necessay [Huynh and Feldt, 1976]. Images ae displayed by neuological convention, with left side coesponding to the left hemisphee. Effects ae significant at P < and at a cluste size of 10 o moe contiguous voxels. Mean paamete estimates fo the diffeent conditions ae shown fo all contasts (odinate in abitay units). Eo bas epesent s.e.m. We added the locations of 112 ACC activations to ou contast in Figue 4A-2 using coodinates fom a eview by Bach et al. [2001]. The activations wee collected fom tasks falling unde the categoies of esponse inhibition, undedetemined esponding, and commission of eos (e.g., Stoop, Go/No-Go, and Flanke-tasks). The steeotactic coodinates efeing to the Talaiach coodinate system wee tansfomed to MNI coodinates using the tal2mni.m scipt available fom M. Bett. ( doc_m2html/bioelectomagnetism/tal2mni.html). The esult is shown in Figue 4B. Fo geate claity, we used the pependicula line on the intesection of the bicommissual line (AC-PC) though the anteio commissue as an additional oientation bode. Functional connectivity with the ACC was calculated by using activity within the functional ROI in the posteio ACC egion (Fig. 4A-2) esulting fom the Phonetic > Semantic -contast, theeby identifying bain egions showing significant covaiation o functional connectivity with this seed location. We used a sphee with 6 mm diamete centeed on the peak voxel as a seed egion. The functional connectivity analysis was conducted using the psychophysiological inteaction method [Fiston et al., 1997]. The method we used elies on coelations in the BOLD time seies data and makes no assumptions about the natue of the neual activity that may have contibuted to the BOLD signal. We extacted the entie time-couse of activity of each individual subject and multiplied that time couse with a condition vecto that was ones fo five TRs following each tial type, and zeos othewise. These esulting vectos wee then used as covaiates in a sepaate egession. Analyses wee pefomed fo each subject individually and wee subsequently enteed into a gouplevel analysis. 3046

5 Modality Specific Activity in Auditoy Stoop TABLE I. Desciptive statistics of behavioal data Condition Reaction time (ms) s.e.m (ms) Eos (%) s.e.m (%) Semantic-conguent Semantic-inconguent Phonetic-conguent Phonetic-inconguent Contol RESULTS Behavioal Results The auditoy Stoop design ceated a obust Stoop intefeence effect. A two-way ANOVA with conguency and semantic-phonetic as epeated measues evealed main effects of each facto ( conguency : F 1, , P ; semantic-phonetic : F 1, , P < 0.001) and a significant conguency 3 semantic-phonetic inteaction (F 1, ; P < 0.001). As expected, the inconguent phonetic tials tuned out to be the citical condition of top-down conflict pocessing in this Stoop task, poducing significantly longe eaction times compaed with the othe conditions (inconguent phonetic tials: 906 ms (s.e.m. 52 ms), othe conditions: < 800 ms (s.e.m. < 45 ms), each P < 0.001, each t 28 < 6.14; two-tailed t tests; fo detailed behavioal data, see Table I, Fig. 2A). In the phonetic contol condition using the wod good, subjects had a eaction time of 854 ms (s.e.m. 48 ms), which diffeed significantly fom the othe conditions (each P < 0.001, each t 28 < 6.2; two-tailed t tests) and was almost at the exact half between the eaction times of the condition of highest conflict (inconguent phonetic) and the othes. The eo ates confimed the esults of the eaction times. Again, Stoop intefeence was maximal in the inconguent-phonetic condition, as the eo ate was significantly highe (11%, s.e.m. 3%) when compaed with the othe conditions (<5%; Fig. 2B). A two-way ANOVA with conguency and semantic-phonetic as epeated measues evealed main effects of each facto ( conguency : F 1, , P ; semantic-phonetic : F 1, , P ) and a significant conguency 3 semanticphonetic inteaction (F 1, ; P ). Pai-wise t tests showed that eo ates in the inconguent-phonetic condition wee lage than in any othe condition (P < 0.05, t 28 > 4.82; two-tailed t tests). A common obsevation duing the Stoop task is that pocessing of inconguent stimuli is facilitated by pevious pocessing of inconguent stimuli, which has been explained by behavioal adjustments [Botvinick et al., 2001]. Thus, an inconguent tial following an inconguent tial (ii) should esult in faste eaction times than on inconguent tials following conguent (ci) tials. Similaly, eaction times should be slowe on ic than on cc tials. We calculated the eaction times fo each of the fou conditions; the esults ae shown in Figue 2C. Consistent with pevious data, we found that eactions fo ii-tials wee significantly faste than fo ci tials (P < 0.001, t 28 > 5.9; two-tailed t tests) and wee also faste fo cc-tials than fo ic tials (P < 0.001, t 28 > 5.49; two-tailed t tests). A two-way ANOVA with Position1 (conguent/ inconguent) and Position2 (conguent/inconguent) as epeated measues evealed a main effect fo Position2 (F 1, , P < 0.001) and a significant Position1 3 Position2 inteaction (F 1, ; P ). To contol fo epetition piming effects and thei contibution to the Stoop effect, we fist calculated eaction times fo evey condition without epeating tials, i.e., tials with exact the same stimulus. We found a significant incease in eaction times (mean: ms, std: 2.6 ms; not shown) fo the tials excluding diect epetitions. A thee-way ANOVA with conguency, semantic-phonetic, and epetition (epeated tials vs. excluded) as epeated measues evealed main effects of each facto ( conguency : F 1, , P < 0.001; semantic-phonetic : F 1, , P < 0.001; epetition : F 1, , P < 0.001) and a significant conguency 3 semanticphonetic inteaction (F 1, , P < 0.001). We futhe tested the effect of excluding all epeated tials fom the statistics of the behavioal adjustments following conflict and again found that eaction times wee inceased when compaed with the analysis including epeated tials (cc:129 ms; ci:11 ms; ii:12 ms; ic:159 ms). The incease in eaction times did not change the significance of the diffeent condition inteactions. A theeway ANOVA with epetition, position1, and position2 as epeated measues evealed a main effect fo epetition (F 1, , P < 0.001) and a significant position1 3 position2 inteaction (F 1, , P < 0.001). FMRI Results We fist investigated egions showing an inceased activation duing pocessing of inconguent infomation in each of the two conditions sepaately and then compaed pocessing of inconguent items acoss modalities. In the phonetic condition, the eaction times and accuacy ates indicated that intefeence occued duing pocessing of inconguent items (e.g., esponding high to the wod low when it was ponounced in high pitch). Indeed, the inconguent phonetic > conguent phonetic contast 3047

6 Haupt et al. semantic condition, howeve, the contast of inconguent vs. conguent items was only associated with inceased activation in the pecuneus (MNI coodinates: 2/256/26; Fig. 3B). Next, the contast inconguent phonetic > inconguent semantic was calculated because exactly identical stimuli (the wod high spoken in low pitch and the wod low spoken in high pitch) wee used in both conditions. We obseved activations in the posteio pat of the anteio cingulate cotex (ACC), the medial fontal cotex, left and ight dosolateal pefontal cotex (DLPFC), thalamus, and the pesupplementay moto aea (pe-sma) close to the ACC. The esults fo the contast inconguent phonetic > inconguent semantic ae shown in the Figue 4A, and Table II povides an oveview of all significantly activated egions fo all contasts. The paamete estimates shown in Figue 4 demonstate that the activations ae clealy diven by the conflict pocessing oiginating fom the inconguent phonetic condition. Regading the discussion about conflict-adaptation vesus piming-effects, we tested how an analysis excluding all epeating tials influences the Stoop-intefeence activation netwok. Fo the second analysis, we emoved evey event containing a diect epetition of a tial fom the egessos of the fist analysis. This way we excluded an aveage of 16% of the tials (fom an aveage of 152 events Figue 2. Behavioal esults. (A) Reaction times. (B) Pecentage of incoect tials. (C) Behavioal adjustments following conflict. Pevious tial (conguent vesus inconguent) by cuent tial (conguent vesus inconguent) inteaction. evealed inceased activation in egions peviously associated with conflict pocessing such as the lateal pefontal cotex (ight: MNI coodinates 40/16/32; left: MNI coodinates 248/18/10) and the pe-sma (MNI coodinates 2/ 18/46). These egions ae shown in Figue 3A. In the Figue 3. Conflict pocessing in the sepaate domains. (A) In the phonetic condition, esponding to inconguent items elicited an inceased activation in egions peviously associated with conflict pocessing such as the pe-sma o the lateal pefontal cotex. (B) In the semantic condition, howeve, the contast of inconguent vs. conguent items was only associated with inceased activation in the pecuneus. 3048

7 Modality Specific Activity in Auditoy Stoop Figue 4. (A) Inconguent phonetic > inconguent semantic. (B) Plot eviewing 112 pe-sma/acc activations associated with vocal and manual esponses. Coodinates wee collected and eviewed by Bach and colleagues (Bach et al., 2001) and tansfeed to MNI space. to 127). The esults evealed activations coesponding to the aeas shown in Figue 4A, although the numbe of activated voxels deceased (ACC 58 to 3; DLPFC 135 to 19; not shown). A compaison of the activation-values fo the voxels of the ACC egion in the analysis with epetitions and without epetitions acoss all subjects evealed that the ACC activation without epetitions is significantly smalle (P , t 28 > 3.29; two-tailed t tests). A citical objection to this esult could be the fact that the numbe of tials fo the two analyses did not match. To test this idea, we epeated the fist analysis while andomly emoving 16% of the tials to match the numbe of events. Indeed, this evealed a significantly deceased numbe of activated voxels (ACC 58 to 3; DLPFC 135 to 42; P < 0.001, t 28 > 3.93; two-tailed t tests; not shown). Inteestingly the activation-values fo the analysis without epetitions and the tial-matched analysis did not diffe significantly (P , t 28 > 1.43; two-tailed t tests). Finally, we aimed at elucidating the mechanism by which the activated clustes paticipate in a conflict pocessing netwok. Inteaction of one egion with anothe is eflected in coelated activations in both egions. We thus 3049

8 Haupt et al. TABLE II. Significantly activated egions in the diffeent conditions Region L/R BA MNI coodinates x y z z-scoe Left DLPFC L ,9 White matte L ,3 Insula L ,9 Cingulate gyus L ,9 Lentifom nucleus L ,8 Medial fontal gyus L ,8 Right DLPFC R ,7 Thalamus L ,7 Anteio cingulate L ,7 Cingulate gyus L ,6 PeSMA M ,6 Thalamus L ,5 Sub-gyal L ,5 Supeio fontal gyus M ,4 The table displays the coodinates of the maximally activated voxel in each activation cluste fo the incong. phonetic > incong. semantic contast. Bold enties identify connectivity netwok. pefomed functional connectivity analyses using the psychophysiological inteaction appoach [Fiston et al., 1997], with a seed egion located in the activated posteio pat of the ACC (see aow in Fig. 4A-2). The esults show a stong connectivity with the left DLPFC and the pe- SMA (see Fig. 5). measues exactly sound fequencies [Hendee and Wells, 1997; Handel, 1989]. This led to ou hypothesis that a classical Stoop task used with auditoy stimuli should esult in a obust conflict effect, wheeas at the same time ecuiting a netwok of well-known conflict-elated egions, but with adjustments to the diffeent sensoy modality. The esults confim ou hypothesis by showing a obust behavioal effect, with a highly significant eaction time diffeence of about 100 ms between the conflict condition and the othe conditions. We found that Stoop intefeence (as measued by esponse times and accuacy ates) occued in the phonetic condition (in which subjects wee equied to espond against inconguent semantic infomation), but not in the semantic condition (in which they esponded against inconguent pitch infomation). This esult may be most pasimoniously explained by the fact that semantic infomation is moe automatically pocessed when compaed with the naming of pitch infomation. In othe wods, conflict in the phonetic condition aises fom the fact that the moe automatic opeation of wod pocessing is suppessed in this condition. This behavioal effect emained significant even afte exclusion of all epetition tials (see Fig. 2). The activated netwok meets ou expectations by demonstating aeas well known fo conflict management, including the ACC, the DLPFC, the pe- SMA, the medial fontal cotex, and the thalamus. DISCUSSION Ou motivation fo implementing the auditoy Stoop appoach via functional imaging was theefold: (1) Conflict pocessing might be diffeent in the auditoy when compaed with the visual domain. We thus wondeed whethe the neual basis undelying Stoop intefeence shows modality specific alteations. (2) The ongoing discussion egading the ole of piming in the Stoop task motivated ou investigations on the influence of epeating tials on the activity of the conflict pocessing netwok. (3) Since the auditoy domain is especially affected by cetain psychiatic disodes, we discuss the usefulness of an auditoy Stoop appoach in clinical eseach. Conflict Pocessing in the Auditoy as Compaed to the Visual Domain Ou majo inteest in this study was to find out if the use of a diffeent sensoy modality in a Stoop intefeence task would epoduce the common conflict effect in geneal o if the auditoy stimuli pe se would esult in a diffeent behavioal outcome. Although visual input undegoes a lage amount of filteing and econstuction on the way fom the etina to the cotex, auditoy infomation Figue 5. Connectivity analysis contast phonetic > semantic using the ACC activation (Fig. 4A-2) as seed egion. Activity is shown at P

9 Modality Specific Activity in Auditoy Stoop Use of diffeent contasts eveals diffeent levels of conflict pocessing The (moe conventional) contast inconguent phonetic > conguent phonetic involves inconguent stimuli only in one condition, while task demands ae identical in the two conditions. Theefoe, this contast eveals inconguency oiginating aleady at the level of stimulus pocessing. Thus, activation of the pe-sma/acc egion shown in Figue 3 suppots a lowe, moe stimulus-elated level of conflict pocessing. This egion has been obseved in a lage numbe of pevious studies on the Stoop effect [Bach et al., 2001]. In addition to the contast inconguent phonetic > conguent phonetic, the contast inconguent phonetic > inconguent semantic was calculated because exactly identical stimuli (the wod high spoken in low pitch and the wod low spoken in high pitch) wee used in both conditions. Theefoe, the diffeence in activation evealed by this contast cannot be explained at the sensoy level: The amount of stimulus inconguency is equal in the two conditions, and only task demands diffe, so that this contast eveals conflict at the level of action monitoing and/o esponse. This contast activated a paticulaly posteio and infeio egion of the cingulate cotex (Fig. 4A-2) which was peviously only obseved in a small minoity of studies (Fig. 4B). ACC/pe-SMA Inteestingly, the ACC egion activated in the inconguent phonetic > inconguent semantic contast is located at the vey posteio/caudal pat of the ACC (it should be noted that the maximum diffeence of the BOLD esponse is localized to the white matte). This was in contast to the vast majoity of pevious studies investigating Stoop intefeence, conflict, and eo detection, which epoted activation of moe anteio egions of the ACC [Bach et al., 2001]. This even led Bach and colleagues to hypothesize that especially this anteio pat of the ACC is moe stongly associated with monitoing conflict. Howeve, the ACC activation in ou study was evealed in the inconguent phonetic > inconguent semantic contast, while the esults fom the Stoop tasks discussed in the aticle by Bach et al. [2001] wee based on conventional contasts of inconguent vs. conguent/ neutal tials. While the inconguent phonetic > inconguent semantic contast eflects task-elated intefeence, the conventional inconguent phonetic > conguent phonetic contast may captue both, sensoy level and highe-level intefeence. In the latte contast, howeve, the posteio/caudal pat of the ACC was not significantly activated at the conventional theshold of P < (uncoected). On the othe hand, diffeent esponse modalities in conflict tasks using oculomoto, manual, and speech esponses, activate slightly diffeent ACC egions [Paus et al., 1993; Picad and Stick, 1996], indicating a functional heteogeneity of the ACC suppoting diffeent aspects of cognitive pocessing. Unfotunately, the geneal findings elated to functional subdivisions of the ACC ae heteogeneous. Wheeas activation of the caudal egion of the ACC is associated with cognitive functions such as attention, fo instance detection of an inceasing numbe of stimuli [Posne and Petesen, 1990], the ostal egions of the ACC appea to suppot the egulation of emotional pocessing [Bush et al., 2000; Devinsky et al., 1995]. Futhemoe, it was poposed that conflict pocessing and esponse selection ae associated with the activity of the ostal cingulate cotex, while the actual movement execution is linked to the caudal cingulate zone of the ACC [Picad and Stick, 2001]. Inteestingly, a ecent study using dynamic causal modeling claimed that the intinsic connectivity between diffeent subegions of the ACC (e.g., the medial cingulate zone and the caudal cingulate zone) is inceased duing conflict pocessing to facilitate selection and esponse execution [Fan et al., 2008]. To visualize the spectum of conflict-elated activations and to futhe investigate the degee to which the netwok found in ou study diffes fom pevious findings elated to conflict pocessing, we added the locations of anothe 112 ACC activations to ou contast using coodinates as they wee eviewed by Bach et al. [2001]. It is stiking that of 112 activations, only 14 (12.5%) ae located posteio to the anteio commissue line. Especially, the vey posteio and infeio pats of the ACC wee exclusively found to be activated in fou studies investigating Stoop intefeence using vocal esponses. Based on ou data, two intepetations ae possible. Fist, it is possible that inceasing integation of the auditoy sense in conflict pocessing esults in a posteio/caudal and infeio/vental shift of ACC activity due to the diffeent sensoy modality. Altenatively, the specific activation diffeing fom the majoity of pevious studies may be due to task-elated intefeence in the inconguent phonetic > inconguent semantic contast. Findings fom a ecent study, [Robets and Hall, 2008] diectly compaing visual and auditoy Stoop tasks athe suppot the second intepetation. In this study, vey simila activations within the pe-sma/acc egion wee obseved in both modalities based on the conventional Stoop contast and no additional activations in othe (posteio and caudal) ACC egions wee epoted. The activation of the pe-sma duing the inconguent condition may appea supising at fist sight, because the SMA and pe-sma egions ae moe commonly epoted fom studies involving complex moto contol tasks [fo eview see Picad and Stick, 1996]. Nevetheless, activation of the pe-sma has been epoted in numeous studies involving cognitive contol [Bach et al., 2001; Ikeda et al., 1999; Zysset et al., 2001], and also appeas fequently in Stoop intefeence tasks, without being always clealy chaacteized. One eason fo that may lie in the fact that the teminology in this histoically old eseach field is often not compelling. The pe-sma is sometimes epoted as ostal/anteio dosal ACC [e.g., Bush et al., 2002; 3051

10 Haupt et al. Citchley et al., 2005] o in combination with the ostal/ anteio dosal ACC [Bave et al., 2001; Holoyd et al., 2004; Milham et al., 2002; Ruff et al., 2001]. The fact that we found significant coelation between activity in the posteio infeio cingulate cotex and the pe-sma egion (see Fig. 5 and discussion below), futhe suggests that these egions suppot simila pocesses. DLPFC Togethe with the ACC, the DLPFC is the most commonly epoted egion in Stoop intefeence tasks. It has been suggested that if a conflict is detected by the ACC, a cognitive contol system located in the DLPFC is aleted, which is esponsible fo educing conflict by biasing infomation pocessing towad successful task completion [Botvinick et al., 2001]. Accodingly, neuoimaging studies have shown the engagement of the left and ight DLPFC in executive functioning, and moe specifically duing selective attention [Duston et al., 2003; Kens et al., 2004; MacDonald et al., 2000; Milham et al., 2003] and attentionelated and conflict-elated activity [Weismann et al., 2004]. While the DLPFC is a citical component of the decision-making netwok ecuited fo the Stoop intefeence task, its activation seems to be independent of esponse modality [Heekeen et al., 2006]. A modality specific adjustment of activity of the DLPFC is not descibed fo conflict intefeence, but geate activation of the same DLPFC aea was obseved duing an auditoy compaed with the visual woking memoy task [Cottaz-Hebette et al., 2004]. Results fom a divided attention task (involving competing auditoy and visual stimuli) have evealed, that the activity of the DLPFC is moe stongly modulated by the pefomance of the subjects (poo pefomes ecuit moe DLPFC in an attempt to impove pefomance), than by the actual sensoy modality [Johnson and Zatoe, 2006]. Additional egions In addition to the ACC, the DLPFC and the pe-sma egion whee an inceased activation in the Inconguent phonetic when compaed with the inconguent semantic condition can be elatively easy explained by the enhanced intefeence in this condition [because of esponse competition; Teisman and Feanley, 1969]. Howeve, as indicated in Table II, we also found significant effects in othe egions. Most of these activations could be attibuted to enhanced conflict pocessing in the inconguent phonetic condition. The enhanced activity in the white matte (MNI coodinates 228; 8; 28) may be attibutable to the adjacent left middle fontal gyus, which is pat of the DLPFC (see above). Activation of the insula was also peviously obseved in the Stoop task, but is pobably elated to a moe geneal mechanism and not specifically to intefeence, because it was also obseved duing pocessing of infequent items [Leung et al., 2000]. The lentifom nucleus compises the putamen and the globus pallidus within the basal ganglia. Both stuctues ae elevant fo moto and executive functions; in situations whee conflicting infomation is being pocessed, moto outputs elated to one type of esponse pattens need to be selected, which is elated to inhibition of the putamen by fontal and paietal egions [e.g., Jaffad et al., 2008]. Thus, the inceased activation of the lentifom nucleus in the inconguent phonetic > inconguent semantic condition might be due to this enhancement of inhibitoy GABAegic action within the putamen [fo a discussion of the complex elationship between inhibitoy neual signaling and the BOLD signal, see Logothetis, 2008]. Enhanced neual metabolism in the Stoop task was also found in the thalamus using PET imaging [Ravnkilde et al., 2002] and is most likely elated to the inceased attentional demands duing pocessing of inconguent infomation [Cate et al., 1995]. Futhemoe, esults fom seveal studies suggest that activity in the thalamus is actually necessay fo coping with intefeing infomation, because patients with thalamic infacts [Shim et al., 2008] and afte thalamotomy [Schuuman et al., 2002] ae indeed impaied in the Stoop task. Finally, the inceased activity in the supeio fontal gyus (and in the sub-gyal egion at MNI coodinates of 218/28/62, which is also close to the supeio fontal gyus) might also be pat of the pefontal contol netwok. Functional connectivity The powe in the inconguent phonetic > inconguent semantic contast was not high enough to show a significant functional connectivity, howeve, we wee able to show the connectivity-netwok fo the moe geneal phonetic > semantic contast. The connectivity analysis demonstated that a netwok including the ACC, the pe-sma, and the DLPFC is ecuited fo contol and adjustment of the behavio duing conflict pocessing. Seveal ecent studies using functional connectivity ae in accodance with the esults of ou connectivity analysis. Functional connectivity of the ACC with the pe-sma and the DLPFC was shown fo the intefeence-elated condition of a Stoop colo-wod paadigm [Haison et al., 2005], fo a counting Stoop paadigm [Zheng and Rajapakse, 2006], espectively, suppoted by ecent findings in a study of ACC esting-state functional connectivity [Maguilies et al., 2007]. The stong coelation between the activity of the caudal ACC and the lateal pefontal cotex as well as medial fontal gyus, paticulaly the egion of the pe-sma, is also consistent with a meta-analysis of functional connectivity of the ACC within the human fontal lobe [Koski and Paus, 2000]. These findings ae futhe suppoted by the esults of seveal studies in monkeys. Using neuonal taces, it has been demonstated that both the pimay [Moecaft and Van Hoesen, 1992] and supplementay [Bates and Goldman-Rakic, 1993] moto aeas ae densely inteconnected with the caudal ACC. 3052

11 Modality Specific Activity in Auditoy Stoop Sensoy-Level vs. Task-Related Intefeence In addition to the contast inconguent phonetic > inconguent semantic, we also analyzed the conventional inconguent > conguent contasts sepaately fo the semantic and the phonetic condition (see Fig. 3). As expected, we found an inceased activation in egions associated with conflict pocessing only in the phonetic condition, whee eaction times and accuacy ates indicated intefeence, but not in the semantic condition. Howeve, no activation of the anteio cingulate cotex was obseved in these contasts. This divegence with the esults fom the inconguent phonetic > inconguent semantic contast shown in Figue 4 may be explained by the diffeent levels of intefeence: The classical Stoop contast (inconguent vs. conguent tials sepaately fo the semantic and the phonetic condition) compaes tials with diffeential intefeence aleady at the level of sensoy pocessing (e.g., the wod High ponounced in low pitch when compaed with the wod High ponounced in high pitch). Theefoe, intefeence occus aleady at the sensoy level and not only at highe pocessing levels. On the othe hand, the contast inconguent phonetic > inconguent semantic compaes tials with an equal amount of sensoy intefeence which diffe with egad to esponse intefeence, because inconguent phonetic tials equie subjects to espond against the moe automatic esponse (based on semantic pocessing), wheeas in inconguent semantic tials, subjects can espond in line with thei automatic esponse. The finding that the anteio cingulate cotex was activated only in the inconguent phonetic > inconguent semantic contast but not in the inconguent phonetic > conguent phonetic contast might theefoe be explained by an impotant ole of this egion fo the esolution of esponse-based intefeence, but not fo sensoy intefeence [Bach et al., 2001; Zysset et al., 2001]. Influence of Stimulus Repetition We found that an exclusion of epeating tials esults in significantly inceased eaction times fo all conditions but did not eliminate the Stoop effect. The esults fo the behavioal adjustment following conflict ae only slightly influenced by the exclusion of epeating tials and do not change thei significance. This esult could be explained by both the conflict theoy and stimulus-specific epetition piming. The ecuitment of fontal cognitive contol would as well esult in faste eactions as the utilization of piming elated memoies. Using the data fom fmri, we found that an analysis without tial epetitions esulted in significantly lowe activations of the conflict aeas than an analysis with all tials. An additional analysis with the same numbe of tials as the actual stimulus epetitions andomly emoved confimed that this effect was athe due to the educed tial numbe, than a tial epetition effect. Both tial-educed analyses wee significantly diffeent fom the oiginal analysis, but thei activation values did not diffe significantly fom each othe. These esults suggest that pocessing of the epeating tials is most likely not elated to piming effects, because events elated to piming activity should not educe powe in an aea assigned to conflict monitoing in the same way as andomized chosen events do. While these findings suppot the conflict adjustment theoy moe than they do the piming theoy, the intepetation of a null finding (no diffeence between the data afte emoval of epeated inconsistent tials when compaed with the data afte andom emoval of an equal numbe of tials) should, of couse, always be egaded cautiously. We cannot exclude the possibility that the lack of a diffeence might not be due to a lack of powe. Futhe studies ae necessay to confim these esults. The Auditoy Stoop Appoach fo Clinical Puposes It has been shown that the ability to pefom tasks elated to conflict management is alteed in bipola patients [Konhaus et al., 2006], patients with, e.g., attention-deficit/hypeactivity disode [Lansbegen et al., 2007] o in paanoid schizophenia [Henik and Salo, 2004; Nodahl et al., 2001; Stauss, 1993]. Among the diffeent sensoy modalities, the auditoy modality is of paticula inteest fo schizophenia [Veuillet et al., 2001], because schizophenia paticulaly affects auditoy pocessing [Bentaleb et al., 2002]. While pocessing deficits of the visual domain ae typically evoked by stuctual bain damages [Pigatano and Wong, 1999], auditoy vebal hallucinations ae one of the most chaacteistic symptoms of schizophenia [David, 1999]. Futhemoe, ecent studies have shown that patients with schizophenia, who fequently expeience auditoy hallucinations, exhibit dysfunctions of the ACC and bilateal tempoal lobe [Cleghon et al., 1992; Shegill et al., 2000], espectively, do not show activation of the ACC duing Stoop task pefomance [Cate et al., 1997]. Many studies also epoted abnomalities in the geneation of peattentive automatic pocessing of auditoy stimuli (e.g., mismatch negativity) in schizophenia [fo oveview see Umbicht and Kljes, 2005]. Futhemoe, a ecent study has shown that patients with schizophenia pefomed wose on an auditoy emotional peception task than paticipants fom othe goups [Vaskinn et al., 2007]. Since ou Stoop task showed a vey obust behavioal effect fo the auditoy modality, the suggested vesion of the Stoop intefeence task may be paticulaly useful fo clinical investigations. Stoop esults in the tial-by-tial vesion may be used fo the discimination of diffeent subtypes of schizophenia. Although the undiffeentiated subtype exhibited an inceased facilitation effect fo conguent stimuli, the paanoid subtype showed an inceased intefeence effect fo inconguent stimuli [Cate et al., 1993]. Hee, we have descibed an auditoy Stoop expeiment showing vey 3053

12 Haupt et al. obust behavioal effects in healthy subjects. Both the deficits in auditoy and in attentional/conflict pocessing of schizophenia patients ae elevant fo the auditoy vesion of the Stoop task. Theefoe, auditoy Stoop esults may epesent even moe sensitive tait makes fo schizophenia o may be even bette suited to diffeentiate schizophenia subtypes than conventional findings. Hence, the suggested vesion of the Stoop intefeence task may be paticulaly useful fo clinical investigations. CONCLUSIONS This study aimed at investigating the neual coelates of a newly developed auditoy appoach to the Stoop intefeence task using fmri. The auditoy Stoop design ceated a obust Stoop intefeence effect, poducing significantly longe eaction times fo the conflict elated condition. Excluding epeating tials did not change the behavioal as well as fmri esults, when compaed with a matched numbe of andomly chosen tials. Although the vast majoity of visual Stoop intefeence tasks esulted in the activations of the anteio/dosal pat of the ACC, we descibe a posteio/vental activation of the ACC in the contast of inconguent phonetic vs. inconguent semantic tials, which is stictly due to task-elated intefeence. In contast, the conventional compaison of inconguent phonetic vs. conguent phonetic tials activated a egion in the pe-sma/acc, which was also epoted in seveal visual Stoop studies. Finally, a connectivity analysis evealed that the thee most significantly activated aeas in the inconguent phonetic vs. inconguent semantic contast (ACC, DLPFC, and pe-sma) constitute a conflict pocessing netwok with highly coelated activity. ACKNOWLEDGMENTS The authos thank Pete Tautne fo his help with the development of the paadigm, and Bend Webe and Klaus Fließbach fo thei help with fmri logistics. 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