Preferential responses to extinguished face stimuli are preserved infrontal and occipito-temporal cortex at initial but not later stagesof processing

CHRISTIAN STEINBERG,a,b ANN-KATHRIN BRÖCKELMANN,a CHRISTIAN DOBEL,a,b LUDGER ELLING,a,b

PETER ZWANZGER,c CHRISTO PANTEV,a,b and MARKUS JUNGHÖFERa,b

aInstitute for Biomagnetism and Biosignalanalysis, University of Muenster, 48149 Muenster, GermanybOtto Creutzfeldt Center for Cognitive and Behavioral Neuroscience, University of Muenster, 48149 Muenster, GermanycDepartment of Psychiatry, University of Muenster, 48149 Muenster, Germany

Abstract

Magnetoencephalographic correlates of rapid emotional responses (50–80 ms) in frontal and occipito-temporal regionshave recently been reported using a novel MultiCS Conditioning paradigm with odor-conditioned faces. As thoseshort-latency responses were supposed to partially reflect initial access to nonextinguished emotional memories, it couldbe predicted that they outlast the extinction phase. To test this hypothesis, appetitively and aversively odor-conditionedfaces were frequently presented during extinction while event-related magnetic fields were recorded. Affect-specificresponses in frontal and occipito-temporal areas were found in the early (50–80 ms) but not in the later (130–190 ms)time interval following extinction learning. These results suggest that previously acquired emotional memories can beaccessed at initial processing stages but become ineffective in modulating processing at later stages as extinctionproceeds.

Descriptors: Emotion, Conditioning, MEG, Normal volunteers

Previous electrophysiological research on emotional processinghas shown that the processing of emotionally salient material isreflected in several distinct event-related potential (ERP) and mag-netic field components at midlatency (120–200 ms; e.g., Dolan,Heinze, Hurlemann, & Hinrichs, 2006; Junghöfer, Bradley, Elbert,& Lang, 2001; Keil et al., 2002) and late time intervals (> 250 ms;e.g., Schupp, Flaisch, Stockburger, & Junghöfer, 2006; Schupp,Junghofer, Weike, & Hamm, 2004) for various kinds of visualstimuli, including faces. Even earlier emotional modulations occur-ring between 60 and 90 ms, well in the time range of the C1 visualERP component, have been found in response to simple visualgratings after affective learning (e.g., Keil, Stolarova, Moratti, &Ray, 2007; Stolarova, Keil, & Moratti, 2006) and also for morecomplex stimuli such as, for example, faces (Pourtois, Grandjean,Sander, & Vuilleumier, 2004). These early activations have beenassumed to originate in more perceptual, early sensory (V1) oroccipito-temporal visual areas. In addition, there is some evidencethat even frontal regions can be engaged in early emotional

processing with latencies starting around 90–100 ms after stimulusonset (Bayle & Taylor, 2010; Rudrauf et al., 2008).

Brain regions such as amygdala and prefrontal cortex (PFC)regions are thought to play a vital role in the extinction of fearmemories in animals (e.g., Maren & Quirk, 2004) and humans(e.g., Gottfried & Dolan, 2004; Phelps, Delgado, Nearing, &LeDoux, 2004). Typically, extinction describes a weakening ofconditioned responses (CR) following repeated presentations of theconditioned stimulus (CS) alone (e.g., Rogan, Staubli, & LeDoux,1997), after it had been paired with the unconditioned stimulus(US). Importantly, extinction is short lived, is context dependent,and does not simply erase previously learned CS-US associationsbut more likely reflects the learning of new CS–no US representa-tions (e.g., Quirk & Mueller, 2008; Rescorla, 1996). These inhibi-tory memories, in turn, are able to suppress previously acquiredCRs (e.g., Delamater, 2004; Rescorla, 1996). This is mirrored byfindings from two functional magnetic resonance imaging (fMRI)studies investigating extinction in humans (Phelps et al., 2004). Forinstance, Gottfried and Dolan found differential activity in PFC andamygdala during extinction of olfactorily conditioned faces. Spe-cifically, they showed that the storage of previously learned CS-USassociations (formed during conditioning) was maintained inventral medial prefrontal areas throughout extinction, whereasinformation about CS–no US associations (formed during extinc-tion) was encoded in lateral orbitofrontal cortex (OFC) regions.Corroborating previous behavioral results, these findings clearly

We thank the anonymous reviewers for their helpful comments andsuggestions to improve the quality of this work. This work was supportedby the Deutsche Forschungsgemeinschaft grant SFB TRR-58 C01.

Address correspondence to: Christian Steinberg, Malmedyweg 15,D-48149 Münster, Germany. E-mail: christian.steinberg@uni-muenster.de

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Psychophysiology, 50 (2013), 230–239. Wiley Periodicals, Inc. Printed in the USA.Copyright © 2013 Society for Psychophysiological ResearchDOI: 10.1111/psyp.12005

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show that, although the CS no longer predicts the US in extinction,the original link between CS and US is preserved in frontal areas.Thus, extinction appears to form new (inhibitory) memories inprefrontal areas while leaving previously learned CS-US associa-tions intact but rendering them ineffective.

In a recent magnetoencephalographic study, Steinberg, Dobel,and colleagues (2012) reported on rapid activations in response toolfactorily conditioned faces using a novel MultiCS Conditioningparadigm (see Steinberg, Bröckelmann, Rehbein, Dobel, & Jung-höfer, 2012, for more detailed information on this paradigm). Inthis study, initial (50–80 ms) and later (130–190 ms) affect-specificresponse enhancements were observed in both frontal and occipito-temporal areas. Most importantly, these responses occurredalthough more than 100 different CS faces with neutral expressionhad to be differentiated from each other and based on a brieflearning history with only two reinforced CS presentations. Thus,in an extention of previous electrophysiological research, emo-tional modulations not only occur at midlatency time intervals butalso at initial stages of processing.

On the basis of the reviewed literature regarding extinction inhumans and in view of the results in our preceding study, wehypothesized that neuronal network activity at initial stages (50–80 ms) of affective processing (Steinberg, Dobel, et al., 2012)would be less modulated by extinction, as they are supposed toreflect fast access to already stored (extinction-resistant) CS-USassociations (Gottfried & Dolan, 2004). For the midlatency interval(130–190 ms), we expected an extinction-mediated decline of con-ditioned responses. That is, there should be no differences betweenconditions for the midlatency interval as affective processing isassumed to be modulated by reentrant and top-down influencessuppressing previously acquired emotional memories (e.g., Schuppet al., 2006; Vuilleumier, 2005). In other words, after extinction,original CS-US representations should still be accessible that allowfor a clear differentiation between CS+ and CS- at initial stagesreflected by amplified processing in frontal areas. In contrast,processing in the midlatency time interval should be stronglyreduced as the saliency of the CS+ faces decreases and, hence,motivated attention toward these stimuli should become progres-sively gratuitous during extinction.

In the present work, we investigated neural activity by means ofwhole-head high-density magnetoencephalography (MEG) incombination with distributed source localization methods. In avisuo-olfactory version of classical conditioning, three different,previously neutral face stimuli acquired affective meaning throughrepeated pairings with pleasant and unpleasant odors. Because onlythree different CS were used (as opposed to 104 different CS inSteinberg, Dobel, et al., 2012), which were frequently repeatedafter conditioning, previously learned conditioned responsesshould became extinguished. This is suggested by evidenceshowing that extinction can occur within the first few CS+ presen-tations at both the behavioral and the neuronal level (Lesting et al.,2010). To investigate the influence of extinction processes on pre-viously reported fast affect-specific emotional responses (e.g.,Steinberg, Dobel, et al., 2012), the data analysis was entirely basedon our hypotheses regarding differential activity in the above men-tioned intervals (50–80 ms and 130–190 ms) and regions (frontaland occipito-temporal). That is, neural activity was analyzed withinsimilar brain regions and in a priori defined time intervals origi-nally identified by Steinberg, Dobel, et al. (2012). The aim of thepresent work was to investigate whether these rapid and midlatencyresponses to affect-associated faces can still be detected afterextinction learning took place.

Method

Participants

Twenty-three healthy, right-handed volunteers (11 men, mean age:24, age range: 20–29) with no past history of neurological orpsychiatric disorders participated in this study. None of the subjectsreported respiratory problems or other putative deficits in smelling.All had normal or corrected-to-normal vision and were paid forparticipation. Written informed consent was obtained before theexperiment, which was approved by the ethics board of the Uni-versity of Muenster.

Stimuli

The CS comprised six expressionless faces (3 female), which weretaken from the face database of our own lab. All faces were cropped(including hair), converted to grayscale, and scaled to the sameheight (142 pixels) using Adobe Photoshop software. Faces werepresented with the nasion positioned at the center of the screenabove a gray background and were adjusted to a mean brightness.In the behavioral tests (see below), four additional male or femalefaces served as fillers for the female or male subjects. Regardingthe importance of smell in human mate selection (e.g., Herz &Inzlicht, 2002), we assumed that olfactory conditioning mightmodulate motivated attention toward an opposite sex face to astronger degree than toward same sex faces. Thus, in an attempt topresumably maximize ecological validity and effect sizes, femaleparticipants were presented with the three male faces and maleparticipants with the three female faces.

Three odors comprised the US. Citral, an aroma compound usedin perfumery for its citrus effect, was chosen as the pleasant US.With a concentration of 0.1% w/v in water, the intensity of thisUS was comparable with the odor of a freshly cut lemon.Hydrosulfide—the unpleasant US—has a characteristic foul odorand is typically produced by humans in only small amounts. Witha concentration of 0.1% w/v in water, this US has been perceived asa mild but clearly unpleasant odor. Humid air served as neutral USand therefore as the control condition.1

Experimental Procedure

The experimental design followed a pre-treatment-post structure(baseline, conditioning, extinction). These three phases had to becompleted in the MEG scanner first, and then two behavioral testswere administered to the subjects at the very end of the experiment.

Prior to MEG measurements, landmark coils were attached tothe auditory canals and the nasion to monitor the participant’sposition during MEG data acquisition. Individual head shapes weredigitized using a Polhemus 3Space Fasttrack. Subjects were seatedin a dimly lit, sound-attenuated, and magnetically shielded room.Visual stimulation in the chamber was provided via a mirror systempassing the image onto a projection screen that was set to a viewingdistance of 57 cm (6° viewing angle).

In the baseline session, three faces were shown 60 times eachfor 500 ms with an interstimulus interval (ISI) of 1200 � 600 ms.Stimuli were pseudo-randomized such that transition probabilitiesbetween conditions were matched. Participants were instructed to

1. We chose a “nonsmell odor” to ensure that the control odor wasperceived as emotionally neutral and hence behaviorally irrelevant (cf.Steinberg, Dobel, et al., 2012).

Preferential responses to extinguished face stimuli 231

passively view the images on the screen. In the following twoconditioning runs, each CS was paired 20 times with its corre-sponding US to ensure high contingency awareness. Assignment ofCS and US was balanced across participants. The pairing schemefor the affective associative learning followed a modified delayedconditioning protocol: First, a CS appeared for 500 ms, and with itsoffset the US was presented for 6 s. Within the time of US presen-tation the CS appeared three additional times for 500 ms eachwith a pseudo-randomized ISI between the (same four) CS of1500 � 400 ms such that in every trial the (last) CS and US dis-appeared simultaneously. During the ISIs a fixation cross was pre-sented in the center of the screen. Odors were delivered using acustom-made nonferromagnetic stimulator. Odor delivery was cali-brated such that no perceivable tactile, thermal, or acoustic stimu-lation occurred. In trials with odor presentations (conditioningphase), we ensured that an ISI of 2000 ms (between offset andonset of two consecutively presented odors) was enough time forthe odorants to vanish. Thus, possible carryover effects of odorsbetween conditioning trials were avoided (see Steinberg, Dobel,et al., 2012, for more details on odor presentation).

Except for a different randomization, stimulation parameters forthe following extinction phase were identical with the baselinesession. Between the phases (6 min for pre- and postconditioningsessions, 7.5 min for each conditioning session), short breaks wereinterspersed. An illustration of the experimental paradigm in theMEG is given in Figure 1. After MEG recordings were finished,two behavioral tests had to be completed.

In a first test, before and after MEG sessions, subjects had toperform complete pair comparisons including the three CS as wellas four additional faces. For each possible pair of faces (21),subjects were required to decide which face they preferred, and allpairings were repeated 3 times to obtain more reliable data. Pres-entation time was not limited, and the next pair of faces appeared as

soon as the subject made a response. Pair comparison data wereanalyzed using rank analysis.

In a second test, self-report measures, obtained at the end of theexperiment, were collected from every subject to assess US quality.Each US was evaluated three times on valence and arousal dimen-sions as measured by the Self-Assessment-Manikin (SAM) scale(Bradley & Lang, 1994). The order of presentation was fully ran-domized, and mean values for valence and arousal ratings across allthree presentations of every CS were calculated.

MEG Data Recording and Processing

Visual evoked magnetic fields were acquired continuously using a275 MEG whole-head sensor system (CTF, VSM Medtech Ltd.)with first-order axial SQUID gradiometers. Brain responses weresampled at 600 Hz and filtered online with a frequency bandpass of0–150 Hz. MEG data preprocessing; artifact rejection; and correc-tion, averaging, statistics, and visualization were conducted withthe Matlab-based EMEGS software (www.emegs.org; Peyk, DeCesarei, & Junghöfer, 2011). Artifact correction was based on themethod for statistical control of artifacts in high density EEG/MEGdata for single trial data (Junghöfer, Elbert, Tucker, & Rockstroh,2000). Next, data were averaged for epochs lasting from 200 msbefore to 600 ms after stimulus onset. After averaging, corticalsources of the evoked magnetic fields were estimated using theL2-Minimum-Norm-Estimates method (L2-MNE; Hämäläinen &Ilmoniemi, 1994). The L2-MNE is an inverse modeling techniqueapplied to reconstruct the topography of the primary current under-lying the magnetic field distribution. It allows the estimation ofdistributed neural network activity without a priori assumptionsregarding the location or number, or both, of current sources (Hauk,2004). A spherical shell with evenly distributed 2 (azimutal andpolar direction; radial dipoles do not generate magnetic fields

Figure 1. Schematic overview of the experimental design. a: Stimulation in the pre- and postconditioning phases. Tilted green bars indicate the interstimulusinterval (ISI). Presentation times (small numbers) are given in milliseconds. b: Conditioning procedure. Please note that the order of CS appearance wasrandomized across subjects. Tilted green bars indicate the ISI, and presentation times are given in milliseconds (small numbers). Colored rectangles representthe aversive (red), appetitive (blue), and neutral US.

232 C. Steinberg et al.

outside of a sphere) ¥ 350 dipoles was used as a source model. Asource shell radius of 87% of the individually fitted head radius waschosen, roughly corresponding to the gray matter volume.

Although the sphere-based reconstruction of distributed sourcesin MEG does not provide information about the precise localizationof neural sources, it allows for a fairly good approximation ofcortical generators and their allocation to larger cortical structures.Across all participants and conditions, a Tikhonov regularizationparameter k of 0.2 was applied. Topographies of source directionindependent neural activities—the vector length of the estimatedsource activities at each position—were calculated for each indi-vidual participant, condition, and time point based on the averagedmagnetic field distributions and the individual sensor positions foreach participant and run.

MEG Data Analysis

Data analysis was based on neuronal generator activity obtained forevery test dipole and subject over time within regions and intervalsoriginally described by Steinberg, Dobel, and coworkers (2012).Accordingly, responses to CS stimuli in frontal and occipito-temporal areas in an early (50–80 ms) as well as in a later interval(130–190 ms) were analyzed. Data were submitted to a repeated-measures analysis of variance (ANOVA) including the factorssession (baseline and extinction) and CS type (unpleasant, neutral,and pleasant). As data did not violate the sphericity assumption,Greenhouse–Geisser correction was not applied. Based on theresults of this spatiotemporal waveform analysis, statistical effectswithin one frontal and two mirror-symmetric occipito-temporalregions were further analyzed using post hoc t tests to specify thedirection of effects. Effects were considered meaningful only ifthey were present for at least 30 ms and occurred in a regioncovered by at least 10 neighboring dipoles. Data from 5 subjectshad to be excluded from further analysis of MEG data becausethere were either too few trials left after artifact correction (2subjects) or because of an overall low signal-to-noise ratio2 (3subjects) leaving 18 subjects for the final analysis. Please note thatconditioning effects were identified by comparing activity in base-line and extinction with each other, when no odor was present at all.The baseline measure has been introduced to (a) eliminate possibleinfluences of preexisting variations in the processing of the differ-ent faces (in spite of the balanced assignment across subjects) and(b) to elucidate how brain responses to CS stimuli behave in termsof increasing or decreasing activity across sessions.

Results

MEG Data

In the next section, results of the spatiotemporal waveform analysiswill be presented. All following calculations are based on the meanneural activity within the regions of interest (frontal and occipito-temporal) and a priori defined intervals according to Steinberg,Dobel, et al. (2012). To evaluate conditioning effects, activity in theextinction phase was compared with activity in the baseline phase.In addition, testing activity in the baseline session did not yield any

systematic differences in the processing of the CS between condi-tions (all ps > .2 obtained by one-way ANOVAs with factor CStype (positive, negative, neutral) for baseline activity in the regionsof interest and for the a priori defined intervals).

Prefrontal cortexEarly interval. Consistent with our hypotheses, a first signifi-

cant emotional modulation occurred in the early (50–80 ms) inter-val that was located over medial and right inferior frontal cortexregions (Figure 2a, middle column). This effect was reflected by aSession ¥ CS type interaction, F(2,34) = 5.141, p = .011, whichfollowed a linear trend, F(1,17) = 8.074, p = .011. Post hoc ttests revealed that activity for unpleasant CS was increased,t(17) = -2.55, p = .021, whereas activity for the pleasant,t(17) = 1.298, p = .212, and the neutral, t(17) = 1.277, p = .219, CSdid not change significantly from baseline to extinction sessions,although a numerical decline of responses was evident (Figure 2b,middle column).

Unpleasant CS not only showed a within-category increase ofactivity across sessions (circles in Figure 2) but also differedbetween affective conditions (asterisks in Figure 2) after condition-ing. That is, activity for the unpleasant CS was significantlystronger as compared to pleasant, t(17) = 2.842, p = .011, andneutral CS, t(17) = 2.620, p = .018, in frontal regions. Neutral andpleasant CS did not differ between each other (p > .05).

Midlatency interval. In the later interval (130–190 ms) a sig-nificant main effect of session was found, F(1,17) = 10.201,p = .005, showing that activity decreased from baseline to extinc-tion in all three categories (Figure 3, middle column). There wereno significant differences between categories (all p > .05).

Thus, processing of unpleasant CS was increased in frontalareas in a markedly early interval after conditioning whereas activ-ity in the later interval was characterized by a reduction ofresponses across affective categories.

Occipito-temporal cortexEarly interval. Significant emotional modulations within the

50–80-ms interval were found in bilateral occipito-temporalregions. Consistent with our hypotheses, we found a significantSession ¥ CS type interaction, F(2,34) = 11.752, p = .000), in aright occipito-temporal region (Figure 2a, right column). Quadratictrends for this effect were significant, F(1,17) = 12.08, p = .003.Specifically, activity to unpleasant CS increased, t(17) = -2.17,p = .044, from baseline to extinction sessions whereas activity toneutral CS significantly decreased, t(17) = 3.976, p = .001, asrevealed by post hoc t tests. Brain responses to the pleasant CSremained unchanged, t(17) = 1.534, p = .143, across sessions. Inaddition, all three categories differed from each other such thatunpleasant CS elicited stronger activation relative to neutral,t(17) = 4.092, p = .001, and positive CS, t(17) = 3.33, p = .004,whereas activity to positive CS was increased when compared toneutral stimuli, t(17) = 2.194, p = .042; see Figure 2b, rightcolumn). Thus, following a quadratic response profile, both emo-tional CS received amplified processing, but responses to unpleas-ant relative to pleasant CS were even more increased. In contrast,activity to neutral CS decreased over time.

In the left hemisphere, we found a Session ¥ CS type interac-tion in the early interval covering occipito-temporal regions,F(2,34) = 4.506, p = .018 (Figure 2a, left column) mirroring theright hemispheric effect. Trend analysis showed a marginal signifi-cant quadratic effect, F(1,17) = 4.408, p = .051. Although neural

2. The signal-to-noise ratio was defined as the strength of global(across all conditions and all test sources) neural activity within the tworelevant time intervals of interest in comparison to baseline activity. Inaddition, the reported effects stay significant when data of the threeexcluded subjects is included in the analysis again.

Preferential responses to extinguished face stimuli 233

responses seem to be less pronounced in the left hemisphere, thisinteraction shows a similar effect when compared to the effectsfound in the right hemisphere, as changes in activity all point intothe same direction. However, unlike in the right hemisphere, sta-tistical analysis showed a significant decrease of activity for theneutral CS, t(17) = 2.589, p = .019, only. Unpleasant CS stillreceived boosted processing as compared to neutral, t(17) = 2.829,p = .012, and pleasant, t(17) = 2.158, p = .046, stimuli. Neutral andpleasant CS did not differ between each other (p > .05; Figure 2b,left column).

Midlatency interval. As in the frontal region within this timeinterval, significant main effects of session were observed in theright, F(1,17) = 19.228, p = .000, and in the left, F(1,17) = 23.901,p = .000, occipito-temporal regions, showing that activity was sig-nificantly decreased from baseline to extinction sessions. Accord-ingly, there were also no significant differences between conditionsat both hemispheres (all p > .05; Figure 3, left and right columns).

Hemispheric differences. An additional analysis including thefactor hemisphere, using symmetrical left and right occipito-temporal dipole groups, yielded a significant effect of laterality,

F(1,17) = 26,815, p = .000, in the early interval. Accordingly,overall activity was stronger in the right (mean = 6.62, SD = 1.11)as compared to the left hemisphere (mean = 5.35, SD = 0.69).Although there was no three-way interaction of session, CS type,and hemisphere, however, differences between conditions seem tobe more pronounced in the right hemisphere (see Figure 3b). Therewas neither a main effect of hemisphere nor an interaction ofsession, CS type, and hemisphere in the later interval (all p > .05).Please note that lateralization of the prefrontal effect was notassessed because more medial and right-hemispheric activationswere expected (Steinberg, Dobel, et al., 2012). Indeed, effects inthis region not only covered right hemispheric but also medialportions of prefrontal cortex (see Figure 3, middle column).

An early Session ¥ CS type interaction at right parietal regions(see Figure 3) with relatively enhanced processing for theunpleasant as compared to the pleasant and neutral CS was sig-nificant by trend, F(2,34) = 2.753, p = .078. A similar region withrelatively enhanced processing for the unpleasant CS was notice-able but also not significant in the MultiCS conditioning paper(Steinberg, Dobel, et al., 2012). This area has thus not been con-sidered as a target region and this effect is—for brevity—not dis-cussed in more detail.

Figure 2. Differential responses in the early interval. a: Statistical parametric map. Spherical projection of statistical values (p) onto a 3D brain modelshowing significant difference activations for the interaction of session and CS type. b: Neural activity in the frontal and both occipito-temporal regions.Dipoles in the regions of interest (ROI) are shown in the 3D brain model (black dots). Bar graphs represent regional amplitude differences between pre- andpostconditioning for aversive (red), neutral (gray), and appetitive (blue) CS. Significant differences between pre- and postconditioning phases withinconditions (red circles) and between conditions (red asterisks) are depicted. *p < .05, **p < .01; °p < .05, °°p < .01.

234 C. Steinberg et al.

In sum, unpleasant CS evoked increased brain activity in bilat-eral occipito-temporal regions whereas activity to pleasant CSremained unchanged from baseline to extinction sessions, but stillshowed an relative amplification of responses as compared toneutral stimuli. Activity for neutral CS was reduced in bothhemispheres.

Behavioral Data

US sam rating. In line with our predictions, an one-wayANOVA with the factor US-valence (citral, hydrosulfide, humidair) yielded significant differences between odors for bothhedonic valence, F(1,23) = 404.81, p = .000, and emotionalarousal, F(1,23) = 8.181, p = .001, ratings. Post hoc t tests revealedthat hydrosulfide (valence: M = 1.6, SD = 0.54, arousal: M = 4.89,SD = 2.2) was perceived as more unpleasant, t(23) = 18.976,p = .000, and more arousing, t(23) = -2.827, p = .01, whereas citral(valence: M = 7.64, SD = 0.84, arousal: M = 5.31, SD = 2.16) wasperceived as more pleasant, t(23) = 9.6, p = .000, and more arous-ing, t(23) = 5.822, p = .000, than humid air (valence: M = 5.63,SD = 0.83, arousal: M = 3.11, SD = 1.56). Arousal ratings of citraland hydrosulfide did not differ, t(23) = 0.574, p = .572. However,the difference of valence ratings between hydrosulfide and thecontrol odor (absolute mean difference: 4.04) was doubly as strongas the corresponding absolute difference between citral and humidair (absolute mean difference: 2.01). This “negativity bias” for odorvalence was shown by 23 out of 24 participants, t(23) = 5.59,p = .000.

Pair comparisons. In this complete pair comparison task, subjectswere required to choose one of two simultaneously displayed faces(neutral CS, pleasant CS, unpleasant CS, and four filler faces)according to their initial preference. As described in the Methodsection a rank analysis was performed. In line with our predictions,across all subjects, the pleasant CS occupied the highest rank, 1(most preferred), the unpleasant CS was placed at the lowest rank,7 (least preferred), and the neutral CS was placed in between (rank

3). The absolute rank difference was 2 (rank 3 - rank 1) for thepleasant and neutral CS comparison but 4 (rank 7 - rank 3)—andthus doubly as strong—for the unpleasant versus neutral CS com-parison, which agrees with the negativity bias of the US valenceratings. Individual ranking data were further analyzed using posthoc Wilcoxon tests (one-tailed). Confirming the global rankingresult, this test revealed that unpleasant CS (p = .023) were less andpleasant (p = .035) CS were more preferred in the extinction com-pared to the baseline session. No significant differences were foundfor neutral CS (p = .376). Using Mann–Whitney tests, no differ-ences in the pair comparison data between men and women werefound (all p > .1).

Discussion

In summary, consistent with our predictions, fast emotional catego-rization of affectively conditioned stimuli was observed at initialbut not later stages of processing. The results of the present studyshow that the processing of faces that became associated withaffective odors is relatively increased in frontal and occipito-temporal cortex regions in an early time interval, even as extinctionproceeds. In contrast, activity in all three affective categories didnot differ but was significantly reduced in the midlatency interval.Behavioral results suggest that subjects gained explicit knowledgeabout CS-US contingencies, as they were able to categorize the CSaccording to their (previously acquired) emotional meaning.

Early Interval (50–80 ms)

Rapid affect-specific responses in the 50–80-ms interval werefound in medial, right prefrontal, and bilateral occipito-temporalareas. In line with our hypotheses, aversively conditioned neutralfaces received amplified processing in the frontal region at theinitial stage of processing. Notably, such a kind of amplificationwas absent for the appetitive CS, as it was for the neutral CS aswell. That is, the increased CS processing in frontal areas wasspecific to the aversively conditioned faces. This result is consistent

Figure 3. Main effect of session in the region of interest (ROI) for the midlatency interval (130–190 ms). Bar graphs represent neural activity within ROIfor the pre- and postconditioning phases. Asterisks indicate significant differences between pre- and postconditioning phases. **p < .01.

Preferential responses to extinguished face stimuli 235

with previous work showing increased activity toward multipleaversively conditioned faces and replicates the results of Steinberg,Dobel, and colleagues (2012). Although repeated non-reinforcedexposure to CS+ in the extinction phase typically should have ledto extinguished conditioned responses (Quirk & Mueller, 2008),previously acquired emotional memories were obviously pre-served, as indicated by differential CS+ processing in frontal andoccipito-temporal cortices. This result suggests that, after extinc-tion, information about the acquired emotional meaning is obvi-ously still available, which agrees with several previous studiesarguing that conditioned responses are not simply erased but ratherthat extinction reflects a kind of (new) inhibitory learning (Dela-mater, 2004; Maren & Quirk, 2004; Rescorla, 1996). The presentdata also show that recently established emotional memories aremaintained in prefrontal cortex. The prefrontal cortex, especiallythe orbitofrontal, ventromedial, and medial sectors, has been impli-cated in processes related to extinction (Gottfried & Dolan, 2004;Maren & Quirk, 2004; Phelps et al., 2004). More specifically, itwas shown that specific regions in human prefrontal cortex not onlyparticipate in extinction learning and the retention of extinctionmemories (Phelps et al., 2004) but also that previously acquiredCS-US associations are preserved (Gottfried & Dolan, 2004)throughout extinction. These findings clearly show that, in humans,mPFC and OFC regions are involved in extinction, substantiatingour source localization result of heightened cortical activity forpreviously learned CS-US associations in the first interval. Theearly prefrontal effects found here resemble those reported in theaforementioned fMRI studies, as the increase in CS+ processingcould either signal extinction-related activity (extinction learning)or the access to memorized CS-US representations or both.Because the ventromedial prefrontal cortex seems to be moreinvolved in the retention of extinction memory, the prefrontaleffects found here might be more related to the access of previouslylearned CS-US associations.

Differential responses to emotional as compared to neutral CSstimuli were found in bilateral occipito-temporal areas. In the rightand left hemispheres, aversively conditioned faces elicited strongeractivity as compared to neutral and appetitive CS. Moreover, neuralactivity in response to appetitively conditioned faces was evenslightly reduced when compared between sessions (baseline vs.extinction), albeit this difference failed to reach significance. Refer-ring to the increase of aversive CS+ processing, results of Stein-berg, Dobel, and co-workers (2012) could have been replicated.This finding indicates that a significant cross talk could take placebetween specific prefrontal and temporal areas regarding visualemotional processing. Indeed, the categorization of affectivestimuli has been shown to occur in several closely intertwinedareas, including lateral PFC, orbital PFC, and inferior temporalcortex (e.g., Bar, 2003; Freedman, Riesenhuber, Poggio, & Miller,2003). Importantly, these areas share numerous connections withother structures implicated in emotional processing, such as theamygdala (e.g., Cavada, Company, Tejedor, Cruz-Rizzolo, &Reinoso-Suarez, 2000). Consequently, there is evidence fromanimal (e.g., Quirk & Beer, 2006) and human hemodynamic(Adolphs, 2002; Gottfried & Dolan, 2004; Phelps et al., 2004) andelectrophysiological studies (e.g., Kringelbach & Rolls, 2004)demonstrating that these areas contribute to affective stimulusanalysis.

According to the results of Rudrauf and colleagues (2008),early visual areas might rapidly transmit relevant emotional infor-mation to anterior frontal regions via, for example, long-rangeassociation fibers. In a recent review, Pessoa and Adolphs (2010)

claimed that speed of cortical visual affective stimulus processingis by no means faster than cortical processing of neutral material,but, indeed, that cortical visual stimulus processing per se might befaster than previously thought. For instance, short-latencyresponses to complex stimuli have been recorded in human frontalcortex (Kirchner, Barbeau, Thorpe, Régis, & Liégeois-Chauvel,2009). Thus, there is evidence from different fields of researchinvestigating (emotional) vision suggesting that the speed ofprocessing can be considerably faster as is assumed in the “fast-brain” model (Bullier, 2001) or the “multiple-waves” model(Pessoa & Adolphs, 2010) relative to more traditional models ofvisual (emotional) processing.

However, possible pathways conveying such rapid responsesare currently under debate (for a recent review, see Pessoa &Adolphs, 2010). Theoretically, three putative pathways appear fea-sible: (a) an extrageniculostriate pathway, (b) a thalamo-amygdalapathway, and (c) a fast geniculo-cortico-cortical pathway. The rapidresponses found in the present work probably rely on (c) or acombination of (b) and (c), but see Steinberg, Dobel, et al. (2012)for more detailed information.

The impact of appetitive conditioning on neural activity wasdistinctively weaker when compared to aversive conditioningeffects. In fact, in the early time interval, right prefrontal areas didnot show any hint for an enhanced processing of pleasant comparedto neutral CS faces, and, regarding the occipito-temporal areas,preferential processing for pleasant compared to neutral CSreached significance only at the right hemisphere. This result mightsuggest that the rapid emotional categorization found here is ratherspecific to stimuli belonging to the unpleasant continuum, empha-sizing the more exclusive role of brain areas (PFC, amygdala, andtemporal and primary sensory areas) dedicated to the (fast) detec-tion of threat signals (e.g., Vuilleumier et al., 2001; Vuilleumier,Richardson, Armony, Driver, & Dolan, 2004). However, one mustaccount for the fact that the effects in the behavioral CS and USratings were doubled in the aversive compared to the appetitivecondition. In this regard, the obviously less pronounced effects forpleasant CS in the occipito-temporal areas cannot be taken asevidence for rapid affective processing being exclusive for aversivestimuli. In fact, a recently finished olfactory face conditioningstudy in our lab revealed rapid preferential processing of positiveCS (vanillin and a human pheromone) at occipito-temporal and,interestingly, left prefrontal regions areas (Klinkenberg et al.,2011). This corroborates findings from studies claiming that dis-tinct neuronal circuits, especially in the prefrontal cortex region,are specialized for different kinds of emotional signals whereasthose systems share some but not all brain structures implicated inemotional processing (e.g., Pessoa, 2008).

Results in the early time interval could also be related to con-ditioning effects found in studies using a Steady State VisualEvoked Field (SSVEF) paradigm. For instance, when simple visualgratings, presented with 12.5-Hz oscillation, were previouslypaired with an aversively loud sound, relatively enhanced process-ing within occipito-temporo-parietal areas when compared tounpaired gratings has been reported (Moratti & Keil, 2009;Moratti, Keil, & Miller, 2006). However, SSVEF paradigms do notprovide direct information about effect latencies because ERFcomponents of subsequent stimuli overlap but the tuning or reso-nance frequency of strongest effect size might give an indirect signfor effect latencies. With 12.5 Hz, early event-related field (ERF)difference components with latencies around 80 ms (12.5-Hzwavelength) receive resonance. The preference for the rather high12.5-Hz tuning frequency might thus converge with our finding of

236 C. Steinberg et al.

preserved conditioning effects at early time intervals but missing orat least strongly reduced midlatency effects (these later effectswould receive resonance at frequencies between 5 and 8 Hz).Finally, we would like to point out that our results also relate tofindings from perceptual learning studies (Chaumon, Drouet, &Tallon-Baudry, 2008; Pourtois, Rauss, Vuilleumier, & Schwartz,2008). Short-latency responses (< 100 ms) in, for example, ventralvisual and PFC regions have been associated with unconsciousvisual memory for trained stimuli. Interestingly, a recent MEGstudy using faces in a perceptual learning paradigm found an earlyOFC activation (60–85 ms) that appears to be very similar to therapid orbitofrontal cortex responses shown in the present work(Gamond et al., 2011). That is, our findings mirror recent reportsabout rapid visual processing that is capable of categorizingcomplex stimuli based on prior experience. The results obtainedhere thus appear not specific to affective face conditioning butcould be integrated in a larger learning framework.

Midlatency Interval (130–190 ms)

Although the rather strong conditioning effects in the early timeinterval nicely converge with effects in the prior MultiCS condi-tioning study, midlatency interactions were absent or at least notdetectable,3 contradicting the even stronger midlatency effects inthe Steinberg, Dobel, et al. (2012) study. Previous work has shownthat repeated non-reinforced exposure to conditioned stimuli typi-cally leads to strongly reduced or eliminated conditioned responses(e.g., Quirk & Mueller, 2008; Rogan et al., 1997) as extinctionforms new inhibitory memories that, in turn, suppress conditionedreactions (e.g., Delamater, 2004; Rescorla, 1996). Moreover, somestudies showed that substantial extinction can be reached withinjust one or two trials in animals (e.g., Quirk, 2002) and humans(e.g., LaBar, Gatenby, Gore, LeDoux, & Phelps, 1998), respec-tively, when using a 100% reinforcement strategy plan. Thus, giventhat conditioned stimuli were frequently presented in the extinctionphase, it can be assumed that previously conditioned responses toCS faces were fully extinguished. This is mirrored by indistin-guishable brain responses between affective categories in theregions of interest.

However, as a consequence of the 100% reinforcement strategy,this study cannot provide direct evidence for a differential process-ing at midlatency time intervals preceding extinction.4 It might be

that midlatency effects of conditioning have not rapidly been extin-guished, as we would argue, but alternatively have never developedin the course of learning. In fact, apart from contingency aware-ness, the MultiCS conditioning study and the classical conditioningstudy at hand predominately differ with respect to the number ofCS faces used (104 vs. 3). As a consequence, stimulus differentia-tion of three faces only—which differ already in simple featureslike shape—could be sufficiently performed within the early waveof processing, and a second reentrant control processing loop atmidlatency time intervals was necessary for the highly complex CSdifferentiation in the MultiCS study only. This interpretation wouldfit to the findings by Stolarova et al. (2006) and Keil et al. (2007),who found conditioning effects for simple gratings during inter-mittent conditioning at early (60–90 ms) but not at midlatency timeintervals.

However, we would still argue that the distinct separation ofstrong effects in the early interval but absent or at least stronglyreduced effects in the midlatency interval—also when compared toearly and midlatency conditioning effects in the MultiCS condi-tioning study—represent neural correlates of extinction. At firstglance, the behavioral effects appear to contradict this view,because subjects categorized the CS according to their previouslyacquired emotional meaning after they underwent 60 extinctiontrials. However, we have to keep in mind that subjects should havebeen completely aware of CS-US contingencies in this classicalconditioning study. In case of awareness, the pair comparison tasktests not only implicit but also explicit knowledge about CS-USassociations. With recollection of the explicit CS-US memories,subjects could have categorized the stimuli in a purely cognitivefashion. The explicit recall of the US and CS-US associationsmight have additionally evoked some form of imaginary “reacqui-sition and/or reinstatement” and might thus have recovered previ-ous affective associations. Future studies should additionally applyimplicit tests such as implicit priming in order to track the course ofextinction independent of awareness also on a behavioral level.

In the present study, differential responses to previously condi-tioned face stimuli were preserved at early but not later stages ofneural processing, following extensive extinction learning incontingency-aware subjects. Thus, rapid responses, originallydescribed by Steinberg, Dobel, et al. (2012), are apparently notspecific to the deployed MultiCS Conditioning paradigm withwhich previously conditioned emotional responses can be capturedin the beginning of the extinction phase. We propose that previ-ously learned CS-US associations, presumably represented in pre-frontal cortex, are accessed at initial stages of stimulus analysis,leading to inhibited or strongly reduced activity at later stages, oncethey undergo extinction and thus become no longer relevant for theorganism in the current situation. The change in neural responsesseen in frontal and occipito-temporal areas might predominatelyreflect automatic stimulus-driven activity at the initial wave ofprocessing, whereas processing at later stages might be guided, atleast to a stronger degree, by top-down influences (e.g., Adolphs,2002), resulting in a response pattern typically expected afterextinction.

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(Received February 9, 2012; Accepted October 13, 2012)

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