error detection in patients with lesions to the medial prefrontal cortex: an erp study

Neuropsychologia 42 (2003) 118–130

Research report

Error detection in patients with lesions to themedial prefrontal cortex: an ERP study

Brigitte Stemmera,b,∗, Sidney J. Segalowitzc, Wolfgang Witzked, Paul Walter Schönleea Centre de Recherche, Institut Universitaire de Gériatrie de Montréal, 4565 Chemin Queen Marry, Montreal, Que., Canada H3W1W5

b Département de linguistique et traduction, Université de Montréal, Montreal, Que., Canadac Department of Psychology, Brock University, St. Catharines, Canada

d Kliniken Schmieder, Allensbach, Germanye Neurological Rehabilitation Center, Magdeburg, Germany

Received 16 February 2001; received in revised form 11 June 2001; accepted 30 April 2003

Abstract

When people detect their own errors in a discrimination task, a negative-going waveform can be observed in scalp-recorded EEG that hasbeen coined the error-related negativity (Ne/ERN). Generation of the Ne/ERN has been associated with structures in the prefrontal cortex,especially the anterior cingulate region, but also the supplementary motor cortex and subcortical structures. There is some controversy asto whether the Ne/ERN is a necessary concomitant to error detection. We examined the Ne/ERN in five patients with damage to the medialprefrontal cortex, including the anterior cingulate region. Our findings support the implication of the rostral anterior cingulate in Ne/ERNproduction, but they also show that subjects can be aware of errors and yet not produce an Ne/ERN. Thus, error detection leads to theNe/ERN process and damage to the anterior cingulate region may interrupt this relay, suggesting that error detection may be supported bycircuits outside the anterior cingulate region.© 2003 Elsevier Ltd. All rights reserved.

Keywords:ERP, Ne/ERN; Anterior cingulate; Prefrontal cortex; Error detection; Error awareness; Error negativity; Conscious control

1. Introduction

Patients with a ruptured aneurysm of the anterior com-municating artery (ACoA) can show a variety of behavioraland cognitive disturbances such as apathy, unawareness ofdeficit, confabulation, disorientation and attention, memory,control and monitoring problems (Gilboa & Moscovitch,2002; Ptak & Schnider, 1999; Schnider & Ptak, 1999;Shallice, 1999; von Cramon & Müller, 1998). The area mostlikely to be damaged in these patients is the anterior cingu-late and adjacent region (including Brodmann areas (BA)24, 25, 32) (von Cramon & Müller, 1998), a structure in thefrontal lobes that is characterised by a complex architecturalorganization and rich interconnections with the dorsolateralprefrontal and orbitofrontal regions, motor and parietal cor-tex, the basal ganglia and the limbic system (Burruss, Hurley,Taber, Rauch, Norton, & Hayman, 2000; Cummings, 1995;Mega & Cummings, 1994; Mega, Cummings, Salloway,& Malloy, 1997). It has been proposed that the prominentlimbic affiliations of the anterior cingulate, with its ma-

∗ Corresponding author. Tel.:+1-514-340-3540; fax:+1-514-340-3548.E-mail address:[email protected] (B. Stemmer).

jor connections coming from the amygdala, play a rolein linking drive and emotion to extrapersonal events andmental states (Mesulam, 1999, 2000a,b). The functionalsignificance of the anterior cingulate has been widely de-bated and empirical evidence suggests that it is implicatedin attentional, monitoring and control processes (Braver,Barch, Gray, Molfese, & Snyder, 2001; Carter, Botvinick,& Cohen, 1999; Cohen, Kaplan, Zuffante, Moser, Jenkins,& Salloway, 1999; Janer & Pardo, 1991; Luks, Simpson,Feiwell, & Miller, 2002; Luu, Collins, & Tucker, 2000) andspecifically the dorsal anterior cingulate in reward-baseddecision making (Bush et al., 2002). Recently, it has alsobeen suggested that the anterior cingulate is implicated insituations when human beings make errors in stimulus dis-crimination tasks. The function of the anterior cingulate inerror processing is currently actively investigated.

1.1. The Ne/ERN—an electrophysiological marker forerror processing

The anterior cingulate has been proposed to be the neuralgenerator site of a specific electrophysiological waveformthat occurs in discrimination tasks when people make errors.

0028-3932/$ – see front matter © 2003 Elsevier Ltd. All rights reserved.doi:10.1016/S0028-3932(03)00121-0

B. Stemmer et al. / Neuropsychologia 42 (2003) 118–130 119

When a subject has to react to auditory or visual stimulipresented in such a way that errors are likely to occur, theaveraged EEG time-locked to such incorrect responses con-sistently shows a negative-going waveform in comparisonto correct responses. This has been coined the error nega-tivity (Ne) or error-related negativity (ERN) (Falkenstein,Hohnsbein, Hoormann, & Blanke, 1991; Falkenstein,Hohnsbein, & Hoormann, 1990; Gehring, 1992; Gehring,Coles, Meyer, & Donchin, 1990; Gehring, Goss, Coles,Meyer, & Donchin, 1993). The Ne/ERN occurs when er-rors of choice (incorrect responses in choice–reaction timetasks), errors of action (uninhibited response on NoGotrials) (Scheffers, Coles, Bernstein, Gehring, & Donchin,1996), and errors of inaction (taking too long to respond)(Luu, Flaisch, et al., 2000) are made. The Ne/ERN can alsobe elicited under error feedback conditions, that is detectionof the error can be internally driven or signalled by externalcues (Badgaiyan & Posner, 1998; Miltner, Braun, & Coles,1997). These observations have raised the question whetherfor the Ne/ERN to occur, conscious internal monitoring isnecessary, that is, whether the subject needs to be aware ofhaving committed an error. The Ne/ERN is not affected bystimulus (Bernstein, Scheffers, & Coles, 1995) nor modalitydifferences (Falkenstein, Hoormann, Christ, & Hohnsbein,2000; Miltner et al., 1997) and is output independent(Holroyd, Dien, & Coles, 1998). The Ne/ERN does not seemto be associated with motor or pre-motor events nor is theNe/ERN part of the stimulus–response pathway (Badgaiyan& Posner, 1998; Leuthold & Sommer, 1999). Finally, theNe/ERN has been associated with individual differences inthe general impulsivity of response style (Gehring, Himle,& Nisenson, 2000; Pailing, Segalowitz, Dywan, & Davies,2002) and affective distress (Luu, Collins, et al., 2000).

The Ne/ERN peaks around 100–150 ms following EMGactivity onset (approximately 50–80 ms after the key pressresponse), shows an amplitude in the range of 10�V orlarger in individuals, and is most prominent over the frontand middle of the scalp (Dehaene, Posner, & Tucker, 1994).Localising the neural generator site of the Ne/ERN has ledto various suggestions with a preference for the anterior cin-gulate by most authors. High-density event-related potentialrecordings and treatment of the data with a forward-searchdipole localisation algorithm (BESA) have pointed to theanterior cingulate cortex or the supplementary motor area(SMA) as potential generator sites (Badgaiyan & Posner,1998; Dehaene et al., 1994; Miltner et al., 1997). AGo–NoGo task with Stroop-like visually presented stim-uli was used byVidal, Hasbroucq, Grapperon and Bonnet(2000)during EEG and EMG recording, producing a simi-lar topography. Using the event-related functional magneticresonance imaging (fMRI) techniqueCarter, Braver, Barch,Botvinick, Noll and Cohen (1998)found activation in theanterior cingulate cortex on incorrect trials and in areaBA 24c extending partly onto BA 24b and 32 on correcttrials with high response competition. Bilateral prefrontalregions and a pre-motor region also showed some degree of

error-related activity.Kiehl, Liddle and Hopfinger (2000)investigated errors of commission in a visually and audi-torily presented Go–NoGo task using event-related fMRI.Comparing errors of commission with correctly rejectedtrials showed a significant activation in the rostral anteriorcingulate and in the left lateral frontal cortex only for errorbut not for correct trials.Braver et al. (2001)corroboratedthese findings and reported additional activity in responseto low-frequency events (conflict) in the frontal operculum,superior parietal cortex, supplementary motor areas anddorsolateral prefrontal cortex (DLPFC). Based on computa-tional modelling and empirical findings,Holroyd and Coles(2002)locate the generator of the Ne/ERN in the cingulatemotor areas, that is, the ventral bank of the cingulate sulcus.

Although most researchers have related the Ne/ERN tothe anterior cingulate, the contribution of other prefrontal ar-eas to error processing has also been discussed. In functionalmagnetic resonance imaging studies, error-related activityhas also been reported in the dorsolateral frontal cortex, theleft pre-motor cortex (Carter et al., 1998), the left and rightinsular and adjoining frontal operculum (Menon, Adleman,White, Glover, & Reiss, 2001). The dorsolateral frontal cor-tex is a structure in the prefrontal cortex that has, like theanterior cingulate, been related to monitoring of responsetendencies and the control of attention (Kammer et al., 1997;Pailing et al., 2002), but unlike the anterior cingulate, ithas also been related to working memory (Ferreira, Verin,Pillon, Levy, Dubois, & Agid, 1998; Kammer et al., 1997;Klingberg, O’Sullivan, & Roland, 1997). Furthermore, dif-ferent generator sites within the cingulate have been sug-gested for response selection tasks and error feedback tasks(Badgaiyan & Posner, 1998).

The Ne/ERN is frequently (but not obligatorily) followedby a positive deflection, the Pe (Falkenstein et al., 2000).Whereas the Ne/ERN has also been observed in correct tri-als, the Pe only appears after incorrect responses (Vidal et al.,2000) and both the Ne/ERN and the Pe are significantly di-minished or disappear when errors are made intentionally(Stemmer, Witzke, & Schönle, 2001).

1.2. Functional significance of the Ne/ERN and Pe

These findings have led to various interpretations of thefunctional significance of the Ne/ERN. In their original pa-pers,Falkenstein et al. (1991, 1990)interpreted the Ne/ERNas reflecting error detection, that is, a mismatch signal ofa process in which the actual response (i.e. the error) iscompared with the required response. However, it has sincebeen shown that an amplitude-reduced Ne/ERN can alsooccur on correct trials (Coles, Scheffers, & Holroyd, 2001;Falkenstein et al., 2000; Vidal et al., 2000). This has ledVidalet al. (2000)to suggest that the Ne/ERN signifies a responseevaluation process, such as a comparison that secondarilyleads to error detection, and the detection process is reflectedin the positivity (Pe) that follows the Ne/ERN. Alternatively,these authors hypothesize that error detection comes first and

120 B. Stemmer et al. / Neuropsychologia 42 (2003) 118–130

leads to an emotional response that produces the Ne/ERN.Falkenstein et al. (2000)modified their original hypothesisand, similar to Vidal et al., suggest that the Ne/ERN reflectsa comparison process rather than the outcome of a com-parison process, i.e. the error detection. Thus, Ne/ERN-likeactivity could occur after correct responses as a reflectionof the comparison process, while the Ne/ERN on error trialswould reflect this process plus an overlaid error signal.

It has also been proposed that the Ne/ERN is related to asystem that monitors the accuracy of the response system andcompensates for errors (Gehring et al., 1993; Luu, Collins,et al., 2000). Again others argue that the Ne/ERN indexesa conflict between competing processes during response se-lection (conflict hypothesis) and serves an evaluative ratherthan strategic function (Carter et al., 1998, 1999, 2000). Ithas further been proposed that the Ne/ERN is implicatedin the remediation of erroneous behavior, and in particularthe reflection of inhibitory processes (Bernstein et al., 1995;Falkenstein, Hohnsbein, & Hoormann, 1999; Gehring et al.,1993). Holroyd and Coles (2002)link the function and gen-eration of the Ne/ERN to the activity of the mesencephalicdopamine system. Based on computational modelling andempirical findings, they argue that when people commit er-rors in discrimination tasks, the mesencephalic dopaminesystem, which projects to the basal ganglia and prefrontalcortex, transmits a negative reinforcement learning signal tothe motor areas of the anterior cingulate. This leads to a dis-inhibition of pyramidal neurons in this area which becomedepolarised and thereby generate the Ne/ERN.

The functional significance of the Pe is also a matterof debate. From the findings of a series of experiments,Falkenstein et al. (2000)conclude that the Pe is not a delayedparietal P3 but rather the reflection of additional processingafter errors possibly indicating the subjective assessment ofan error. This interpretation is supported byNieuwenhuis,Ridderinkhof, Blom, Band and Kok (2001)who recordedEEG and monitored eye movements during an antisaccadetask. They report the occurrence of the Ne/ERN in responseto both perceived and unperceived error trials whereas thePe was much more pronounced after perceived than unper-ceived errors. They conclude that the error detection processreflected by the Ne/ERN operates independently of con-scious error perception whereas the Pe reflects a later errormonitoring process which is strongly associated with aware-ness of the occurrence of the actual (erroneous) response.

1.3. Patients with damage to the anterior cingulate andadjacent region

The anterior part of the cingulate cortex is comprisedof Brodmann areas (BA) 24a, 24b, 24c, 24a′, 24b′, 24c′,24c′g, 25, 32 and 32′ (Devinsky, Morrell, & Vogt, 1995;Vogt & Devinsky, 2000; Vogt, Nimchinsky, Vogt, & Hof,1995). The anterior cerebral arteries near the basal surfaceof the cerebral hemispheres are interconnected by the an-terior communicating artery. In the vast majority of cases

the ACoA and its branches supply the middle portion ofthe anterior commissure, and its vascular territory may fre-quently include the cortical region of BA 25 and sometimeseven extends beyond the genu of the corpus callosum (vonCramon & Müller, 1998). Patients with a ruptured aneurysmof the ACoA are particularly likely to show damage in theanterior cingulate region including anterior and dorsal BA24 and 32, and the more ventrally located region BA 25due to pressure on the tissue in proximity to the lesion andan interrupted blood supply to the fornical columns and theseptal nuclei (both regions in close proximity to the anteriorcingulate) (von Cramon & Müller, 1998). The view that theNe/ERN is a physiological marker for error processing andits proposed relationship to the anterior cingulate region ledus to hypothesize that Ne/ERN production would be ham-pered in patients who have suffered damage to the medialprefrontal cortex, and in particular the anterior cingulate re-gion. To the extent that they do not produce an Ne/ERN,these patients should not be aware of committing errors. Thatis, if the Ne/ERN represents a response evaluation processwhich leads to error detection, then patients with a damagedanterior cingulate region and no Ne/ERN should not showindications of error detection.

We investigated Ne/ERN production in five patients witha ruptured aneurysm of the ACoA and damage in the me-dial prefrontal cortex including the anterior cingulate, andcompared these patients with healthy control participants.

2. Method

2.1. Participants

Five patients with a ruptured aneurysm of the ACoAand ensuing neurosurgical intervention (clipping of theaneurysm) were investigated and compared with 11 healthycontrols (seeTables 1 and 2for demographic details). Al-though, on average, the control participants were somewhatyounger than the patients with the ruptured aneurysm (35.6years versus 49.8 years), it has been shown that theoccur-renceof the Ne/ERN is not dependent on age (Gehring &Knight, 2000). In subjects older than our group (i.e. between55 and 80 years), a reduction in amplitude has been ob-served (Falkenstein et al., 2000; Nieuwenhuis et al., 2002).

All patients had clinical MRIs taken in the acute carehospitals or in the neurological rehabilitation hospital.1 Asall scans were clinical and not research oriented the scan-ning parameters, orientation and number of slices obtained,and the quality of the scans differed. Localising the lesionsprecisely is not possible for a variety of reasons, includ-ing movement and clip artefacts. However, all patients didshow lesions in the anterior cingulate regions as definedin Section 1.3above, albeit to different degrees and not

1 The MRI scans of patients EM, EZ, IE and RF, and the lesion recon-struction of patient MH can be viewed athttp://cogprints.ecs.soton.ac.uk.

http://cogprints.ecs.soton.ac.uk


Table 1Summary of demographic data: patients

Patients Gender School education inyears and profession

Age at the timeof testing (years)

Time span betweenlesion onset andtesting (weeks)

EM Female 13, industrial clerk 57 20EZ Female 13, saleswoman 47 40IE Female 16, teacher 51 8MH Male 10, merchant 36 24RF Female 12, lawyer’s assistant 58 32

necessarily at overlapping sites. All patients showed bilateralinvolvement, but the lesion was more pronounced on the leftside in patient EM and on the right side in patients IE andMH. EM, IE and RF demonstrated lesions in the dorsal partof the anterior cingulate. MH’s and EZ’s lesions were moreventrally located compared to the other patients. EM and MHalso showed some involvement of the posterior orbitofrontalareas. In addition, the anterior part of the corpus callosumwas affected to different degrees in all patients, least in MH.EM showed involvement of the left basal ganglia, and EZ ofthe right thalamus, temporal pole and hippocampus. PatientMH also demonstrated a small lesion in the dorsolateral pre-frontal cortex on the left side due to the surgical procedure.

At the time of examination, all patients were at an inten-sive rehabilitation ward (post-acute care) set up for patientswith severe behavioral and cognitive impairment after braindamage. All patients were right handed with German as theirnative language.

All participants (or their legal guardians) were informedas to the aims and methods of the procedure and consentwas obtained. The protocol was approved by the ethics com-mittee.

2.2. Procedure and apparatus

2.2.1. Ne/ERN paradigmTwo versions of the Eriksen flanker paradigm were con-

structed in order to elicit ERNs, one with letter and one withgeometric stimuli (Eriksen & Eriksen, 1974). In the letterflanker task, participants were required to press a button with

Table 2Summary of demographic data: control participants

Controls Gender School education inyears and profession

Age at time oftesting (years)

BG Female 16, mathematician 31CK Female 13, physiotherapist 37ER Female 16, teacher/housewife 59HG Male 16, psychologist 30KZ Female 14, student 25MS Female 9, housewife 49MT Female 16, social worker 25RK Male 16 yrs, university diploma 48SA Female 16, psychologist 25SL Female 16, psychologist 30UV Female 16, psychologist 33

the left index finger when the letter S appeared in the centreof a five-letter array on the computer screen and the right in-dex finger when H appeared. Each target letter was flankedto the right and left by either congruent (HHHHH, SSSSS)or incongruent (HHSHH, SSHSS) letters. There was a totalof 480 trials, 80 trials for each congruent array (HHHHH,SSSSS) and 160 trials for each incongruent array (HHSHH,SSHSS). For four control participants the total number oftrials was 440. Each array remained on the screen for 250 msfollowed by an inter-stimulus interval of 1000 ms.

In order to accommodate patients who may have readingproblems after damage to the brain, we constructed a task inwhich the letters were replaced by geometrical forms (cir-cles and squares) similar in size to the letters. The partici-pants had to press the right button if the target was a circleand the left button if the target was a square. For patientswith motor or mental slowing, for each condition (letter orform) a version with an inter-stimulus interval of 1750 mswas constructed. Of the patients reported here, the “slow”version was only presented to patient RF and only in theletter condition.

2.2.2. EEG recording and analysesThe EEG was recorded from 19 Ag/AgCl-cup electrodes

according to the 10/20 system referenced to linked ear-lobes with Fpz as ground. Signals were amplified usinga 32-channel dc amplifier (MES) and the SCAN softwarepacket (NeuroScan). Data were sampled at a rate of 256points/s with a 70 Hz low pass filter and a time constant of5 s. Horizontal and vertical eye movements were recordedfrom standard locations. Impedance for EEG and electroocu-logram (EOG) electrodes was kept below 10 k�.

We selected an EEG epoch beginning 800 ms before andending 800 ms after the response for each Ne/ERN trial.Eye-movement artefacts were corrected by regression analy-sis (Semlitsch, Anderer, Schuster, & Presslich, 1986), wave-forms with signals greater than±100�V in healthy controlsand ±200�V in patients were eliminated and a low passfilter of 20 Hz applied. After artifact reduction, the averagenumber of error epochs included in the averaging processwas 32 (minimum 9, maximum 93) for the controls and 51(minimum 14, maximum 90) for the patients in the formcondition, and 29 (minimum 8, maximum 52) for the con-trols and 39 (minimum 20, maximum 73) for the patientsin the letter condition. Thus, a sufficient number of error


epochs was obtained as the Ne/ERN has been shown to bea very robust waveform that can be detected even in singletrials (Falkenstein et al., 2000), and, as research has demon-strated, an average based on eight or nine trials is sufficientfor the ERN to appear. The EEG epochs were time-lockedto the response on each trial and averaged separately for cor-rect and incorrect trials for each participant. The waveformswere examined at frontal (Fz), central (Cz) and parietal (Pz)midline sites.

2.2.3. Response timesResponse times were calculated from stimulus onset to

button press, with averages based on those greater than100 ms.

2.2.4. Neuropsychological proceduresPatients were examined with regard to their attention,

memory, executive, language and gnostic functions usingstandard neuropsychological tests. A summary of the pro-cedures used and results obtained are presented inSection 3(see alsoTable 7).

3. Results

3.1. Production of Ne/ERN

Every control participant produced a clearly identifiableNe/ERN–Pe complex in response to both paradigms in theincorrect trials, that is, a negative deflection starting aroundthe response time and reaching a peak within 100 or 150 msafter the response followed by a strong positivity (seeFigs. 1and 2), although in one individual for one paradigm thiscomplex is more defined by the Pe than the Ne/ERN. Oncorrect trials, a positive peak was produced followed by anegative deflection to or below baseline.

Ne/ERN and Pe production in some of the patients dif-fered noticeably from that of the control participants andcould not be scored in the traditional manner. Therefore,we have focused on the presence or absence of these ERPcomponents. Patients EM, IE and RF did not produce anNe/ERN in either of the two paradigms (seeFigs. 3 and 4).In patient EM’s waveforms, there was a difference for cor-rect and error trials in the letter paradigm showing a ratherlate (starting 200 ms after the response) and broad (morethan 600 ms) negativity for error trials that deviated froma regular Ne/ERN in latency, amplitude and wave shape(controls’ Ne/ERN is always about 100 ms in breadth). Pa-tient RF produced a strong negativity 400 ms after the re-sponse to both correct and error trials in the form paradigm.IE had no Ne/ERN but did produce a Pe-like waveform forboth errors and correct trials in the form but not the lettercondition (Table 3). RF and EM produced no Pe or Pe-likecomponent. Patient EZ produced an Ne/ERN and Pe in theletter paradigm but not in the form paradigm. Patient MHproduced an Ne/ERN and a Pe in the form and questionablyalso in the letter condition.

Fig. 1. Waveforms for correct and error trials for each control participantin the form and letter conditions at the Cz site.

3.2. Error rate and response times

It might be argued that the lack of Ne/ERN in some of thepatients could be attributed to a lack of distinction betweencorrect and incorrect trials. We therefore compared error rateof the two subject groups and found that the overall taskperformance was similar in the two groups: Although the

Table 3Summary of patient results

Patients ERN-form ERN-letter Pe-form Pe-letter

EM No No No NoEZ No Yes No YesIE No No Yes NoMH Yes Yes Yes Yes (?)RF No No No No


Fig. 2. Waveforms for correct and error trials averaged across all control participants in the form and letter conditions at the three midline sites.

average error rate was lower in the control participants thanin the patients, the patients did not differ significantly fromcontrols [t(14) = 1.4, n.s. for letter andt(14) < 1, n.s. forform task] (Table 4). The controls produced significantlyfewer no responses than the patients [t(14) = 3.1 and 3.0 forletter and form tasks, respectively,P < 0.01], although thesedifferences just failed to reach significance when adjustingfor unequal variances in the samples [t(4.7) = 2.3,P < 0.07for both tasks].

In a further step, we investigated the response times. Thepatients were significantly slower than the controls in boththe letter and form conditions for correct trials [t(14) = 5.5and 4.4 for letter and form tasks, respectively,P < 0.01]and in the letter condition for incorrect trials [t(14) = 3.9,P < 0.01]. There was no significant difference in responsetimes in the form condition for incorrect trials [t(14) = 1.7,n.s.]. Slowing of response times is a common observation

Table 4Mean error rate, no-response rate and reaction times of controls andpatients in the form and letter paradigms

Response trial Controlform

Controlletter

Patientform

Patientletter

Mean error rate (%) 7.2 6.8 9.8 9.7Error range (%) 2.1–18.5 1.7–11.8 2.5–15.6 6.0–14.4Rate of no-responses

(%)6.2 4.6 29.7 23.6

Mean response time (ms)Correct trials 366 373 486 531Incorrect trials 325 320 377 439

Response time range (ms)Correct trials 292–446 295–498 442–529 495–564Incorrect trials 253–417 247–449 321–445 365–516

in patients with brain damage and not necessarily indicativeof different processing mechanisms. All participants showedfaster response times to incorrect than to correct trials, cor-roborating previous findings (Table 4) (Gehring et al., 1993;Pailing et al., 2002).

3.3. Post-error trials

Once a response has been made, one can ask whether thetype of response produced (correct or incorrect) influencesthe following response trial. On average, the mean time forcorrect responses following an erroneous trial (post-error re-sponse) was slower than the mean time for correct responsesfollowing a correct trial (post-correct response) [(mean RTslowing for controls= 7 ms, for patients= 25 ms,t < 1,n.s. in the form paradigm and 19 ms versus 49 ms slow-ing, t(14) = 1.2, n.s. in the letter paradigm (Table 5)].However, post-error slowing was not consistent across in-dividuals (Table 6). Of the 11 controls, only 5 significantlyslowed correct responses after making errors on the formtask [t(d.f . > 120) > 2.18; P < 0.05 for 5 individualsand t(d.f . > 120) < 1.96, n.s., for 6 individuals]. Four of11 controls showed significant post-error slowing in the let-ter task [t(d.f . > 120) > 2.04, P < 0.05 for 4 individualsand t(d.f . > 120) < 1.96, n.s. for 7 individuals). Two pa-tients (EM and IE) showed significant post-error slowing inthe form task [t(d.f . > 120) = 3.97 and 2.80, respectively,P < 0.05] and two patients (EZ and IE) in the letter task[t(d.f . > 120) = 2.56 and 4.20, respectively,P < 0.05].The other patients did not significantly slow their correctresponses after an error trial [t(d.f . > 120) < 1.15, n.s.,for form paradigm andt(d.f . > 120) < 0.89, n.s., for let-ter paradigm]. Thus, when significant post-error differences


Fig. 3. Waveforms for correct and error trials for each patient in theform condition. Some patients produced large EEG overall power inthe averaged ERP, indicated by the�Volt indications on the ordinate.Waveforms have a 13-point (50 ms) moving window filter applied.

occurred, they were always in the direction of slowing aftererrors.

3.4. Error awareness

The experimenter documented for the patients for eachtrial whether the participants behaviourally showed signs(exclamations, whispered swearing, grimaces) of having

Table 5Mean reaction times in post-response trials across participants in the form and letter paradigms

Post-response trials Control form (meanresponse time (ms))

Control letter (meanresponse time (ms))

Patient form (meanresponse time (ms))

Patient letter (meanresponse time (ms))

Post-error responseCorrect trial (PEc) 392 391 511 575

Post-correct responseCorrect trial (PCc) 363 372 486 526

Difference (PEc− PCc) +29 +19 +25 +49

Fig. 4. Waveforms for correct and error trials for each patient in theletter condition. Some patients produced large EEG overall power inthe averaged ERP, indicated by the�Volt indications on the ordinate.Waveforms have a 13-point (50 ms) moving window filter applied.

noticed that they had made an error. Patients IE and RFclearly noticed when they had made an error. The other threepatients’ behavior was mixed, in that one did not show anyovert error detection while the others did so inconsistently.

3.5. Results of neuropsychological examination

Behavioral observation showed spontaneous confabu-lation to various degrees in all patients at the time of


Table 6Mean reaction times in post-response trials for each individual participant in the form and letter paradigms

Participants Post-response trials in form paradigm Post-response trials in letter paradigm

Post-error response(PEc) (ms)

Post-correct response(PCc) (ms)

Difference(PEc− PCc)(ms)a

Post-error response(PEc) (ms)

Post-correct response(PCc) (ms)

Difference(PEc− PCc)(ms)a

ControlsBG 364 340 24 (2.32)∗ 434 373 61 (4.77)∗CK 397 371 26 (1.85) 336 360 −24 (−1.64)ER 477 421 56 (2.18)∗ 375 408 −33 (−1.27)HG 318 310 8 (0.66) 357 341 16 (1.20)MS 530 409 121 (3.26)∗ 617 499 118 (3.02)∗KZ 325 336 −11 (−0.52) 313 299 14 (1.18)MT 289 292 −3 (−0.49) 297 294 3 (0.33)RK 503 442 61 (2.39)∗ 419 442 −23 (−1.16)SA 383 353 30 (2.40)∗ 374 351 23 (2.04)∗SL 420 426 −6 (−0.37) 435 392 43 (2.84)∗UV 306 298 8 (0.95) 341 331 10 (0.90)

PatientsEM 574 494 80 (3.97)∗ 568 546 22 (0.89)EZ 513 534 −21 (−0.73) 585 531 54 (2.56)∗IE 562 463 99 (2.80)∗ 618 491 127 (4.20)∗MH 447 504 −57 (−1.15) 572 565 7 (0.23)RF 461 436 25 (0.79) 530 495 35 (0.87)

a t values.∗ P < 005.

Table 7Neuropsychological results

Patient WMS-Rgeneralmemory

Delayedrecall

Attention Verbalfluency

d2cancellationtask

Trailmaking A

Trailmaking B

Wisconsincardsorting test

Tower ofHanoi

Officeorganisationtask

HAWIE (Germanversion of WAIS)(non-verbal)

IE n n n n – n n – – – –EM ↓↓ ↓↓ ↓ ↓↓ ↓↓↓ ↓ ↓ ↓ ↓ ↓ (↓) IQ = 88MH ↓↓ ↓↓ ↓ ↓↓↓ ↓↓↓ ↓ ↓↓↓ ↓↓ ↓ (↓) ↓↓↓ IQ = 42EZ ↓ ↓↓ ↓↓↓ ↓ ↓↓↓ ↓↓ ↓↓↓ ↓↓ ↓↓ ↓↓ ↓↓↓ IQ = 62RF n ↓↓ n ↓ ↓ ↓ ↓↓ ↓↓ ↓ ↓ ↓↓ IQ = 70

(n) within normal range; (–) non-applicable/test not done with patient; ((↓)) some subtests within normal range, some below; (↓) >1 S.D. below normalrange; (↓↓) >2 S.D. below normal range; (↓↓↓) >3 S.D. below normal range or unable to complete test.

testing, a symptom often associated with damage of thissort. Neuropsychological assessment revealed that allpatients, except for IE, showed attention, memory, andexecutive function problems to various degrees in stan-dardised testing procedures (Table 7). MH, EZ, and RF’snon-verbal IQ scores were well below average. Althoughpatient IE performed within the average range on all stan-dard tests, she still showed conspicuous signs of confu-sion and confabulation as observed by the experimenterand consistently reported by the staff on the ward. Suchbehavior is usually not captured by standard neuropsy-chological testing. The patient herself complained aboutmemory problems although standard memory testing waswithin average range. Patient RF performed somewhatbetter than the other patients, his WMS-R general mem-ory score and the attention subtest being in the averagerange.

4. Discussion

The control participants showed an Ne/ERN–Pe complexon trials with incorrect but not correct responses in boththe letter and form versions of the flanker task. For the pa-tients a different picture emerged. Three patients did notproduce an Ne/ERN in either paradigm, one patient pro-duced an Ne/ERN in one paradigm but not the other andone patient produced an Ne/ERN in both paradigms. Thepatients who showed an Ne/ERN also showed a Pe in atleast one of the paradigms. Although the average error rateof the controls was somewhat lower than the error rate ofthe patients, this difference did not reach statistical signifi-cance. Controls as well as patients showed faster responsetimes to incorrect than to correct trials. Post-error slowingwas inconsistent in controls as well as patients. These re-sults will be discussed in relation to issues of generator site,


awareness of error, cognitive functions and functional signi-ficance.

4.1. The generator question

EEG and fMRI studies have implicated the anterior cingu-late as a major contributor to the generation of the Ne/ERNalthough the role of the SMA region and subcortical struc-tures remain unclear. For example, it has been hypothesisedthat the mesencephalic dopamine system is implicated inerror processing (Holroyd & Coles, 2002). However, em-pirical evidence for this hypothesis is ambiguous. Seekingsupport for this hypothesis, two studies have investigatedpatients with Parkinson’s disease. The neuropathologicalcharacteristic of Parkinson’s disease is the degeneration ofthe midbrain dopamine nuclei. WhereasFalkenstein et al.(2001)found an attenuated Ne/ERN in Parkinson’s patients,Holroyd, Praamstra, Plat, and Coles (2002)could not repli-cate this finding. Their Parkinson’s patients produced a nor-mal Ne/ERN. These discrepancies might be due to somemethodological differences.

A similarly ambiguous situation concerns the findings inpatients with lesions to the lateral frontal lobes. WhereasGehring and Knight (2000)found a normal Ne/ERN in re-sponse to incorrect trials but also a negativity with increasedamplitude in response to correct trials (correct-related neg-ativity, CRN) in patients with prefrontal lesions,Ullsperger,von Cramon and Müller (2002)reported a reduced Ne/ERNin response to incorrect trials but an unaffected negativityin response to correct trials in patients with lateral frontallesions. The diverging results may at least partially beexplained by two factors: (1) differing task requirements:Gehring et al. used a cued discrimination task that includedworking memory component whereas Ullsperger et al. aused a modified flanker task; and (2) heterogeneity of pa-tients: the extent of damage and etiology of the lesionsdiffered considerably.2

2 Gehring et al.’s patients had all suffered an infarction of the middlecerebral artery and showed involvement of the prefrontal cortex to varyingdegrees. Some patients showed involvement of the superior, medial andinferior frontal gyrus, others only of the medial and inferior frontal gyrus.Most patients showed involvement of the insular region but one did notand one only partially. Four of the six patients also showed damage to thesuperior temporal gyrus, and in one patient the hippocampus and fornixwere lesioned. Furthermore, in some patients the lesion extended to theprecentral gyrus and in some to the inferior parietal lobule. The patientsinvestigated by Ullsperger et al. showed diversity as to their etiologyincluding ischemic and haemorrhagic infarction, traumatic brain injury,tumor and herpes encephalitis. The frontolateral group consisted of mainlyinfarct patients but included one traumatic brain injury and one patientwith arteriovenous malformation. The bifrontopolar–orbitofrontal groupconsisted of only traumatic brain injury patients and the temporal grouppatients was the most diverse in etiology. The neuropsychological andrecovery pattern of such patients can differ quite dramatically functionally,speaking to probably different underlying physiological processes. It isunclear whether and if so to what degree the heterogeneity of patients interms of etiology and lesions has influenced the results. Unfortunately,neither Gehring and Knight nor Ullsperger et al. provide individual patientdata and results.

In general, our findings are consistent with the view thatthe anterior cingulate, or some region dependent on it, is in-volved in Ne/ERN generation. Whereas three patients (EM,IE and RF) with damage to the anterior cingulate region didnot show any Ne/ERN, one patient (EZ) showed an Ne/ERNin one and another patient (MH) in both paradigms. For rea-sons outlined previously, precise lesion localisation is notpossible in our patients. However, based on what we canclearly identify, it seems that the more ventral region of theanterior cingulate region (e.g. BA 25) is less critical for gen-erating an Ne/ERN component. This hypothesis is supportedby a fMRI study using a modified flanker task showing se-lective activation of the cingulate motor area (BA 32/24c′)during error processing (Ullsperger & von Cramon, 2001).Indirect support for this hypothesis comes from various stud-ies. Using a Go–NoGo task in an event-related fMRI study,Kiehl, Liddle, and Hopfinger (Kiehl et al., 2000) reportedselective activation in the rostral anterior cingulate and in theleft lateral frontal cortex for errors of commission. The au-thors found activation at the Talairach co-ordinatesx = −8,y = 45, z = 16 andx = 12,y = 36,x = 12 when errors ofcommission occurred. In order to be able to compare Kiehlet al.’s findings with the patients’ lesions, we used the Ta-lairach Demon version 1.1 (Lancaster et al., 2000) to checkfor the location of the co-ordinates given by Kiehl et al. forthe rostral anterior cingulate in the Talairach space and trans-ferred the Talairach co-ordinates to (modified) Brodmannareas (Devinsky et al., 1995). Both sets of co-ordinates in-volve the anterior cingulate corresponding to BA 24b at andabove the genu of the corpus callosum and extending to BA32. Therefore, it seems that Kiehl et al.’s rostral anteriorcingulate area comes closest to the lesion described in ourpatients EM, IE and RF although the overlap is only par-tial. The findings by Kiehl et al. have been corroborated inan event-related fMRI study using a three-choice discrimi-nation task byBraver et al. (2001). These authors showedactivation of the superior caudal region of the anterior cin-gulate cortex extending into the supplementary motor areain response to conflict and a more rostral inferior region inresponse to errors, although both regions did show some re-sponsiveness as well to the other condition. Further indirectsupport comes from ERP studies using high-density scalprecording and the brain electric source analysis (BESA) fora forward-search dipole localisation (Dehaene et al., 1994;Miltner et al., 1997) or Laplacian transformation (Vidalet al., 2000). These researchers reject a deep source con-tributing to Ne/ERN production but interpret their findingsas indicative of a more shallow source either in the anteriorcingulate region or a more distributed source in the SMAareas.

Our findings demonstrate that damage to the anterior cin-gulate region can alter the Ne/ERN response although it isstill possible for patients to detect errors. It thus seems thaterror detection per se does not rely on the anterior cingu-late region. Although neuroimaging studies have repeatedlyshown activation of the anterior cingulate in error tasks,


activation of other brain structures have also been observedpointing to a distributed and interconnected neural systemsinvolved in error processing. For example,Ullsperger andvon Cramon (2001)investigated response competition anderror processing in an event-related fMRI study using amodified flanker task. In the response competition condi-tion, the pre-SMA area (BA 6 and 8) extending to the banksof the anterior cingulate sulcus (BA 32/24c′), the poste-rior cingulate cortex, the right inferior frontal gyrus, theright intraparietal sulcus, left sensorimotor cortex, bilateralanterior superior insula and the middle frontal gyrus wereactivated. In the error condition, activation was found in thepre-SMA area (BA 6), on the banks of the anterior cingulatesulcus (BA 32/24c′), in the anterior insula and intraparietalsulcus.Menon et al. (2001)investigated error-related brainactivity and response inhibition in a Go–NoGo task. Theyfound error-related brain activation in the rostral aspect ofthe right cingulate and adjoining medial prefrontal cortex,the left and right insular cortex and adjoining frontal op-erculum and left precuneus/posterior cingulate. Activationrelated to response inhibition showed in the dorsolateralprefrontal cortex, the inferior frontal cortex, pre-motor cor-tex, inferior parietal lobule, lingual gyrus, caudate and rightdorsal anterior cingulate cortex.

A role for the DLPFC in error processing has been sug-gested by various studies (Carter et al., 1998; Gehring &Knight, 2000; Kiehl et al., 2000; Menon et al., 2001). Oneof our patients (MH) presented with a small lesion in thedorsolateral prefrontal cortex, which, however, did not pre-vent Ne/ERN production. This is compatible withGehringand Knight’s (2000)andUllsperger et al.’s (2002)findingswhich showed that patients with a lesioned prefrontal cortexproduced an Ne/ERN. Gehring and Knight suggest that aninteraction between the anterior cingulate and the prefrontalareas may be necessary for a well-formed Ne/ERN to occurand they discuss the possibility of a feedback mechanismbetween the anterior cingulate and the prefrontal cortex.Their argument is based on their findings of an Ne/ERN inresponse not only to incorrect but also to correct trials inpatients with a stroke in the middle cerebral artery, that is, ina patient group with an intact anterior cingulate but a dam-aged prefrontal cortex. In comparison to ours, Gehring andKnight’s paradigm was more complex and the additionalprocesses involved in their task may have raised the levelof uncertainty when responding, and this, in turn, may haveproduced an Ne/ERN on trials even when the response itselfwas correct. That the Ne/ERN observed on correct trialscan indeed reflect error processing has convincingly beenshown byColes et al. (2001). Further support comes frommonkey studies where error potentials recorded from theanterior cingulate became weaker with waning uncertaintyabout task fulfilment (Gemba, Sasaki, & Brooks, 1986). Inanother monkey study, increased unit firing from cingulatecortex cells occurred in response to errors as well as inresponse to omission of reinforcement for correct responses(Niki & Watanabe, 1979).

The previous discussion was aimed at localisation basedon the relationship between Ne/ERN production and siteof lesion, although extrapolating from lesion data such asours requires cautious interpretation because the regions arehighly interconnected and it is impossible to determine pre-cisely which connections were interrupted. Another line ofargument comes from the relationship between the Ne/ERNand the contingent negative variation (CNV) which has beenassociated with the DLPFC (Basile, Brunder, Tarkka, &Papanicolaou, 1997; Rosahl & Knight, 1995). In this context,it is particularly noteworthy that the two patients (IE and RF)who did not produce an Ne/ERN but did show detection oferrors did, however, produce a well-formed CNV. (The CNVparadigm was performed as a clinical routine [visual stimuli:ISI = 2.8 s, ITI = 4.8 s]). Conversely, MH had a secondarylesion in his left DLPFC related to the surgery to clip theaneurysm, and his CNV was highly abnormal. This disso-ciation is compatible with the view that Ne/ERN and CNVproduction do not rely on the same neural circuitry (Davies,Segalowitz, Dywan, & Pailing, 2001) and that different func-tional mechanisms underlie Ne/ERN and CNV production.

4.2. The error awareness question

There has been relatively little explicit discussion as towhat degree Ne/ERN production involves conscious aware-ness. Current observations suggest that conscious awarenessis not a sufficient condition for Ne/ERN production. Ne/ERNproduction has been observed after erroneous actions thathave escaped our conscious control and are committed un-intentionally and unwillingly, i.e. after slips, and not afterpurposefully made inappropriate responses (Dehaene et al.,1994; Stemmer et al., 2001). In monkeys, error potentialshave been shown in the anterior cingulate area 24 in re-sponse to non-rewarded, inappropriate motor movementsbut not after rewarded and intentionally made movements(Gemba et al., 1986). The relationship between the perceivedaccuracy (i.e. the awareness of making errors), behavioralaccuracy and Ne/ERN amplitude has been investigated byScheffers and Coles (2000). Using a visual flanker task andhaving participants rate the accuracy of their response, theseauthors found an increase in the amplitude of the Ne/ERNassociated with an increase in the strength with which theparticipants believed that their response was incorrect. Thatis, the more confident the participants were that they hadmade an error, the higher the Ne/ERN amplitude. Simi-larly, for correct trials, there was a decrease in a similarlytimed negativity the more confident the participants were ofthe correctness of their response. The authors suggest thatthese findings indicate a strong association between thoseprocesses that lead to the Ne/ERN and those that relate tothe participant’s judgements. Although the authors do notmake any explicit claim concerning the awareness question,it seems that these findings suggest that having a subjectiveawareness of making an error is associated with Ne/ERNamplitude. On the other hand,Nieuwenhuis et al. (2001)


found that the Ne/ERN occurred on error trials even when(healthy) subjects did not rate their performance as an erroron a binary choice task.

During task performance it has been observed that sub-jects sometimes overtly demonstrate a verbal reaction in theform of expletives when they make an error thus suggestingthat they are aware of their errors (Scheffers et al., 1996).In our study, we found that explicit awareness of errors wasdissociated from Ne/ERN production in two patients: IE andRF overtly noticed when they had made an error and nei-ther produced a clear Ne/ERN. Of the five patients, IE andRF were the least impaired in terms of attention and mem-ory functions. In fact, at the time of the Ne/ERN recording,patient IE had recovered from her previous severe orienta-tion, attention and memory impairments to a point wherethe results of the neuropsychological tests were in the av-erage range although she still showed behavioral problems.IE was about to be transferred from the intensive to the reg-ular rehabilitation ward. Patient RF’s cognitive functioningwas worse than that of IE but generally better than that ofthe other patients. Thus, these two patients showed cognitivefunctioning that was relatively good compared to the otherpatients and they detected their errors, yet did not producean Ne/ERN. These findings argue for some sort of dissoci-ation between Ne/ERN production and error awareness, i.e.that the process leading to the Ne/ERN cannot be requiredfor error awareness although the reverse could hold.

Nieuwenhuis et al. (2001)also found that although theNe/ERN occurred in aware and unaware error trials, thePe was significantly more pronounced for acknowledgedthan unacknowledged errors. In line withFalkenstein et al.(2000), Nieuwenhuis et al. (2001)suggest that the Ne/ERNand Pe reflect functionally different components in error pro-cessing and associate the Pe with conscious error recognitionand remedial action. Our own data show mixed results. Thetwo patients who produced an Ne/ERN also produced a Pe. Ifone adopted the view that the Pe is associated with consciouserror recognition, then the occurrence of the Pe in these twopatients would be indicative of conscious error recognitiondespite a lack of overt error recognition (which of course ispossible if unusual). However, both IE and RF showed overterror recognition in both paradigms, yet did not produce aPe. These observations are not compatible with the view thatthe Pe necessarily appears when errors are recognised.

4.3. The Ne/ERN and cognitive functions

The Ne/ERN also seems to be dissociated somewhat fromintact attention, memory and executive functions in that IE,who did not produce an Ne/ERN, performed in the averagerange on all neuropsychological tests tapping these functionswhereas patients MH and EZ with clearly impaired attention,memory, and executive functions did produce Ne/ERN-likewaveforms in at least one paradigm.

Another issue to address in this context is the observationthat all patients presented with confabulation to varying de-

gree and whether this is related to their performance in errordetection. It has been shown that in dementia and Korsakoffpatients, mild confabulators showed a greater tendencytoward verbal self-correction than severe confabulatorswhose ability to monitor or self-correct is impaired (Mercer,Wapner, Gardner, & Benson, 1977). However, as we havenot systematically and objectively investigated the patients’confabulations, addressing this issue in more detail wouldbe an over-interpretation of our data. Furthermore, it hasnot been established that confabulation and problems witherror detection necessarily co-occur (Gilboa & Moscovitch,2002).

4.4. Functional significance of Pe and Ne/ERN

Post-error slowing has been related to controlled pro-cesses which require prior conscious error recognition(Rabbit, 1966, 1967). Nieuwenhuis et al. (2001)found thatperceived errors were associated with substantial post-errorslowing but that post-error slowing was absent in unper-ceived errors. Although co-variation of post-error slowingwith Pe amplitude does not necessarily imply a causal re-lationship, the authors point out that this is consistent withFalkenstein et al.’s (2000)hypothesis that the Pe reflectspost-error adjustment processes. However, Falkenstein et al.found larger post-error slowing for elderly subjects withoutan enlargement of the Pe and conclude that these resultsargue against the view that the Pe reflects conscious errorprocessing or the post-error adjustment of response strate-gies. Our data are not conclusive in this regard (see previoussection). The patients who produced an Ne/ERN followedby a Pe did not show much overt error recognition, and thepatients who showed overt error recognition did not pro-duce a Pe (or if they did, like IE, it was in response to bothcorrect and error trials). Therefore, no clear conclusion withregard to conscious error awareness can be drawn.

Similarly, we have an inconsistency in the relationshipbetween the Ne/ERN and post-error slowing in our controlsubjects’ data: All our controls produced a scorable Ne/ERNand Pe in each paradigm, while only 8 of 11 demonstratedpost-error slowing at all, and only 5 demonstrated statisti-cally significant post-error slowing. If significant post-errorslowing is a definitive marker of conscious error recogni-tion, then in healthy controls the Ne/ERN and Pe may reflectmore than error recognition because they were present moreoften than post-error slowing. On the other hand, it may bethe case that the Ne/ERN and Pe are more reliable than ispost-error slowing, and what we are seeing is simply thisdifference in their psychometric properties.

4.5. The anterior cingulate, error detection andthe Ne/ERN

Our data demonstrate that damage to the anterior cingu-late region can alter the standard Ne/ERN response and thatit is nonetheless possible for patients to clearly detect errors.


These data are consistent with the hypothesis that the pro-cesses producing the Ne/ERN follow error detection and arenot actually part of it. In other words, error detection leadsto the Ne/ERN process and damage to the anterior cingulateregion may interrupt this relay, suggesting that error detec-tion may be supported by circuits outside the anterior cin-gulate region (Holroyd & Coles, 2002).

Acknowledgements

Preparation of this paper was supported by the Centrede Neurosciences de la Cognition, Université du Quebec àMontréal, Canada, in part by the German Federal Ministryfor Education and Research (BMBF) grant 01GD9821/3,and in part by grant # 122222-98 from the Natural Sciencesand Engineering Research Council of Canada. We wouldlike to thank Sieglinde Lacher for help in data collectionand Jane Dywan and an anonymous reviewer for helpfulcomments and discussion.

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