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 the medial prefrontal cortex: an ERP study Brigitte Stemmer a,b,∗ , Sidney J. Segalowitz c , Wolfgang Witzke d , Paul Walter Schönle e a

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., Canada c Department of Psychology, Brock University, St. Catharines, Canada d Kliniken Schmieder, Allensbach, Germany e 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 has been 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 as to whether the Ne/ERN is a necessary concomitant to error detection. We examined the Ne/ERN in five patients with damage to the medial prefrontal cortex, including the anterior cingulate region. Our findings support the implication of the rostral anterior cingulate in Ne/ERN production, but they also show that subjects can be aware of errors and yet not produce an Ne/ERN. Thus, error detection leads to the Ne/ERN process and damage to the anterior cingulate region may interrupt this relay, suggesting that error detection may be supported by circuits 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 communicating artery (ACoA) can show a variety of behavioral and cognitive disturbances such as apathy, unawareness of deficit, 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 most likely to be damaged in these patients is the anterior cingulate and adjacent region (including Brodmann areas (BA) 24, 25, 32) (von Cramon & Müller, 1998), a structure in the frontal lobes that is characterised by a complex architectural organization and rich interconnections with the dorsolateral prefrontal and orbitofrontal regions, motor and parietal cortex, 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 prominent limbic 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).

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

jor connections coming from the amygdala, play a role in linking drive and emotion to extrapersonal events and mental states (Mesulam, 1999, 2000a,b). The functional significance of the anterior cingulate has been widely debated and empirical evidence suggests that it is implicated in 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) and specifically the dorsal anterior cingulate in reward-based decision making (Bush et al., 2002). Recently, it has also been suggested that the anterior cingulate is implicated in situations when human beings make errors in stimulus discrimination tasks. The function of the anterior cingulate in error processing is currently actively investigated. 1.1. The Ne/ERN—an electrophysiological marker for error processing The anterior cingulate has been proposed to be the neural generator site of a specific electrophysiological waveform that occurs in discrimination tasks when people make errors.

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When a subject has to react to auditory or visual stimuli presented in such a way that errors are likely to occur, the averaged EEG time-locked to such incorrect responses consistently shows a negative-going waveform in comparison to correct responses. This has been coined the error negativity (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 errors of choice (incorrect responses in choice–reaction time tasks), errors of action (uninhibited response on NoGo trials) (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 also be elicited under error feedback conditions, that is detection of the error can be internally driven or signalled by external cues (Badgaiyan & Posner, 1998; Miltner, Braun, & Coles, 1997). These observations have raised the question whether for the Ne/ERN to occur, conscious internal monitoring is necessary, that is, whether the subject needs to be aware of having committed an error. The Ne/ERN is not affected by stimulus (Bernstein, Scheffers, & Coles, 1995) nor modality differences (Falkenstein, Hoormann, Christ, & Hohnsbein, 2000; Miltner et al., 1997) and is output independent (Holroyd, Dien, & Coles, 1998). The Ne/ERN does not seem to be associated with motor or pre-motor events nor is the Ne/ERN part of the stimulus–response pathway (Badgaiyan & Posner, 1998; Leuthold & Sommer, 1999). Finally, the Ne/ERN has been associated with individual differences in the 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 EMG activity onset (approximately 50–80 ms after the key press response), shows an amplitude in the range of 10 ␮V or larger in individuals, and is most prominent over the front and middle of the scalp (Dehaene, Posner, & Tucker, 1994). Localising the neural generator site of the Ne/ERN has led to various suggestions with a preference for the anterior cingulate by most authors. High-density event-related potential recordings and treatment of the data with a forward-search dipole localisation algorithm (BESA) have pointed to the anterior cingulate cortex or the supplementary motor area (SMA) as potential generator sites (Badgaiyan & Posner, 1998; Dehaene et al., 1994; Miltner et al., 1997). A Go–NoGo task with Stroop-like visually presented stimuli was used by Vidal, Hasbroucq, Grapperon and Bonnet (2000) during EEG and EMG recording, producing a similar topography. Using the event-related functional magnetic resonance imaging (fMRI) technique Carter, Braver, Barch, Botvinick, Noll and Cohen (1998) found activation in the anterior cingulate cortex on incorrect trials and in area BA 24c extending partly onto BA 24b and 32 on correct trials with high response competition. Bilateral prefrontal regions and a pre-motor region also showed some degree of

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error-related activity. Kiehl, Liddle and Hopfinger (2000) investigated errors of commission in a visually and auditorily presented Go–NoGo task using event-related fMRI. Comparing errors of commission with correctly rejected trials showed a significant activation in the rostral anterior cingulate and in the left lateral frontal cortex only for error but not for correct trials. Braver et al. (2001) corroborated these findings and reported additional activity in response to low-frequency events (conflict) in the frontal operculum, superior parietal cortex, supplementary motor areas and dorsolateral prefrontal cortex (DLPFC). Based on computational modelling and empirical findings, Holroyd and Coles (2002) locate the generator of the Ne/ERN in the cingulate motor areas, that is, the ventral bank of the cingulate sulcus. Although most researchers have related the Ne/ERN to the anterior cingulate, the contribution of other prefrontal areas to error processing has also been discussed. In functional magnetic resonance imaging studies, error-related activity has also been reported in the dorsolateral frontal cortex, the left pre-motor cortex (Carter et al., 1998), the left and right insular and adjoining frontal operculum (Menon, Adleman, White, Glover, & Reiss, 2001). The dorsolateral frontal cortex is a structure in the prefrontal cortex that has, like the anterior cingulate, been related to monitoring of response tendencies and the control of attention (Kammer et al., 1997; Pailing et al., 2002), but unlike the anterior cingulate, it has also been related to working memory (Ferreira, Verin, Pillon, Levy, Dubois, & Agid, 1998; Kammer et al., 1997; Klingberg, O’Sullivan, & Roland, 1997). Furthermore, different generator sites within the cingulate have been suggested for response selection tasks and error feedback tasks (Badgaiyan & Posner, 1998). The Ne/ERN is frequently (but not obligatorily) followed by a positive deflection, the Pe (Falkenstein et al., 2000). Whereas the Ne/ERN has also been observed in correct trials, the Pe only appears after incorrect responses (Vidal et al., 2000) and both the Ne/ERN and the Pe are significantly diminished 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 the functional significance of the Ne/ERN. In their original papers, Falkenstein et al. (1991, 1990) interpreted the Ne/ERN as reflecting error detection, that is, a mismatch signal of a process in which the actual response (i.e. the error) is compared with the required response. However, it has since been shown that an amplitude-reduced Ne/ERN can also occur on correct trials (Coles, Scheffers, & Holroyd, 2001; Falkenstein et al., 2000; Vidal et al., 2000). This has led Vidal et al. (2000) to suggest that the Ne/ERN signifies a response evaluation process, such as a comparison that secondarily leads to error detection, and the detection process is reflected in the positivity (Pe) that follows the Ne/ERN. Alternatively, these authors hypothesize that error detection comes first and

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leads to an emotional response that produces the Ne/ERN. Falkenstein et al. (2000) modified their original hypothesis and, similar to Vidal et al., suggest that the Ne/ERN reflects a comparison process rather than the outcome of a comparison process, i.e. the error detection. Thus, Ne/ERN-like activity could occur after correct responses as a reflection of the comparison process, while the Ne/ERN on error trials would reflect this process plus an overlaid error signal. It has also been proposed that the Ne/ERN is related to a system that monitors the accuracy of the response system and compensates for errors (Gehring et al., 1993; Luu, Collins, et al., 2000). Again others argue that the Ne/ERN indexes a conflict between competing processes during response selection (conflict hypothesis) and serves an evaluative rather than strategic function (Carter et al., 1998, 1999, 2000). It has further been proposed that the Ne/ERN is implicated in the remediation of erroneous behavior, and in particular the reflection of inhibitory processes (Bernstein et al., 1995; Falkenstein, Hohnsbein, & Hoormann, 1999; Gehring et al., 1993). Holroyd and Coles (2002) link the function and generation of the Ne/ERN to the activity of the mesencephalic dopamine system. Based on computational modelling and empirical findings, they argue that when people commit errors in discrimination tasks, the mesencephalic dopamine system, which projects to the basal ganglia and prefrontal cortex, transmits a negative reinforcement learning signal to the motor areas of the anterior cingulate. This leads to a disinhibition of pyramidal neurons in this area which become depolarised and thereby generate the Ne/ERN. The functional significance of the Pe is also a matter of debate. From the findings of a series of experiments, Falkenstein et al. (2000) conclude that the Pe is not a delayed parietal P3 but rather the reflection of additional processing after errors possibly indicating the subjective assessment of an error. This interpretation is supported by Nieuwenhuis, Ridderinkhof, Blom, Band and Kok (2001) who recorded EEG and monitored eye movements during an antisaccade task. They report the occurrence of the Ne/ERN in response to both perceived and unperceived error trials whereas the Pe was much more pronounced after perceived than unperceived errors. They conclude that the error detection process reflected by the Ne/ERN operates independently of conscious error perception whereas the Pe reflects a later error monitoring process which is strongly associated with awareness of the occurrence of the actual (erroneous) response. 1.3. Patients with damage to the anterior cingulate and adjacent region The anterior part of the cingulate cortex is comprised of 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 surface of the cerebral hemispheres are interconnected by the anterior communicating artery. In the vast majority of cases

the ACoA and its branches supply the middle portion of the anterior commissure, and its vascular territory may frequently include the cortical region of BA 25 and sometimes even extends beyond the genu of the corpus callosum (von Cramon & Müller, 1998). Patients with a ruptured aneurysm of the ACoA are particularly likely to show damage in the anterior cingulate region including anterior and dorsal BA 24 and 32, and the more ventrally located region BA 25 due to pressure on the tissue in proximity to the lesion and an interrupted blood supply to the fornical columns and the septal nuclei (both regions in close proximity to the anterior cingulate) (von Cramon & Müller, 1998). The view that the Ne/ERN is a physiological marker for error processing and its proposed relationship to the anterior cingulate region led us to hypothesize that Ne/ERN production would be hampered in patients who have suffered damage to the medial prefrontal cortex, and in particular the anterior cingulate region. To the extent that they do not produce an Ne/ERN, these patients should not be aware of committing errors. That is, if the Ne/ERN represents a response evaluation process which leads to error detection, then patients with a damaged anterior cingulate region and no Ne/ERN should not show indications of error detection. We investigated Ne/ERN production in five patients with a ruptured aneurysm of the ACoA and damage in the medial prefrontal cortex including the anterior cingulate, and compared these patients with healthy control participants.

2. Method 2.1. Participants Five patients with a ruptured aneurysm of the ACoA and ensuing neurosurgical intervention (clipping of the aneurysm) were investigated and compared with 11 healthy controls (see Tables 1 and 2 for demographic details). Although, on average, the control participants were somewhat younger than the patients with the ruptured aneurysm (35.6 years versus 49.8 years), it has been shown that the occurrence of the Ne/ERN is not dependent on age (Gehring & Knight, 2000). In subjects older than our group (i.e. between 55 and 80 years), a reduction in amplitude has been observed (Falkenstein et al., 2000; Nieuwenhuis et al., 2002). All patients had clinical MRIs taken in the acute care hospitals or in the neurological rehabilitation hospital.1 As all scans were clinical and not research oriented the scanning parameters, orientation and number of slices obtained, and the quality of the scans differed. Localising the lesions precisely is not possible for a variety of reasons, including movement and clip artefacts. However, all patients did show lesions in the anterior cingulate regions as defined in Section 1.3 above, albeit to different degrees and not 1 The MRI scans of patients EM, EZ, IE and RF, and the lesion reconstruction of patient MH can be viewed at http://cogprints.ecs.soton.ac.uk.

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Table 1 Summary of demographic data: patients Patients

Gender

School education in years and profession

Age at the time of testing (years)

Time span between lesion onset and testing (weeks)

EM EZ IE MH RF

Female Female Female Male Female

13, 13, 16, 10, 12,

57 47 51 36 58

20 40 8 24 32

industrial clerk saleswoman teacher merchant lawyer’s assistant

necessarily at overlapping sites. All patients showed bilateral involvement, but the lesion was more pronounced on the left side in patient EM and on the right side in patients IE and MH. EM, IE and RF demonstrated lesions in the dorsal part of the anterior cingulate. MH’s and EZ’s lesions were more ventrally located compared to the other patients. EM and MH also showed some involvement of the posterior orbitofrontal areas. In addition, the anterior part of the corpus callosum was affected to different degrees in all patients, least in MH. EM showed involvement of the left basal ganglia, and EZ of the right thalamus, temporal pole and hippocampus. Patient MH also demonstrated a small lesion in the dorsolateral prefrontal cortex on the left side due to the surgical procedure. At the time of examination, all patients were at an intensive rehabilitation ward (post-acute care) set up for patients with severe behavioral and cognitive impairment after brain damage. All patients were right handed with German as their native language. All participants (or their legal guardians) were informed as to the aims and methods of the procedure and consent was obtained. The protocol was approved by the ethics committee. 2.2. Procedure and apparatus 2.2.1. Ne/ERN paradigm Two versions of the Eriksen flanker paradigm were constructed in order to elicit ERNs, one with letter and one with geometric stimuli (Eriksen & Eriksen, 1974). In the letter flanker task, participants were required to press a button with Table 2 Summary of demographic data: control participants Controls

Gender

School education in years and profession

Age at time of testing (years)

BG CK ER HG KZ MS MT RK SA SL UV

Female Female Female Male Female Female Female Male Female Female Female

16, mathematician 13, physiotherapist 16, teacher/housewife 16, psychologist 14, student 9, housewife 16, social worker 16 yrs, university diploma 16, psychologist 16, psychologist 16, psychologist

31 37 59 30 25 49 25 48 25 30 33

the left index finger when the letter S appeared in the centre of a five-letter array on the computer screen and the right index finger when H appeared. Each target letter was flanked to the right and left by either congruent (HHHHH, SSSSS) or incongruent (HHSHH, SSHSS) letters. There was a total of 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 of trials was 440. Each array remained on the screen for 250 ms followed by an inter-stimulus interval of 1000 ms. In order to accommodate patients who may have reading problems after damage to the brain, we constructed a task in which the letters were replaced by geometrical forms (circles and squares) similar in size to the letters. The participants had to press the right button if the target was a circle and the left button if the target was a square. For patients with motor or mental slowing, for each condition (letter or form) a version with an inter-stimulus interval of 1750 ms was constructed. Of the patients reported here, the “slow” version was only presented to patient RF and only in the letter condition. 2.2.2. EEG recording and analyses The EEG was recorded from 19 Ag/AgCl-cup electrodes according to the 10/20 system referenced to linked earlobes with Fpz as ground. Signals were amplified using a 32-channel dc amplifier (MES) and the SCAN software packet (NeuroScan). Data were sampled at a rate of 256 points/s with a 70 Hz low pass filter and a time constant of 5 s. Horizontal and vertical eye movements were recorded from standard locations. Impedance for EEG and electrooculogram (EOG) electrodes was kept below 10 k. We selected an EEG epoch beginning 800 ms before and ending 800 ms after the response for each Ne/ERN trial. Eye-movement artefacts were corrected by regression analysis (Semlitsch, Anderer, Schuster, & Presslich, 1986), waveforms with signals greater than ±100 ␮V in healthy controls and ±200 ␮V in patients were eliminated and a low pass filter of 20 Hz applied. After artifact reduction, the average number of error epochs included in the averaging process was 32 (minimum 9, maximum 93) for the controls and 51 (minimum 14, maximum 90) for the patients in the form condition, and 29 (minimum 8, maximum 52) for the controls and 39 (minimum 20, maximum 73) for the patients in the letter condition. Thus, a sufficient number of error

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epochs was obtained as the Ne/ERN has been shown to be a very robust waveform that can be detected even in single trials (Falkenstein et al., 2000), and, as research has demonstrated, an average based on eight or nine trials is sufficient for the ERN to appear. The EEG epochs were time-locked to the response on each trial and averaged separately for correct and incorrect trials for each participant. The waveforms were examined at frontal (Fz), central (Cz) and parietal (Pz) midline sites. 2.2.3. Response times Response times were calculated from stimulus onset to button press, with averages based on those greater than 100 ms. 2.2.4. Neuropsychological procedures Patients were examined with regard to their attention, memory, executive, language and gnostic functions using standard neuropsychological tests. A summary of the procedures used and results obtained are presented in Section 3 (see also Table 7). 3. Results 3.1. Production of Ne/ERN Every control participant produced a clearly identifiable Ne/ERN–Pe complex in response to both paradigms in the incorrect trials, that is, a negative deflection starting around the response time and reaching a peak within 100 or 150 ms after the response followed by a strong positivity (see Figs. 1 and 2), although in one individual for one paradigm this complex is more defined by the Pe than the Ne/ERN. On correct trials, a positive peak was produced followed by a negative deflection to or below baseline. Ne/ERN and Pe production in some of the patients differed noticeably from that of the control participants and could not be scored in the traditional manner. Therefore, we have focused on the presence or absence of these ERP components. Patients EM, IE and RF did not produce an Ne/ERN in either of the two paradigms (see Figs. 3 and 4). In patient EM’s waveforms, there was a difference for correct and error trials in the letter paradigm showing a rather late (starting 200 ms after the response) and broad (more than 600 ms) negativity for error trials that deviated from a regular Ne/ERN in latency, amplitude and wave shape (controls’ Ne/ERN is always about 100 ms in breadth). Patient RF produced a strong negativity 400 ms after the response to both correct and error trials in the form paradigm. IE had no Ne/ERN but did produce a Pe-like waveform for both errors and correct trials in the form but not the letter condition (Table 3). RF and EM produced no Pe or Pe-like component. Patient EZ produced an Ne/ERN and Pe in the letter paradigm but not in the form paradigm. Patient MH produced an Ne/ERN and a Pe in the form and questionably also in the letter condition.

Fig. 1. Waveforms for correct and error trials for each control participant in 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 the patients could be attributed to a lack of distinction between correct and incorrect trials. We therefore compared error rate of the two subject groups and found that the overall task performance was similar in the two groups: Although the Table 3 Summary of patient results Patients

ERN-form

ERN-letter

Pe-form

Pe-letter

EM EZ IE MH RF

No No No Yes No

No Yes No Yes No

No No Yes Yes No

No Yes No Yes (?) No

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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 than in the patients, the patients did not differ significantly from controls [t(14) = 1.4, n.s. for letter and t(14) < 1, n.s. for form task] (Table 4). The controls produced significantly fewer no responses than the patients [t(14) = 3.1 and 3.0 for letter and form tasks, respectively, P < 0.01], although these differences just failed to reach significance when adjusting for unequal variances in the samples [t(4.7) = 2.3, P < 0.07 for both tasks]. In a further step, we investigated the response times. The patients were significantly slower than the controls in both the letter and form conditions for correct trials [t(14) = 5.5 and 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 response times in the form condition for incorrect trials [t(14) = 1.7, n.s.]. Slowing of response times is a common observation Table 4 Mean error rate, no-response rate and reaction times of controls and patients in the form and letter paradigms Response trial

Control form

Control letter

Patient form

Patient letter

Mean error rate (%) Error range (%) Rate of no-responses (%)

7.2 2.1–18.5 6.2

6.8 1.7–11.8 4.6

9.8 2.5–15.6 29.7

9.7 6.0–14.4 23.6

Mean response time (ms) Correct trials 366 Incorrect trials 325

373 320

486 377

531 439

Response time range (ms) Correct trials 292–446 Incorrect trials 253–417

295–498 247–449

442–529 321–445

495–564 365–516

in patients with brain damage and not necessarily indicative of different processing mechanisms. All participants showed faster response times to incorrect than to correct trials, corroborating 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 the type of response produced (correct or incorrect) influences the following response trial. On average, the mean time for correct responses following an erroneous trial (post-error response) was slower than the mean time for correct responses following a correct trial (post-correct response) [(mean RT slowing for controls = 7 ms, for patients = 25 ms, t < 1, n.s. in the form paradigm and 19 ms versus 49 ms slowing, t(14) = 1.2, n.s. in the letter paradigm (Table 5)]. However, post-error slowing was not consistent across individuals (Table 6). Of the 11 controls, only 5 significantly slowed correct responses after making errors on the form task [t(d.f. > 120) > 2.18; P < 0.05 for 5 individuals and t(d.f. > 120) < 1.96, n.s., for 6 individuals]. Four of 11 controls showed significant post-error slowing in the letter task [t(d.f. > 120) > 2.04, P < 0.05 for 4 individuals and t(d.f. > 120) < 1.96, n.s. for 7 individuals). Two patients (EM and IE) showed significant post-error slowing in the 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 correct responses after an error trial [t(d.f. > 120) < 1.15, n.s., for form paradigm and t(d.f. > 120) < 0.89, n.s., for letter paradigm]. Thus, when significant post-error differences

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Fig. 3. Waveforms for correct and error trials for each patient in the form condition. Some patients produced large EEG overall power in the 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 after errors.

Fig. 4. Waveforms for correct and error trials for each patient in the letter condition. Some patients produced large EEG overall power in the 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 RF clearly noticed when they had made an error. The other three patients’ behavior was mixed, in that one did not show any overt error detection while the others did so inconsistently.

3.4. Error awareness 3.5. Results of neuropsychological examination The experimenter documented for the patients for each trial whether the participants behaviourally showed signs (exclamations, whispered swearing, grimaces) of having

Behavioral observation showed spontaneous confabulation to various degrees in all patients at the time of

Table 5 Mean reaction times in post-response trials across participants in the form and letter paradigms Post-response trials Post-error response Correct trial (PEc) Post-correct response Correct trial (PCc) Difference (PEc − PCc)

Control form (mean response time (ms)) 392

Control letter (mean response time (ms)) 391

Patient form (mean response time (ms)) 511

Patient letter (mean response time (ms)) 575

363

372

486

526

+29

+19

+25

+49

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Table 6 Mean 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

Controls BG CK ER HG MS KZ MT RK SA SL UV

364 397 477 318 530 325 289 503 383 420 306

340 371 421 310 409 336 292 442 353 426 298

24 26 56 8 121 −11 −3 61 30 −6 8

Patients EM EZ IE MH RF

574 513 562 447 461

494 534 463 504 436

80 −21 99 −57 25

a ∗

Post-error response (PEc) (ms)

Post-correct response (PCc) (ms)

Difference (PEc − PCc) (ms)a

(2.32)∗ (1.85) (2.18)∗ (0.66) (3.26)∗ (−0.52) (−0.49) (2.39)∗ (2.40)∗ (−0.37) (0.95)

434 336 375 357 617 313 297 419 374 435 341

373 360 408 341 499 299 294 442 351 392 331

61 −24 −33 16 118 14 3 −23 23 43 10

(4.77)∗ (−1.64) (−1.27) (1.20) (3.02)∗ (1.18) (0.33) (−1.16) (2.04)∗ (2.84)∗ (0.90)

(3.97)∗ (−0.73) (2.80)∗ (−1.15) (0.79)

568 585 618 572 530

546 531 491 565 495

22 54 127 7 35

(0.89) (2.56)∗ (4.20)∗ (0.23) (0.87)

t values. P < 005.

Table 7 Neuropsychological results Patient

WMS-R general memory

Delayed recall

Attention

Verbal fluency

d2 cancellation task

Trail making A

Trail making B

Wisconsin card sorting test

Tower of Hanoi

Office organisation task

HAWIE (German version of WAIS) (non-verbal)

IE EM MH EZ RF

n ↓↓ ↓↓ ↓ n

n ↓↓ ↓↓ ↓↓ ↓↓

n ↓ ↓ ↓↓↓ n

n ↓↓ ↓↓↓ ↓ ↓

– ↓↓↓ ↓↓↓ ↓↓↓ ↓

n ↓ ↓ ↓↓ ↓

n ↓ ↓↓↓ ↓↓↓ ↓↓

– ↓ ↓↓ ↓↓ ↓↓

– ↓ ↓ ↓↓ ↓

– ↓ (↓) ↓↓ ↓

– (↓) ↓↓↓ ↓↓↓ ↓↓

IQ IQ IQ IQ

= 88 = 42 = 62 = 70

(n) within normal range; (–) non-applicable/test not done with patient; ((↓)) some subtests within normal range, some below; (↓) >1 S.D. below normal range; (↓↓) >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 this sort. Neuropsychological assessment revealed that all patients, except for IE, showed attention, memory, and executive function problems to various degrees in standardised testing procedures (Table 7). MH, EZ, and RF’s non-verbal IQ scores were well below average. Although patient IE performed within the average range on all standard tests, she still showed conspicuous signs of confusion and confabulation as observed by the experimenter and consistently reported by the staff on the ward. Such behavior is usually not captured by standard neuropsychological testing. The patient herself complained about memory problems although standard memory testing was within average range. Patient RF performed somewhat better than the other patients, his WMS-R general memory score and the attention subtest being in the average range.

4. Discussion The control participants showed an Ne/ERN–Pe complex on trials with incorrect but not correct responses in both the letter and form versions of the flanker task. For the patients a different picture emerged. Three patients did not produce an Ne/ERN in either paradigm, one patient produced an Ne/ERN in one paradigm but not the other and one patient produced an Ne/ERN in both paradigms. The patients who showed an Ne/ERN also showed a Pe in at least one of the paradigms. Although the average error rate of the controls was somewhat lower than the error rate of the patients, this difference did not reach statistical significance. Controls as well as patients showed faster response times to incorrect than to correct trials. Post-error slowing was inconsistent in controls as well as patients. These results will be discussed in relation to issues of generator site,

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awareness of error, cognitive functions and functional significance. 4.1. The generator question EEG and fMRI studies have implicated the anterior cingulate as a major contributor to the generation of the Ne/ERN although the role of the SMA region and subcortical structures remain unclear. For example, it has been hypothesised that the mesencephalic dopamine system is implicated in error processing (Holroyd & Coles, 2002). However, empirical evidence for this hypothesis is ambiguous. Seeking support for this hypothesis, two studies have investigated patients with Parkinson’s disease. The neuropathological characteristic of Parkinson’s disease is the degeneration of the midbrain dopamine nuclei. Whereas Falkenstein et al. (2001) found an attenuated Ne/ERN in Parkinson’s patients, Holroyd, Praamstra, Plat, and Coles (2002) could not replicate this finding. Their Parkinson’s patients produced a normal Ne/ERN. These discrepancies might be due to some methodological differences. A similarly ambiguous situation concerns the findings in patients with lesions to the lateral frontal lobes. Whereas Gehring and Knight (2000) found a normal Ne/ERN in response to incorrect trials but also a negativity with increased amplitude in response to correct trials (correct-related negativity, CRN) in patients with prefrontal lesions, Ullsperger, von Cramon and Müller (2002) reported a reduced Ne/ERN in response to incorrect trials but an unaffected negativity in response to correct trials in patients with lateral frontal lesions. The diverging results may at least partially be explained by two factors: (1) differing task requirements: Gehring et al. used a cued discrimination task that included working memory component whereas Ullsperger et al. a used a modified flanker task; and (2) heterogeneity of patients: the extent of damage and etiology of the lesions differed considerably.2 2 Gehring et al.’s patients had all suffered an infarction of the middle cerebral artery and showed involvement of the prefrontal cortex to varying degrees. Some patients showed involvement of the superior, medial and inferior frontal gyrus, others only of the medial and inferior frontal gyrus. Most patients showed involvement of the insular region but one did not and one only partially. Four of the six patients also showed damage to the superior temporal gyrus, and in one patient the hippocampus and fornix were lesioned. Furthermore, in some patients the lesion extended to the precentral gyrus and in some to the inferior parietal lobule. The patients investigated by Ullsperger et al. showed diversity as to their etiology including ischemic and haemorrhagic infarction, traumatic brain injury, tumor and herpes encephalitis. The frontolateral group consisted of mainly infarct patients but included one traumatic brain injury and one patient with arteriovenous malformation. The bifrontopolar–orbitofrontal group consisted of only traumatic brain injury patients and the temporal group patients was the most diverse in etiology. The neuropsychological and recovery pattern of such patients can differ quite dramatically functionally, speaking to probably different underlying physiological processes. It is unclear whether and if so to what degree the heterogeneity of patients in terms of etiology and lesions has influenced the results. Unfortunately, neither Gehring and Knight nor Ullsperger et al. provide individual patient data and results.

In general, our findings are consistent with the view that the anterior cingulate, or some region dependent on it, is involved in Ne/ERN generation. Whereas three patients (EM, IE and RF) with damage to the anterior cingulate region did not show any Ne/ERN, one patient (EZ) showed an Ne/ERN in one and another patient (MH) in both paradigms. For reasons outlined previously, precise lesion localisation is not possible in our patients. However, based on what we can clearly identify, it seems that the more ventral region of the anterior cingulate region (e.g. BA 25) is less critical for generating an Ne/ERN component. This hypothesis is supported by a fMRI study using a modified flanker task showing selective activation of the cingulate motor area (BA 32/24c ) during error processing (Ullsperger & von Cramon, 2001). Indirect support for this hypothesis comes from various studies. Using a Go–NoGo task in an event-related fMRI study, Kiehl, Liddle, and Hopfinger (Kiehl et al., 2000) reported selective activation in the rostral anterior cingulate and in the left lateral frontal cortex for errors of commission. The authors found activation at the Talairach co-ordinates x = −8, y = 45, z = 16 and x = 12, y = 36, x = 12 when errors of commission occurred. In order to be able to compare Kiehl et al.’s findings with the patients’ lesions, we used the Talairach Demon version 1.1 (Lancaster et al., 2000) to check for the location of the co-ordinates given by Kiehl et al. for the rostral anterior cingulate in the Talairach space and transferred the Talairach co-ordinates to (modified) Brodmann areas (Devinsky et al., 1995). Both sets of co-ordinates involve the anterior cingulate corresponding to BA 24b at and above the genu of the corpus callosum and extending to BA 32. Therefore, it seems that Kiehl et al.’s rostral anterior cingulate area comes closest to the lesion described in our patients EM, IE and RF although the overlap is only partial. The findings by Kiehl et al. have been corroborated in an event-related fMRI study using a three-choice discrimination task by Braver et al. (2001). These authors showed activation of the superior caudal region of the anterior cingulate cortex extending into the supplementary motor area in response to conflict and a more rostral inferior region in response to errors, although both regions did show some responsiveness as well to the other condition. Further indirect support comes from ERP studies using high-density scalp recording and the brain electric source analysis (BESA) for a forward-search dipole localisation (Dehaene et al., 1994; Miltner et al., 1997) or Laplacian transformation (Vidal et al., 2000). These researchers reject a deep source contributing to Ne/ERN production but interpret their findings as indicative of a more shallow source either in the anterior cingulate region or a more distributed source in the SMA areas. Our findings demonstrate that damage to the anterior cingulate region can alter the Ne/ERN response although it is still possible for patients to detect errors. It thus seems that error detection per se does not rely on the anterior cingulate region. Although neuroimaging studies have repeatedly shown activation of the anterior cingulate in error tasks,

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activation of other brain structures have also been observed pointing to a distributed and interconnected neural systems involved in error processing. For example, Ullsperger and von Cramon (2001) investigated response competition and error processing in an event-related fMRI study using a modified flanker task. In the response competition condition, the pre-SMA area (BA 6 and 8) extending to the banks of the anterior cingulate sulcus (BA 32/24c ), the posterior cingulate cortex, the right inferior frontal gyrus, the right intraparietal sulcus, left sensorimotor cortex, bilateral anterior superior insula and the middle frontal gyrus were activated. In the error condition, activation was found in the pre-SMA area (BA 6), on the banks of the anterior cingulate sulcus (BA 32/24c ), in the anterior insula and intraparietal sulcus. Menon et al. (2001) investigated error-related brain activity and response inhibition in a Go–NoGo task. They found error-related brain activation in the rostral aspect of the right cingulate and adjoining medial prefrontal cortex, the left and right insular cortex and adjoining frontal operculum and left precuneus/posterior cingulate. Activation related to response inhibition showed in the dorsolateral prefrontal cortex, the inferior frontal cortex, pre-motor cortex, inferior parietal lobule, lingual gyrus, caudate and right dorsal anterior cingulate cortex. A role for the DLPFC in error processing has been suggested by various studies (Carter et al., 1998; Gehring & Knight, 2000; Kiehl et al., 2000; Menon et al., 2001). One of our patients (MH) presented with a small lesion in the dorsolateral prefrontal cortex, which, however, did not prevent Ne/ERN production. This is compatible with Gehring and Knight’s (2000) and Ullsperger et al.’s (2002) findings which showed that patients with a lesioned prefrontal cortex produced an Ne/ERN. Gehring and Knight suggest that an interaction between the anterior cingulate and the prefrontal areas may be necessary for a well-formed Ne/ERN to occur and they discuss the possibility of a feedback mechanism between the anterior cingulate and the prefrontal cortex. Their argument is based on their findings of an Ne/ERN in response not only to incorrect but also to correct trials in patients with a stroke in the middle cerebral artery, that is, in a patient group with an intact anterior cingulate but a damaged prefrontal cortex. In comparison to ours, Gehring and Knight’s paradigm was more complex and the additional processes involved in their task may have raised the level of uncertainty when responding, and this, in turn, may have produced an Ne/ERN on trials even when the response itself was correct. That the Ne/ERN observed on correct trials can indeed reflect error processing has convincingly been shown by Coles et al. (2001). Further support comes from monkey studies where error potentials recorded from the anterior cingulate became weaker with waning uncertainty about task fulfilment (Gemba, Sasaki, & Brooks, 1986). In another monkey study, increased unit firing from cingulate cortex cells occurred in response to errors as well as in response to omission of reinforcement for correct responses (Niki & Watanabe, 1979).

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The previous discussion was aimed at localisation based on the relationship between Ne/ERN production and site of lesion, although extrapolating from lesion data such as ours requires cautious interpretation because the regions are highly interconnected and it is impossible to determine precisely which connections were interrupted. Another line of argument comes from the relationship between the Ne/ERN and the contingent negative variation (CNV) which has been associated 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 of errors did, however, produce a well-formed CNV. (The CNV paradigm was performed as a clinical routine [visual stimuli: ISI = 2.8 s, ITI = 4.8 s]). Conversely, MH had a secondary lesion in his left DLPFC related to the surgery to clip the aneurysm, and his CNV was highly abnormal. This dissociation is compatible with the view that Ne/ERN and CNV production do not rely on the same neural circuitry (Davies, Segalowitz, Dywan, & Pailing, 2001) and that different functional mechanisms underlie Ne/ERN and CNV production. 4.2. The error awareness question There has been relatively little explicit discussion as to what degree Ne/ERN production involves conscious awareness. Current observations suggest that conscious awareness is not a sufficient condition for Ne/ERN production. Ne/ERN production has been observed after erroneous actions that have escaped our conscious control and are committed unintentionally and unwillingly, i.e. after slips, and not after purposefully made inappropriate responses (Dehaene et al., 1994; Stemmer et al., 2001). In monkeys, error potentials have been shown in the anterior cingulate area 24 in response to non-rewarded, inappropriate motor movements but not after rewarded and intentionally made movements (Gemba et al., 1986). The relationship between the perceived accuracy (i.e. the awareness of making errors), behavioral accuracy and Ne/ERN amplitude has been investigated by Scheffers and Coles (2000). Using a visual flanker task and having participants rate the accuracy of their response, these authors found an increase in the amplitude of the Ne/ERN associated with an increase in the strength with which the participants believed that their response was incorrect. That is, the more confident the participants were that they had made an error, the higher the Ne/ERN amplitude. Similarly, for correct trials, there was a decrease in a similarly timed negativity the more confident the participants were of the correctness of their response. The authors suggest that these findings indicate a strong association between those processes that lead to the Ne/ERN and those that relate to the participant’s judgements. Although the authors do not make any explicit claim concerning the awareness question, it seems that these findings suggest that having a subjective awareness of making an error is associated with Ne/ERN amplitude. On the other hand, Nieuwenhuis et al. (2001)

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found that the Ne/ERN occurred on error trials even when (healthy) subjects did not rate their performance as an error on a binary choice task. During task performance it has been observed that subjects sometimes overtly demonstrate a verbal reaction in the form of expletives when they make an error thus suggesting that they are aware of their errors (Scheffers et al., 1996). In our study, we found that explicit awareness of errors was dissociated from Ne/ERN production in two patients: IE and RF overtly noticed when they had made an error and neither produced a clear Ne/ERN. Of the five patients, IE and RF were the least impaired in terms of attention and memory functions. In fact, at the time of the Ne/ERN recording, patient IE had recovered from her previous severe orientation, attention and memory impairments to a point where the results of the neuropsychological tests were in the average range although she still showed behavioral problems. IE was about to be transferred from the intensive to the regular rehabilitation ward. Patient RF’s cognitive functioning was worse than that of IE but generally better than that of the other patients. Thus, these two patients showed cognitive functioning that was relatively good compared to the other patients and they detected their errors, yet did not produce an Ne/ERN. These findings argue for some sort of dissociation between Ne/ERN production and error awareness, i.e. that the process leading to the Ne/ERN cannot be required for error awareness although the reverse could hold. Nieuwenhuis et al. (2001) also found that although the Ne/ERN occurred in aware and unaware error trials, the Pe was significantly more pronounced for acknowledged than unacknowledged errors. In line with Falkenstein et al. (2000), Nieuwenhuis et al. (2001) suggest that the Ne/ERN and Pe reflect functionally different components in error processing and associate the Pe with conscious error recognition and remedial action. Our own data show mixed results. The two patients who produced an Ne/ERN also produced a Pe. If one adopted the view that the Pe is associated with conscious error recognition, then the occurrence of the Pe in these two patients would be indicative of conscious error recognition despite a lack of overt error recognition (which of course is possible if unusual). However, both IE and RF showed overt error recognition in both paradigms, yet did not produce a Pe. These observations are not compatible with the view that the Pe necessarily appears when errors are recognised. 4.3. The Ne/ERN and cognitive functions The Ne/ERN also seems to be dissociated somewhat from intact attention, memory and executive functions in that IE, who did not produce an Ne/ERN, performed in the average range on all neuropsychological tests tapping these functions whereas patients MH and EZ with clearly impaired attention, memory, and executive functions did produce Ne/ERN-like waveforms in at least one paradigm. Another issue to address in this context is the observation that all patients presented with confabulation to varying de-

gree and whether this is related to their performance in error detection. It has been shown that in dementia and Korsakoff patients, mild confabulators showed a greater tendency toward verbal self-correction than severe confabulators whose ability to monitor or self-correct is impaired (Mercer, Wapner, Gardner, & Benson, 1977). However, as we have not systematically and objectively investigated the patients’ confabulations, addressing this issue in more detail would be an over-interpretation of our data. Furthermore, it has not been established that confabulation and problems with error detection necessarily co-occur (Gilboa & Moscovitch, 2002). 4.4. Functional significance of Pe and Ne/ERN Post-error slowing has been related to controlled processes which require prior conscious error recognition (Rabbit, 1966, 1967). Nieuwenhuis et al. (2001) found that perceived errors were associated with substantial post-error slowing but that post-error slowing was absent in unperceived errors. Although co-variation of post-error slowing with Pe amplitude does not necessarily imply a causal relationship, the authors point out that this is consistent with Falkenstein et al.’s (2000) hypothesis that the Pe reflects post-error adjustment processes. However, Falkenstein et al. found larger post-error slowing for elderly subjects without an enlargement of the Pe and conclude that these results argue against the view that the Pe reflects conscious error processing or the post-error adjustment of response strategies. Our data are not conclusive in this regard (see previous section). The patients who produced an Ne/ERN followed by a Pe did not show much overt error recognition, and the patients who showed overt error recognition did not produce a Pe (or if they did, like IE, it was in response to both correct and error trials). Therefore, no clear conclusion with regard to conscious error awareness can be drawn. Similarly, we have an inconsistency in the relationship between the Ne/ERN and post-error slowing in our control subjects’ data: All our controls produced a scorable Ne/ERN and Pe in each paradigm, while only 8 of 11 demonstrated post-error slowing at all, and only 5 demonstrated statistically significant post-error slowing. If significant post-error slowing is a definitive marker of conscious error recognition, then in healthy controls the Ne/ERN and Pe may reflect more than error recognition because they were present more often than post-error slowing. On the other hand, it may be the case that the Ne/ERN and Pe are more reliable than is post-error slowing, and what we are seeing is simply this difference in their psychometric properties. 4.5. The anterior cingulate, error detection and the Ne/ERN Our data demonstrate that damage to the anterior cingulate region can alter the standard Ne/ERN response and that it is nonetheless possible for patients to clearly detect errors.

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