Cerebellar lesions alter performance monitoring on the antisaccade task—An event-related potentials study

Neuropsychologia 50 (2012) 379–389

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Cerebellar lesions alter performance monitoring on the antisaccade task—An event-related potentials study Jutta Peterburs a,∗ , Kathrin Gajda b , Benno Koch c , Michael Schwarz c , Klaus-Peter Hoffmann b , Irene Daum a , Christian Bellebaum a a

Institute of Cognitive Neuroscience, Department of Neuropsychology, Faculty of Psychology, Ruhr University Bochum, Universitaetsstrasse 150, 44780 Bochum, Germany Department of Neuroscience and Faculty of Biology and Biotechnology, Ruhr University Bochum, Universitaetsstrasse 150, 44780 Bochum, Germany c Department of Neurology, Klinikum Dortmund, Beurhausstraße 40, 44137 Dortmund, Germany b

a r t i c l e

i n f o

Article history: Received 4 August 2011 Received in revised form 23 November 2011 Accepted 18 December 2011 Available online 28 December 2011 Keywords: Error processing Cerebellum Error-related negativity (ERN) Error negativity (Ne) Error positivity (Pe) Antisaccades Performance monitoring

a b s t r a c t Error processing is associated with distinct event-related potential components (ERPs), i.e. the errorrelated negativity (ERN) which occurs within approximately 150 ms and is typically more pronounced than the correct-response negativity (CRN), and the error positivity (Pe) emerging from about 200 to 400 ms after an erroneous response. The short latency of the ERN suggests that the internal error monitoring system acts on rapidly available central information such as an efference copy signal rather than slower peripheral feedback. The cerebellum has been linked to an internal forward-model which enables online performance monitoring by predicting the sensory consequences of actions, most probably by making use of efference copies. In the present study it was hypothesized that the cerebellum is involved in the fast evaluation of saccadic response accuracy as reflected by the ERN. Error processing on an antisaccade task was investigated in eight patients with focal vascular lesions to the cerebellum and 22 control subjects using ERPs. While error rates were comparable between groups, saccadic reaction times (SRTs) were enhanced in the patients, and the error-correct difference waveforms showed reduced amplitudes for patients relative to controls in the ERN time window. Notably, this effect was mainly driven by an increased CRN in the patients. In the later Pe time window, the difference signal yielded higher amplitudes in patients compared to controls mainly because of smaller Pe amplitudes on correct trials in patients. The altered ERN/CRN pattern suggests that the cerebellum is critically involved in fast classification of saccadic accuracy. Largely intact performance accuracy together with increased SRTs and the altered Pe pattern may indicate a compensatory mechanism presumably related to slower, more conscious aspects of error processing in the patients. © 2011 Elsevier Ltd. All rights reserved.

1. Introduction Error processing has frequently been investigated using electroencephalography (EEG), and has been reported to be reflected in distinct event-related potential (ERP) components: the error negativity (Ne) (Falkenstein, Hohnsbein, Hoormann, & Blanke, 1991) or error-related negativity (ERN) (Gehring, Goss, Coles, Meyer, & Donchin, 1993), a frontocentrally distributed negative deflection occurring within 150 ms after an erroneous response which has been linked to fast, unconscious error processing (Falkenstein et al., 1991), and the error positivity (Pe) (Falkenstein et al., 1991; Falkenstein, Hohnsbein, & Hoormann, 1995), a slow positive deflection with centroparietal topography emerging

∗ Corresponding author. Tel.: +49 234 32 24631; fax: +49 234 32 14622. E-mail addresses: [email protected], [email protected] (J. Peterburs). 0028-3932/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2011.12.009

approximately 200–400 ms after an erroneous response which is associated with conscious error recognition and remedial action (Endrass, Reuter, & Kathmann, 2007; Falkenstein et al., 1991; Nieuwenhuis, Ridderinkhof, Blom, Band, & Kok, 2001). The ERN originates in the anterior cingulate cortex (ACC), as indicated by source localization studies (e.g. Dehaene, Posner, & Tucker, 1994). Functional neuroimaging studies as well as findings of pronounced ERN reduction following damage to the rostral-to-middorsal ACC support the crucial role of the ACC in error monitoring (Carter et al., 1998; Kiehl, Liddle, & Hopfinger, 2000; Swick & Turken, 2002). Generally, the ERN is associated with the activity of the midbrain dopaminergic system (Holroyd & Coles, 2002) and has thus been found to be attenuated in patients suffering from Parkinson’s disease (Falkenstein et al., 2001), Huntington’s disease (Beste, Saft, Andrich, Gold, & Falkenstein, 2006), and basal ganglia lesions (Ullsperger & von Cramon, 2006). Notably, the ERN is not affected by perception of an erroneous response as being false (Endrass et al., 2007; Nieuwenhuis et al., 2001), although it does depend on the

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availability of information necessary for classifying a response as correct or erroneous in a given context (Pailing & Segalowitz, 2004). Since an ERN-like deflection referred to as correct-response negativity (CRN) has been observed in ERPs associated with correct responses (Coles, Scheffers, & Holroyd, 2001; Falkenstein, Hoormann, Christ, & Hohnsbein, 2000), the ERN has been suggested to also reflect processes of (response) conflict evaluation (Suchan, Jokisch, Skotara, & Daum, 2007) rather than a mere comparison process. The short latency of the ERN strongly suggests that the error monitoring system relies on rapidly available internal information, i.e. an “efference copy” of the motor command for the response, since reafferent feedback concerning the sensory consequences or proprioceptive information about the exact metrics of the performed movement would arrive too late to cause the ERN (Allain, Hasbroucq, Burle, Grapperson, & Vidal, 2004; Coles et al., 2001; Falkenstein et al., 2000; Gehring et al., 1993). The efference copy serves to generate a prediction of the sensory consequences of an action (Miall, 1998), which then can be compared to the actual consequences. The cerebellum is believed to learn to predict the sensory consequences of movements by making use of efference copy information and thereby mimicking cortical information processing (Miall, 1998; Miall & Wolpert, 1996; Wolpert, Miall, & Kawato, 1998). In accordance with this, it has been suggested to play a key role in flexible behavioural control and the fine tuning of motor responses, which requires the integration of information about ongoing motor commands with mental representations of intended responses and body state information (Molinari, Restuccia, & Leggio, 2009). Cerebellar activity has been linked to both ongoing motor behaviour and incoming sensory information as well as to predictive motor control (Ito, 1984; Miall, 1998; Reilly, Mesulam, & Nobre, 2008). The neural circuitry responsible for the generation of saccadic eye movements is one of the most extensively studied motor systems. The adaptation of saccade amplitudes in response to perisaccadic target displacements has been shown to critically depend on the integrity of the cerebellum, and cerebellar cells accurately code for the amplitude of saccades (Barash et al., 1999; Golla et al., 2008; Jenkinson & Miall, 2010; Scudder, 2002; Scudder & McGee, 2003; Wallman & Fuchs, 1998). Saccade-related and other signals originating in the cerebellum presumably influence cortical information processing via cerebello-thalamo-cortical feedback loops. There are dense connections between the deep cerebellar nuclei and ventrolateral thalamic regions (Allen & Tsukahara, 1974) as well as the intralaminar nuclei (ILN) (Kalil, 1981) (for a review see Jones, 2007). Deficits in the online monitoring of saccadic eye movements observed after ventrolateral thalamic lesions in humans may thus be caused by disruptions of cerebellar back projections to the cortex (Bellebaum, Daum, Koch, Schwarz, & Hoffmann, 2005). The role of the cerebellum in the online monitoring of movements also has strong implications for more cognitive aspects of performance monitoring such as error processing. A recent study applying Granger causality mapping and functional magnetic resonance imaging (fMRI) (Roebroeck, Formisano, & Goebel, 2005) shows that the cerebellum contributes to error and post-error processing via connections with the thalamus and the supplementary motor area (Ide & Li, 2011). In this study, cerebellar activity was reported to mediate activity in the prefrontal cortex (PFC) during behavioural adjustments in a stop-signal task (Ide & Li, 2011). Cerebellar activations have also been observed for the processing of saccadic errors (Van Broekhoven et al., 2009). Along similar lines, altered error processing in human patients with thalamic lesions has been ascribed to the disruption of pathways from the striatum and/or cerebellum to the ACC (Peterburs et al.,

2011; Seifert, von Cramon, Imperati, Tittgemeyer, & Ullsperger, 2011). However, direct evidence for a critical role of the cerebellum in error processing has yet to be obtained. The present study aimed to address the question of cerebellar contributions to error processing by investigating ERPs in response to correct antisaccades and erroneous prosaccades within the context of an antisaccade task (Hallett, 1978; Mokler & Fischer, 1999) in patients with focal vascular lesions to the cerebellum. The antisaccade task was applied for two reasons: Firstly, the role of the cerebellum in the control of saccades is very well studied (see above). Secondly, most of the previous work on efference copy processing was done with tasks involving saccades (e.g. Bellebaum et al., 2005; Sommer & Wurtz, 2002). In view of the hypothesized role of the cerebellum in efference copy processing and online movement monitoring, it was assumed that cerebellar lesions would affect the fast and automatic processing of saccadic errors as reflected in the ERN. However, deficits in saccade monitoring should not exclusively affect the processing of saccadic errors, but would presumably alter the neural responses to both erroneous and correct saccades. As a consequence, the cerebellar patients’ ERPs were hypothesized to not distinguish reliably between error and correct trials, with ERN (following errors) and CRN (following correct reactions) amplitudes being more similar in patients than in controls. In turn, the Pe, which is thought to reflect later and more conscious aspects of error processing and thus does not rely directly on efference copy signals, was not expected to differ between patients and controls. 2. Methods 2.1. Subjects For the present study, eight patients (4 men, 4 women) with post-acute focal vascular damage to the cerebellum and 22 neurologically healthy volunteers (11 men, 11 women) were recruited. Control subjects were selected from a pool of neurologically healthy registered volunteers at the Department of Neuropsychology at the Institute of Cognitive Neuroscience of the Ruhr University Bochum. Patients were recruited from a patient database at the Klinikum Dortmund, Germany. The inclusion criteria were no history of psychiatric disorders, no lesions outside of the cerebellum or neurological problems apart from those related to the cerebellar lesions, no medication affecting the central nervous system and a neurological outcome enabling the subject to perform the experimental task (based on the assessment of the consulting neurologist). Only few patients fulfilled these criteria, and eight patients finally agreed to participate in the study. A further selection criterion was an IQ estimate of more than 80. However, IQ was only assessed once the patients participated in the experiment, and none of the patients had to be excluded based on this measure. The same inclusion criteria were applied to control subjects, with the exception that any history of neurological disorders led to exclusion from the study. All patients and control subjects were right-handed as determined by the Edinburgh Handedness Inventory (EHI) (Oldfield, 1971). All subjects had normal or corrected-to-normal vision and gave written informed consent prior to participation. Subjects received monetary reimbursement for participation and travel expenses. The study conforms to the Declaration of Helsinki and has received ethical clearance by the Ethics Board of the Medical Faculty of the Ruhr University Bochum, Germany. All patients were treated on an outpatient basis at the Klinikum Dortmund, Germany, and will be referred to as Patients 1–8 in the following. Lesions were documented by magnetic resonance imaging (MRI) using a standard T2-weighted sequence (voxel size: 1 mm × 1 mm × 5 mm). For each patient, the affected brain regions were determined by two experienced, independent neurologists according to an established atlas (Matsui, 1978). Fig. 1 contains MR-images of the lesions for the eight patients. Detailed information about individual patients’ age, lesion location and time since lesion is provided in Table 1. Three patients presented with unilateral left-sided and right-sided lesions. In two patients, damage affected both cerebellar hemispheres. None of the patients reported any residual symptoms majorly affecting their everyday lives. However, Patients 2 and 8 did report experiencing increased fatigue when dealing with strenuous cognitive tasks. Patients were assessed on average 76 months after the lesion event (range: 16–227 months). Controls were selected so that mean age and IQ closely matched the patients’ mean age and IQ (see Table 1). IQ estimates were derived from the “Picture Completion” and the “Similarities” subtests from the short German version of the Wechsler Adult Intelligence Scale (WIP, Dahl, 1986). The WIP comprises four subscales, two verbal and two non-verbal, each allowing for an IQ estimation. In the present study, the subtests “Similarities” representing a verbal subscale and “Picture Completion”

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Fig. 1. Structural transversal T2-weighted MR-images of cerebellar lesion locations in individual patients.

reflecting the performance IQ were administered. The scores of these two subtests combined are frequently used to approximate the full-scale IQ. On the group level, patients and controls did not differ with regard to age or IQ (both p > .10). Reaction times on a tonic and phasic alertness task as well as performance on short-term and working memory tasks (visual and verbal, with visual memory being more important for the task used in the present study – see below) were assessed to determine neuropsychological functioning on tasks potentially relevant to the experimental task applied in the present study. Alertness was assessed with an adaptation of the subtest ‘alertness’ of a computerized German attention test battery (Zimmermann & Fimm, 2002). This test required participants to respond to a visual target stimulus (X) by pressing a button as fast as possible in four blocks of 20 trials (tonic alertness). Following a fixation period of varying length at the beginning of each trial, the target was presented for up to 2000 ms, and was cleared from the screen as soon as the response button was pressed. An auditory warning signal delivered 500–1500 ms prior to target onset preceded the target stimulus in half of the trials. These trials assessed phasic alertness, i.e. the ability to increase attention in response to a warning stimulus. If reaction time exceeded 2000 ms, participants were instructed to respond faster, and the trial was repeated at the end of the block. Reaction times were recorded separately for tonic and phasic alertness trials. Verbal and visual short-term and working memory was assessed with the Digit Span and Block Span subtests from the Wechsler Memory Scale (Wechsler, 2000). Table 2 provides mean alertness and visual and verbal short-term and working memory scores for patients and controls. Verbal short-term memory scores were significantly lower for patients than for controls (t28 = −1.705, p = .050), and a corresponding trend also emerged for verbal working memory (p = .089). There were no significant differences between patient and control group with regard to either alertness or visual short-term and working memory (all p > .136).

in the centre of the screen and two white square frames (3◦ side length), whose centres were located 8◦ to the left or right of the fixation dot. After a variable delay of 1100–1600 ms, the fixation dot disappeared. There were two types of trials in the task. In trials without precue, the white peripheral squares remained on the screen for the next 200 ms. Subsequently, the cue stimulus, a yellow dot (1◦ in diameter), was presented for 100 ms unpredictably in the left or right square frame. In trials with precue, the colour of the square opposite to the cue location was changed to red for 50 ms from 100 to 50 ms before cue onset. The precues always marked the correct target location for the saccade (see Fig. 2 for the sequence of events in both types of trials). Precues were introduced to increase error rates (Fischer & Weber, 1996). Participants were informed that their task was to perform a single horizontal saccade as fast and accurately as possible to the square opposite to the position of the cue stimulus. After a time window of 900 ms for saccade performance, the correct target location was marked with a white cross for 1500 ms. Error awareness was assessed by asking participants to press the space bar during presentation of the cross if they thought they had mistakenly moved their eyes towards the cue, i.e. made a pro- instead of an antisaccade. Button presses had to be made only while the target cross was visible in order to prevent hand movements during the cue-target interval. The task consisted of six blocks of 100 trials and 20 practice trials prior to the first block, amounting to 620 trials in total. Cue (and precue) occurrence on the right or left side was balanced throughout the task. The stimuli were presented on a 17in. LCD computer screen. Stimulus timing was controlled by Presentation software (Neurobehavioral Systems Inc., Albany, CA, USA). Room lights were dimmed for the experiment. Subjects were seated at a viewing distance of 57 cm. A chin-rest was used to stabilize the position of the head. Participants were free to take breaks between blocks. The entire session lasted about 1 h.

2.2. Experimental task

2.3. Procedure

Fig. 2 illustrates the time course of stimulus presentation in the antisaccade task. The onset of each trial was marked with a white fixation dot (.6◦ ) located

Participants were informed that the study investigated visuomotor integration. The experimental task was started after the informed consent form had been signed,

Table 1 Mean age and IQ for patients and controls as groups, and age, IQ, lesion location and lesion age for individual patients. Standard deviations (SDs) in brackets.

Controls mean (SD) Patients mean (SD) Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8

Age

IQ

Side

Lesion age (months)

Affected area

Arterial territory

43.1 (2.1) 42.9 (8.9) 29 33 41 43 45 45 54 54

117.8 (2.3) 112.6 (6.2) 118.3 112.3 103.8 113.5 108.5 110.3 124.0 110.5

L L, R L L, R R R R L

44 85 48 28 16 60 227 100

Left: post CL Bilateral: post CL; right: ant CL Left: post CL Right: ant CL; left: post CL Right: post CL Right: post CL Right: Vermis, ant CL, post CL Left: Vermis, ant CL, post CL

Left PICA, Right SCA Left PICA Bilateral SCA Right PICA Right SCA Right PICA Left PICA

ant: anterior, post: posterior, CL: cerebellar lobe, PICA: posterior inferior cerebellar artery, SCA: superior cerebellar artery.

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Table 2 Mean performance on the tonic and phasic alertness as well as the visual and verbal working and short-term memory tasks for patients and controls. Standard deviations (SDs) in brackets.

Controls mean (SD) Patients mean (SD) * ◦

Alertness (reaction time)

Visual memory

Tonic (ms)

Phasic (ms)

Short-term

Working

Short-term

Verbal memory Working

296 (51) 305 (106)

291 (54) 298 (110)

9.4 (2.4) 8.6 (2.3)

8.7 (1.9) 9.6 (2.3)

9.0 (1.7) 7.6 (2.3)*

7.6 (1.9) 6.5 (2.1)◦

p < .05. p < .10.

Fig. 2. Schematic timeline of stimulus presentation in the antisaccades task for trials with (A) and without (B) precue.

demographic information had been obtained, and after the electrodes had subsequently been attached. Alertness, short-term and working memory tasks were administered after the antisaccade task. 2.4. Recording and analysis of saccade and EEG data The movements of the participants’ right eyes were recorded with an iView XTM Hi-Speed video-based eye tracking system (SensoMotoric Instruments, Berlin, Germany) with a sampling rate of 500 Hz. Eye movement data were analysed offline using MATLAB (Mathworks, Natick, MA, USA). Saccades were detected according to velocity (threshold, 40◦ /s) and distance criteria (minimum saccade length 1.5◦ ). Only trials in which a horizontal saccade starting within the cue-target interval, i.e. within 1000 ms following cue onset, was performed from the fixation point towards either square frame were considered in the EEG analysis (see below). Saccadic reaction time (SRT) was determined as the time between cue onset and onset of the first saccade in the cue-target interval. If SRT was below 80 ms, saccades were considered anticipatory and discarded. In accordance with previous studies (Endrass et al., 2007; Nieuwenhuis et al., 2001), trials with and without precues were pooled, and saccades were classified as correct antisaccades, errors (erroneous prosaccades), and contraversive saccades following a direction error, i.e. second saccades towards the target which were labelled ‘corrective saccades’. Correction time was determined as the time between offset of the erroneous saccade and onset of the corrective saccade. Moreover, the percentages of errors, of trials containing corrective saccades and of trials in which participants recognized erroneous prosaccades (aware errors) were determined. SRTs on correct trials following errors and correct trials following correct trials were compared in order to investigate post-error slowing (Rabbitt, 1966). EEG was recorded from 30 scalp sites using a Brain Products BrainAmp Standard amplifier (Brain Products, Munich, Germany) and the appropriate software at a sampling rate of 500 Hz. An elastic cap was equipped with silver–silver chloride electrodes according to the International 10–20 System (F7, F3, Fz, F4, F8, FT7, FC3, FCz, FC4, FT8, T7, C3, Cz, C4, T8, TP7, CP3, CPz, CP4, TP8, P7, P3, Pz, P4, P8, PO7, PO3, POz, PO4, PO8). Electrodes were referenced to the linked mastoids, and impedances were kept below 5 k. EEG-data were analysed off-line using BrainVision Analyzer 2 software (Brain Products, Munich, Germany) and MATLAB (Mathworks, Natick, MA, USA). First of all, 1 Hz high-pass and 30 Hz low-pass filters were applied to the raw data. In order to correct for blink artefacts, an independent component analysis (ICA) was then performed on single-subject EEG data (Lee, Girolami, & Sejnowski, 1999). This procedure yields an unmixing matrix decomposing the multichannel scalp EEG into a sum of temporally independent and spatially fixed components. The number

of these components in the ICA matches the number of channels, and each component can be characterized by both a unique temporal and topographical distribution of activation. For each subject, a component with a symmetric, frontally positive topography which likely reflected blink artefacts was identified by visual inspection and subsequently removed from the raw data by performing an ICA back transformation. Back-transformed data were visually inspected for a significant reduction of artefacts. In one control subject, back-transformed data still contained a high number of blink artefacts, so that a second component was removed. ERP segments ranging from 200 ms before to 500 ms after saccade onset were created. Baseline correction was performed based on the average signal in the time window from 200 to 100 ms preceding saccade onset to avoid that saccade-related activity occurring before movement onset affected the baseline (see Endrass et al., 2007). Segments containing maximum amplitudes which exceeded an absolute value of 100 ␮V or a voltage step of 50 ␮V were excluded by means of automatic artefact detection. As outlined in Section 1, the present study’s main interest was on the difference between ERPs following erroneous and correct responses. Therefore, difference waves (ERPs on error trials minus those on correct trials) were analysed in a first analysis step. Consistent with the procedure applied in a previous study (Nieuwenhuis et al., 2001), amplitudes of an early negative difference wave peak in the ERN time window and a later positive peak in the Pe time window were extracted. The “early negativity” was defined as the most negative difference wave peak within 160 ms after saccade onset at electrode position FCz. This electrode site was chosen because it yielded the strongest negativity. In order to account for potential latency differences between groups, the “late positivity” was defined as the most positive peak in the difference wave occurring within 150–450 ms after saccade onset at electrode position CPz. This electrode was chosen because it yielded a prominent relative positivity in both patients and controls. However, it has to be noted that in controls the late positivity appeared strongest over more parietal electrode sites, whereas it seemed more frontocentrally distributed in patients (see Fig. 4 for scalp topographies of the late positivity). In a second analysis step, the original ERP waveforms for correct anti- and erroneous prosaccades were analysed to determine whether potential amplitude reductions of the difference wave in patients relative to controls were caused by alterations of the ERPs following errors or correct responses. To this end, the ERN and CRN were determined as the maximum negative peak in the ERPs following erroneous and correct saccades, respectively, in the time window from 0 to 160 ms after saccade onset. In accordance with the procedure applied in previous studies (e.g. Gibbons, Fritzsche, Bienert, Armbrecht, & Stahl, 2011), the Pe was defined as the most positive peak occurring up to 450 ms after the ERN/CRN.

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Fig. 3. Saccade-locked ERP and difference waveforms and horizontal eye position data for errors and correct saccades for all patients and controls. Bar charts provide early negativity and late positivity amplitudes derived from the difference signal.

2.5. Statistical analysis Behavioural and ERP data were investigated in patients and controls as groups. For difference waveform analysis, early negativity and late positivity and corresponding peak latencies were compared between groups using t tests. Amplitude and latency of the ERN/CRN and Pe of the original ERP waveforms were analysed by means of repeated-measures ANOVAs with group (patients or controls) as betweensubjects factor and response type (error or correct) as within-subjects factor. The numbers of included trials and the behavioural measures were compared using t tests or – in case of non-parametric testing – Mann–Whitney U tests. SRTs and saccadic amplitudes were analysed by means of a repeated-measures ANOVA with group (patients or controls) as between-subjects factor and response type (error or correct) as within-subjects factor. Post-error slowing was investigated by means of repeated-measures ANOVA with condition (SRTs on correct trials preceded by correct trials and on correct trials preceded by error trials) as within-subjects factor and group (patient or control) as between-subjects factor. The level of significance was set to p < .05 (one-sided for the t and U tests).

3. Results 3.1. ERP data On average, 461 correct (SD = 93) and 72 erroneous trials (SD = 54) were entered into the analysis for controls, while for patients, on average 421 correct (SD = 118) and 45 erroneous trials (SD = 50) were included. The number of correct trials did not differ significantly between groups (p = .174). There was a trend towards significantly fewer error trials being included for patients than controls (U = 52.5, p = .096).

Fig. 3 shows saccade-locked grand-average ERPs for errors and correct trials and the difference waveforms (error minus correct) for patients and controls at the electrode sites FCz and CPz. Furthermore, horizontal eye position data for errors and correct saccades are provided for patients and controls. Note that spike potentials reflecting the synchronized recruitment of motor units in the extraocular muscles prior to saccade execution (Thickbroom & Mastaglia, 1985a) are clearly visible in the grand-average ERPs. Importantly, spike potentials were very similar for correct anti- and erroneous prosaccades in the original waveforms and are hence not visible in the difference waveforms. Scalp topographies of early negativity and late positivity as derived from the difference waveforms and scalp topographies of ERN/CRN and Pe as derived from the original waveforms are provided in Fig. 4. 3.1.1. Analysis of difference waveforms Mean amplitudes of the early negativity were −5.56 ␮V (SD = 2.66) for controls and −3.19 ␮V (SD = 4.07) for patients. With regard to the late positivity, mean amplitudes were 5.12 ␮V (SD = 2.59) in controls and 7.65 ␮V (SD = 3.03) in patients. Mean peak latency of the early negativity was 83 ms (SD = 48) for controls and 59 ms (SD = 42) for patients. For the late positivity, the respective values were 355 ms (SD = 70) for controls and 246 ms (SD = 72) for patients. With regard to early negativity amplitude, a significant group difference emerged (t28 = −1.867, p = .036), indicating that the early negativity was significantly attenuated in patients. Peak latency of the early negativity did not differ

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Fig. 4. Scalp topographies at the time points of peak amplitudes for the early negativity (as derived from the difference waveforms) and the ERN/CRN in the original waveforms (A) and late positivity (as derived from the difference waveforms) and the Pe in the original waveforms (B) in patients and controls.

between the groups (p = .107). A significant group difference was also observed for the amplitude of the late positivity (t28 = −2.269, p = .016), the late positivity being increased in patients relative to controls, and for the peak latency of the late positivity (t28 = 3.759, p = .001), with shorter latencies in patients compared to controls. 3.1.2. Analysis of original waveforms Mean ERN amplitude (on error trials) was −.11 ␮V (SD = 2.77) and mean CRN amplitude (on correct trials) was 3.24 ␮V (SD = 3.42) for controls. The respective values were −1.98 ␮V (SD = 1.84) for the ERN and −1.29 ␮V (SD = 2.32) for the CRN in patients. Mean

peak latency was 80 ms (SD = 40) for the CRN and 86 ms (SD = 43) for the ERN in controls and 106 ms (SD = 40) for the CRN and 74 ms (SD = 31) for the ERN in patients. While for peak latency, the ANOVA did not yield any significant effects (all p > .130), the ANOVA on mean amplitudes yielded a significant main effect of response type (F[1,28] = 10.069, p = .004), indicating overall more negative amplitudes for error compared to correct trials. The main effect of group was also significant (F[1,28] = 10.041, p = .004), with overall more positive amplitudes in controls compared to patients. Furthermore, there was a significant response type by group interaction (F[1,28] = 4.409, p = .045). Post hoc t tests comparing ERN and CRN

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amplitudes within the groups of controls and patients yielded a significant difference in controls (t21 = 5.100, p < .0001), the ERN being more negative than the CRN, but not in patients (p = .275). This pattern of results indicates more similar early neural responses to errors and correct saccades in patients than in controls, which is consistent with the results of the difference wave analysis. In accordance with the main group effect, an alternative resolution of the interaction comparing the ERN and CRN separately between patients and controls yielded a significant group difference for the ERN (t28 = 1.755, p = .045) and a highly significant difference for the CRN (t28 = 3.454, p = .001). The more positive amplitudes in controls were related to an increased presaccadic positivity, i.e. a larger antecedent potential (AP) or promotion positivity (PMP), which has been linked to preparatory activity associated with the saccade (Kurtzberg & Vaughan, 1982; Richards, 2003) and may reflect group differences in saccadic amplitudes (Thickbroom & Mastaglia, 1985b; see below for the analysis of saccade amplitudes). While this difference in presaccadic activity only marginally affects the general pattern of results and particularly the interaction, it does appear to be a confound for the direct between-group comparisons of ERN and CRN. Therefore, the analysis of ERN/CRN amplitudes was repeated measuring the amplitude relative to an alternative baseline of the 100 ms directly preceding saccade onset (see Wessel, Danielmeier, & Ullsperger, 2011 for an antisaccade task with the same baseline). This procedure yielded mean ERN and CRN amplitudes of −4.16 ␮V (SD = 2.60) and −.99 ␮V (SD = 3.00) for controls. The respective values in patients were −3.92 ␮V (SD = 3.33) for the ERN and −3.34 ␮V (SD = 3.22) for the CRN. The ANOVA revealed a significant main effect of response type (F[1,28] = 6.320, p = .018), amplitudes being more negative on error compared to correct trials, and no group effect (p = .278). The response type by group interaction now approached significance (F[1,28] = 2.982, p = .095). Post hoc tests again showed significantly more negative ERN than CRN amplitudes in controls (t21 = −3.861, p = .001), but not in patients (p = .287). Now, the comparisons between groups yielded a significantly more negative CRN in patients relative to controls (t28 = 1.854, p = .037), while there was no difference for the ERN (p = .420). Mean Pe amplitudes with the original baseline (−200 to −100 ms) were 9.37 ␮V (SD = 3.04) on error and 9.57 ␮V (SD = 4.29) on correct trials for controls. For patients, the respective values were 7.21 ␮V (SD = 3.64) on error and −2.17 ␮V (SD = 3.08) on correct trials. Mean Pe latency was 160 ms (SD = 42) on correct and 245 ms (SD = 67) on error trials for controls and 171 ms (SD = 57) on correct and 206 ms (SD = 73) on error trials for patients. For Pe latency, the ANOVA yielded a significant main effect of response type (F[1,28] = 10.967, p = .003), the Pe emerging earlier on correct than on error trials. Neither the main effect of group nor the response type by group interaction reached statistical significance (both p > .182). For mean Pe amplitude, a significant main effect of response type emerged (F[1,28] = 16.104, p < .0001), with greater amplitudes on erroneous compared to correct trials. The main effect of group was also significant (F[1,28] = 12.127, p = .007), amplitudes overall being more positive in controls compared to patients. Moreover, the response type by group interaction was significant (F[1,28] = 18.883, p < .0001). Post hoc tests comparing

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amplitudes between patients and controls according to response type revealed significantly more positive Pe amplitudes on correct trials in controls compared to patients (t28 = 4.460, p < .0001), and a corresponding trend for errors (t28 = 1.639, p = .056). The alternative resolution of the interaction comparing Pe amplitude between correct and error trials separately for patients and controls yielded a significant difference only for patients (t7 = 6.670, p < .0001), amplitudes being more negative on correct trials, but not for controls (p = .389). Also for the Pe, a second analysis on the amplitudes relative to the −100 to 0 ms baseline was performed. Mean amplitudes of 4.92 ␮V (SD = 2.98) on error and 5.21 ␮V (SD = 4.79) on correct trials emerged for controls. For patients, the respective values were 4.56 ␮V (SD = 4.04) on error and −.49 ␮V (SD = 1.26) on correct trials. Again, main effects of response type (F[1,28] = 4.392, p = .045) and group were found (F[1,28] = 9.265, p = .005), as well as a response type by group interaction (F[1,28] = 4.779, p = .037). Post hoc tests comparing Pe amplitudes between patients and controls now showed a significant group difference only for correct (t28 = 5.109, p < .0001) but not for error trials (p = .350). Amplitudes were more negative on correct compared to error trials for patients (t7 = 3.704, p = .004), but not for controls (p = .479). 3.1.3. Scalp topographies of difference and original waveforms With respect to the difference waveforms, the early negativity was clearly frontocentrally and the late positivity centroparietally distributed in controls. In the controls’ original waveforms, the ERN had a pronounced frontocentral distribution, while correct responses did not appear to be associated with any negativity, and the Pe was parietally distributed for both correct and erroneous saccades (note that the original waveforms’ topographies are illustrated relative to the baseline from −100 to 0 before saccade onset). In the patients, difference waveforms showed a more central topography for the early negativity and a more frontocentral distribution of the late positivity. In the patient’s original waveforms, ERN and CRN were centrally distributed. The Pe was clearly frontocentrally distributed for errors and absent for correct trials. 3.2. Behavioural data Mean SRTs for correct and erroneous saccades, mean correction time and mean percentages of errors, aware errors and corrected errors are presented in Table 3. For SRTs, the ANOVA yielded a highly significant main effect of response type (F[1,28] = 391.546, p < .0001), SRTs overall being shorter for erroneous as compared to correct saccades. The main effect of group was also significant (F[1,28] = 27.400, p < .0001), indicating overall larger SRTs in patients compared to controls. Moreover, a trend towards a significant response type by group interaction (F[1,28] = 3.832, p = .060) emerged, indicating that the difference in SRTs between correct and erroneous saccades was larger for patients than for controls. Error rates, error awareness, the number of corrected errors and correction time did not differ between patients and controls (all p > .159). In order to investigate post-error slowing, SRTs on correct trials preceded by correct trials and on correct trials preceded by error trials were inspected. Mean SRT on correct trials following

Table 3 Mean saccadic reaction time (SRT) for correct, erroneous and corrective saccades and mean percentage errors, corrected errors and aware errors and for patients and controls. Percentages of aware and corrected errors are provided relative to the overall number of errors. Standard deviations (SDs) in brackets. T tests were performed one-sided.

Controls mean (SD) Patients mean (SD) **

p < .01.

Correct SRT (ms)

Errors SRT (ms)

Correction time (ms)

Errors (%)

Aware errors (%)

Corrected errors (%)

383 (47) 512 (91)**

250 (39) 350 (75)**

154 (45) 155 (40)

13.6 (9.9) 9.4 (10.0)

27.1 (25.7) 19.3 (19.4)

84.4 (14.0) 83.1 (13.9)

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Table 4 Mean saccadic amplitudes (provided in degrees of visual angle) for patients and controls. Standard deviations (SDs) in brackets. Saccadic amplitude (◦ )

Controls mean (SD) Patients mean (SD) * **

Correct

Error

Corrective

8.8 (1.4) 7.3 (1.3)**

7.9 (1.0) 6.8 (1.4)*

14.1 (2.6) 12.7 (3.0)

p < .05. p < .01.

correct trials was 382 ms for controls (SD = 48) and 507 ms (SD = 93) for patients, mean SRT on correct trials following error trials was 387 ms (SD = 50) for controls and 502 ms (SD = 102) for patients. The analysis yielded a significant main effect of group (F[1,28] = 20.714, p = .000), thus confirming the previous finding of increased SRTs in patients compared to controls. Both the main effect of condition and the condition-by-group interaction failed to reach statistical significance (both p > .336), indicating a general lack of post-error slowing. Mean amplitudes for correct, erroneous and corrective saccades are presented in Table 4. The ANOVA yielded a significant main effect of response type (F[1,28] = 12.105, p = .002), with overall smaller amplitudes for erroneous compared to correct saccades. Furthermore, the main effect of group was significant (F[1,28] = 7.641, p = .010), indicating that overall saccadic amplitudes were smaller in patients compared to controls. The response type by group interaction failed to reach statistical significance (p = .287). The mean amplitudes of corrective saccades did not differ significantly between groups (p = .388). 4. Discussion The present study investigated error processing on an antisaccade task in patients with focal cerebellar lesions and control participants. To this end, ERPs associated with erroneous prosaccades and correct antisaccades were compared. In accordance with the notion that cerebellar information processing underlies an internal model for the online monitoring of movements, it was hypothesized that early response-locked ERPs in cerebellar lesion patients would not as reliably distinguish between correct and erroneous performance as in healthy controls. In accordance with this hypothesis, an early negativity observed in the error-correct difference signal was less pronounced in patients than in controls. Accordingly, the analysis of the original ERPs showed a significant difference between ERN and CRN in controls, but not in the patients. This analysis further revealed that this group difference was mainly driven by an enhanced CRN in the patients and only to a lesser extent by a reduced ERN. Thus, the pattern of findings for the ERN/CRN time window suggests a general saccade monitoring deficit in the patients rather than a pure error processing deficit. In a later time window, the patients’ difference waveforms showed a significantly increased positivity compared to control subjects. The analysis of the original waveforms again revealed that this effect was driven by altered ERPs on correct trials. The Pe in response to correct saccades was decreased in the patients, while it did not differ between groups for error trials. With respect to the behavioural performance, SRTs were generally prolonged and saccadic amplitudes were decreased for patients, while overall error rate and rates of corrected and aware errors were comparable for patients and controls. In accordance with previous findings, background testing indicated reduced verbal short-term and working memory scores in the patients (Peterburs, Bellebaum, Koch, Schwarz, & Daum, 2010; Ravizza et al., 2006). Importantly, neuropsychological background measures being more relevant to performance on the antisaccade

task – i.e. visual short-term and working memory and alertness – did not differ between groups. Overall, the present data provide direct evidence for a prominent role of the cerebellum in online performance monitoring. The ERN has been associated with fast unconscious processes of error detection (Endrass et al., 2007; Falkenstein et al., 1991; Nieuwenhuis et al., 2001) which rely on rapidly available central information such as efference copy signals (Gehring et al., 1993). Efference copy information is thought to underlie the rapid prediction of the sensory consequences of motor actions by an internal model linked to cerebellar information processing (Miall, 1998; Miall & Wolpert, 1996; Wolpert et al., 1998). On the antisaccade task, efference copy signals providing information about the direction of the upcoming saccade are necessary for the fast classification of the response as correct or erroneous. In the current clinical sample, cerebellar lesions may have disrupted cerebello-thalamo-cortical pathways and thereby the relay of saccade-related information back to cortex, hence disturbing the internal comparison process of the prediction about the consequences of the performed saccade with the intended or appropriate saccade. Importantly, this perturbance did not specifically affect the processing of errors. Instead, the classification of ongoing responses in terms of accuracy was generally impaired in the patients, as reflected in comparable amplitudes of the ERN and CRN. While at first, it may be puzzling that the latter effect was mainly driven by enhanced CRN amplitudes in the patients, descriptively, the ERN was also reduced in the patients (when scored relative to the −100 to 0 ms baseline). Therefore, the deficit in the cerebellar lesion patients can best be described as a general performance monitoring deficit. Activity within a cerebello-thalamo-cortical loop has recently been shown to mediate error processing and post-error slowing on a stop-signal task, with cerebellar activation being strongly associated with activation in the ventrolateral PFC during posterror slowing (Ide & Li, 2011). A critical role of the thalamus in error processing has been further supported by the finding of reduced ERN amplitudes in patients with focal thalamic lesions in the context of an antisaccade task (Peterburs et al., 2011) and a flanker task requiring hand responses (Seifert et al., 2011). Cerebellum and thalamus thus appear to be key constituents of a neural pathway for performance monitoring. Nevertheless, the functional implications of lesions to the thalamus and to the cerebellum may slightly differ. In contrast to the thalamic lesion patients who were also shown to exhibit behavioural impairments with regard to error rates, error awareness and post-error adjustments (Seifert et al., 2011; Peterburs et al., 2011), behavioural performance – at least with regard to error rates and error awareness – was largely intact in the present sample of cerebellar lesion patients. However, some aspects of behavioural performance did differ between patients and controls. SRTs were prolonged in patients relative to controls. Increased SRTs in the cerebellar lesion patients are compatible with findings in monkeys with cerebellar lesions (Ohki et al., 2009; Takagi, Zeem, & Tamargo, 1998) and with delayed onset of smooth pursuit movements in patients with cerebellar degeneration (Moschner et al., 1999). Importantly, it is conceivable that part of the SRT increase was related to a compensatory mechanism. Patients may have responded much slower in order to account for difficulties in the distinction between erroneous and correct responses. Thus, the SRT increase, together with the intact error rate, may reflect a speed-accuracy tradeoff in the patients. On the other hand, alterations in performance monitoring are not necessarily accompanied by behavioural impairments. The present findings in cerebellar lesion patients resemble to some extent the results obtained in patients with selective basal ganglia lesions, in whom the ERN was found to be reduced in the absence of behavioural deficits with regard to

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error rates, error correction or post-error behavioural adjustment (Ullsperger & von Cramon, 2006). In line with this comparable pattern in patients with cerebellar and basal ganglia lesions, it has recently been suggested that motor-related input to the thalamo-ACC pathway in the context of performance monitoring and behavioural adjustment is provided by the striatum and/or the cerebellum (Seifert et al., 2011). Previous research has emphasized the importance of a functional topography within the cerebellum, locating cerebellar contributions to sensorimotor functions in anterior and to higherlevel (non-motor) processing in posterior cerebellar regions (Salmi et al., 2010; see Stoodley & Schmahmann, 2009 for a meta-analysis). Saccade-related efference copy processing therefore is likely to predominantly involve anterior cerebellar regions. Furthermore, the cerebellar vermis has been suggested to play a key role in the online control of saccades, with lesions affecting the accuracy of both saccades and pursuit movements (Vahedi, Rivaud, Amarenco, & Pierrot-Deseilligny, 1995). In turn, posterior regions appear to be recruited for more cognitive aspects of performance monitoring such as appreciation of timing (Jueptner et al., 1995), covert orientation of visuospatial attention (Mao, Zhou, Zhou, & Han, 2007) and decision making under uncertainty (Blackwood et al., 2004). Even though cognitive and motor aspects of behavioural control may not be entirely independent, both systems are necessary for an accurate cerebellar internal model underlying performance monitoring. Unfortunately, in view of to the small sample size and heterogeneous lesion locations, the pattern of results in the present sample of patients does not permit any clear conclusions with respect to the cerebellar regions particularly involved in error processing. Analyses of individual patients’ ERP patterns did not reveal particularly strong alterations in any of the patients. Rather, the pattern was similar in nearly all of the patients. Possibly, different types of disruptions of cerebellar information processing affect performance monitoring in a similar way. More research is needed to further elucidate the extent to which cerebellar subregions are involved in error processing and performance monitoring. An alternative explanation for the present finding of less distinct ERN/CRN amplitudes in cerebellar lesion patients relates to the dense reciprocal connections between PFC and cerebellum. A disruption of cerebello-thalamo-prefrontal projections may have resulted in disturbed error monitoring. Indeed, a comparable ERN and CRN in patients with lesions affecting the lateral PFC (Gehring & Knight, 2000) has been attributed to impaired performance monitoring due to PFC damage. However, lesions to the PFC have also been associated with deficits of corrective behaviour on a letter discrimination task (Gehring & Knight, 2000) and on a flanker task (Ullsperger & von Cramon, 2006). In contrast to this, the present sample of cerebellar lesion patients did not differ from healthy controls with regard to correction time or the percentage of corrected errors on the antisaccade task. An intriguing possibility is that the observed relative enhancement and shorter latency of the late positivity observed in the error-correct difference wave reflects a compensatory mechanism, suggesting that the patients’ performance may rely more heavily on later and more conscious aspects of error processing (Endrass et al., 2007; Falkenstein et al., 1991; Nieuwenhuis et al., 2001). Indeed, the Pe has been suggested to reflect a subjective or emotional error assessment process modulated by the significance of an error in a given context (Falkenstein et al., 2000). While the ERN was shown to be unaffected by error rates, the Pe was much smaller in subjects with high compared to subjects with low error rates on a Go/Nogo task (Falkenstein et al., 2000). Studies applying the antisaccade task have underlined an association of a later portion of the Pe (about 400–600 ms after an erroneous saccade) with error awareness and remedial action (Endrass et al., 2007; Nieuwenhuis et al., 2001). With respect to the observation of a

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higher difference wave amplitude for a late positive component in the error-correct difference wave it may be of interest that the number of error trials included into the analysis was reduced for the patients. Increasing amplitudes of ERP components with decreasing numbers of averaged trials are a common phenomenon in ERP research and may thus have contributed to higher late positivity amplitudes in the patients. To address this potential confound, an explorative additional analysis was performed, matching the numbers of included trials across groups by yoking control participants to individual patients according to the number of error trials. This analysis still yielded a trend towards significantly enhanced late positivity amplitudes (p = .085) in the patients. More importantly, the analysis of the original waveforms revealed that the late positivity effect found in the difference waveforms was mainly driven by a markedly reduced Pe on correct trials in patients compared to controls. Thus, the reduced number of error trials is unlikely to be responsible for the enhanced late positivity in the patients’ difference waves. The relative reduction of the Pe for correct responses in patients is difficult to interpret, because variations of Pe amplitude are typically discussed in relation to error trials. To this end, the Pe may reflect the amount of evidence involved in detecting an error and ultimately evidence strength (Steinhauser & Yeung, 2010), also incorporating sensory feedback (Ullsperger, Harsay, Wessel & Ridderinkhof, 2010). Furthermore, it has recently been proposed that the Pe could reflect a learning strategy for avoiding future mistakes by increasing sensitivity to previous errors, but this notion still needs to be investigated (Orr & Carrasco, 2011). Error awareness did, however, not differ between groups in the present study, so that the Pe findings cannot be caused by such an explicit error avoidance strategy. Along similar lines, neither controls nor patients exhibited pronounced post-error slowing, a finding which is likely due to generally low error awareness in the present sample, as post-error slowing has previously been shown only for aware errors (Endrass et al., 2007; Nieuwenhuis et al., 2001). On the other hand, it is not surprising that a potential compensatory mechanism in the patients in a later time window is mainly driven by ERPs following correct responses, because the patients’ deficit in distinguishing between error and correct trials in the earlier ERN/CRN time window was mainly associated with correct response ERPs resembling those for error responses. In the later time window, the patients thus showed the “usual” Pe for errors, but a reduced Pe for correct trials, so that correct responses could clearly be distinguished from error responses. Generally, the present data corroborate a functional distinction of ERN and Pe, a notion which has been supported by findings of differential variation of these components depending upon conditions of time pressure, error detectability and error awareness (Falkenstein et al., 2000). Accordingly, several studies have also reported distinct ACC sources for ERN and Pe (Herrmann, Rommler, Ehlis, Heidrich, & Fallgatter, 2004; O’Connell et al., 2007; Van Veen & Carter, 2002). Taken together, the present findings support the assumption of cerebellar contributions to performance monitoring and extend our current knowledge of cerebellar functions. The altered ERP patterns with regard to the ERN/CRN suggest that the cerebellum is critically involved in the fast classification of saccadic accuracy via cerebellothalamo-cortical loops. These loops appear to underlie an internal model for the online monitoring of responses, possibly by making use of efference copy information. Largely intact behavioural performance with regard to the percentage of errors, error correction and error awareness in patients may be based on compensatory slower error processing as indicated by increased SRTs as well as alterations of Pe amplitude. In combining different aspects of basic and cognitive neuroscience, i.e. the neural circuitry involved in saccade generation and monitoring and the neural underpinnings of

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