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Biol Psychiatry. Author manuscript; available in PMC 2009 October 1. Published in final edited form as: Published online 2008 March 14. doi: 10.1016/j.biopsych.2007.12.016. | PMCID: PMC2580803 NIHMSID: NIHMS69711 |
Action Monitoring in boys with ADHD, their Nonaffected Siblings and Normal Controls: Evidence for an Endophenotype Bjoern Albrecht,1,2§ Daniel Brandeis,3,4 Henrik Uebel,1 Hartmut Heinrich,5,6 Ueli C. Mueller,3 Marcus Hasselhorn,7 Hans-Christoph Steinhausen,3 Aribert Rothenberger,1 and Tobias Banaschewski1,2 1 Child and Adolescent Psychiatry, University of Göttingen, Germany 2 Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health Mannheim, Germany 3 Child and Adolescent Psychiatry, University of Zürich, Switzerland 4 Center for Integrative Human Physiology, University of Zürich, Switzerland 5 Child and Adolescent Psychiatry, University of Erlangen, Germany 6 Heckscher-Klinik, München, Germany 7 German Institute for International Educational Research, Frankfurt/Main, Germany Background Attention deficit/hyperactivity disorder is a very common and highly heritable child psychiatric disorder associated with dysfunctions in fronto-striatal networks that control attention and response organisation. Aim of this study was to investigate whether features of action monitoring related to dopaminergic functions represent endophenotypes which are brain functions on the pathway from genes and environmental risk factors to behaviour. Methods Action monitoring and error processing as indicated by behavioural and electrophysiological parameters during a flanker task were examined in boys with ADHD combined type according to DSM-IV (N=68), their nonaffected siblings (N=18) and healthy controls with no known family history of ADHD (N=22). Results Boys with ADHD displayed slower and more variable reaction-times. Error negativity (Ne) was smaller in boys with ADHD compared to healthy controls, while nonaffected siblings displayed intermediate amplitudes following a linear model predicted by genetic concordance. The three groups did not differ on error positivity (Pe). N2 amplitude enhancement due to conflict (incongruent flankers) was reduced in the ADHD group. Nonaffected siblings also displayed intermediate N2 enhancement. Conclusions Converging evidence from behavioural and ERP findings suggests that action monitoring and initial error processing, both related to dopaminergically modulated functions of anterior cingulate cortex, might be an endophenotype related to ADHD. Keywords: error negativity, error positivity, N2, action monitoring, ADHD, endophenotype Attention deficit/hyperactivity disorder (ADHD) is a very common child psychiatric disorder. The core symptoms of severe age-inappropriate levels of hyperactivity, impulsivity and inattention affect at least 3–5% of school-aged children ( 1) independent of cultural background ( 2), and with an overrepresentation of boys ( 3). Heritability estimates are high ( 4), but developmental pathways to the phenotype ADHD are not well understood ( 5). This potential gap may be filled by the concept of quantitative trait loci (QTL) and endophenotypes. Following this, multiple susceptibility genes may constitute a rather continuous dimension of ADHD symptoms in which an endophenotype is a simple function more proximal to biological foundations in-between on the one hand genetic and environmental risk factors and on the other hand the phenotype ( 6– 8). Theoretically, associations between genes and endophenotype should be larger than between genes and phenotype, qualifying the endophenotype as a better ground for molecular genetic studies ( 9). Several cognitive theories ascribe impairments in executive functions or self-regulation associated with dysfunctions in fronto-striatal dopaminergic networks that control attention and response organisation to patients suffering from ADHD ( 3; 10– 14). Children with ADHD perform poorly in a wide range of tasks involving executive control. In general, their responses tend to be slower, more variable, and more error prone ( 11; 12; 15; 16). Specific deficits in adaptation to task demands and error monitoring such as diminished post-error slowing have been reported early on ( 17; 18), but little is known about neural mechanisms in ADHD. Using event-related potentials (ERP), covert neurophysiological correlates of task performance can be tracked with high temporal resolution ( 19; 20). Action monitoring comes into play when actual requirements interfere with automatisms, or after errors. For instance, in Go-NoGo tasks which require responding to frequent stimuli but to withhold the response to rare ones, the stimulus-locked ERP usually shows a fronto-central negativity peaking around 200 to 400ms after onset of the stimulus (N2), which is larger for the Nogo than for the Go condition. The same effect can be observed for a target primed with incongruent compared to congruent distractors. This N2-enhancement was originally attributed to response inhibition ( 21– 23), but recent studies suggest that it may reflect a more general monitoring process which is also present without need for response inhibition ( 24; 25). Sources of the N2 as evoked by Go-Nogo- and Stroop-Tasks have been localized in the anterior cingulate cortex (ACC) ( 24; 26; 27). While most studies using CPT or Go-Nogo-tasks in children did not find specific differences in N2 between ADHD and controls ( 16; 28; 29) some studies did, but effects were explained by comorbidity ( 30; 31) or appeared only within time-on-task effects ( 32). However, in more demanding tasks such as the Stop-Task, diminished N2 amplitudes or topographic N2 alteration have been reported ( 33– 36). Error processing is generally accompanied by a negative component (error negativity, Ne) peaking approximately 40–120ms after the erroneous response at fronto-central sites. It is frequently followed by a more parietal positive deflection (error positivity, Pe) within 200 to 500ms after the response ( 37– 39). Ne is described in a variety of tasks ( 38; 40; 41), error types ( 42) and response modalities ( 43; 44). Thus, several hypotheses ascribe Ne a crucial role in error detection and action monitoring such that it may reflect mismatch ( 37; 39) or conflict ( 45) between error and required response. Ne is susceptible to dopaminergic manipulations ( 46), i.e. dopamine agonists enhance ( 47) and antagonists reduce its amplitude ( 48; 49). Dipole modelling showed a generator of Ne located in the ACC ( 43; 50– 53). A number of studies suggest that Ne and N2 may reflect the same process which rely on different aspects of task performance ( 54; 55). Far less research has addressed the subsequent Pe. It is elicited unlike Ne only after full errors of which the subject is aware ( 44) and seems to mature earlier ( 56). The rostral ACC generators of Pe suggest that it rather reflects affective error assessment ( 53). Clinical studies found Ne to be enhanced in patients with obsessive compulsive disorder ( 57) or in subjects with obsessive compulsive or anxiety characteristics ( 58; 59) or negative affect ( 60). Higher sensitivity for punishment also goes along with enhanced Ne while Pe was enhanced in subjects with higher reward sensitivity ( 61). A reduction of Ne but not Pe was found for patients with schizophrenia ( 62; 63) and borderline personality disorder ( 64). Parkinson’s disease associated with dysfunctions in the dopaminergic system of basal ganglia was also accompanied with reduced Ne ( 65; 66), but unimpaired Pe ( 67). Moreover, Ne was found to be reduced in patients suffering from Huntington’s Disease which goes along with neural cell death in the striatum ( 68). Thus, there is converging evidence, that Ne is related to striatal dopaminergic modulations, which leads to the hypothesis that it may also be impaired in ADHD ( 14; 69). However, the few studies on ADHD or ADHD-related behaviours yielded mixed results. While Ne was found to be reduced in adult subjects with higher impulsiveness ( 70) and in children suffering from ADHD ( 71), other studies with younger ADHD children found no error-specific Ne and similar amplitude reductions for errors and correct responses ( 72), failed to find a reduction of Ne but instead Pe was reduced ( 73) or even observed an enhanced Ne in ADHD children ( 74), which may again in part be explained by heterogeneity of the methods used. In search for ADHD endophenotypes, this study is focused on action-monitoring and error-processing using a simple, nonverbal flanker-task that is highly demanding ( 75– 77). It was hypothesized that control children exhibit higher task performance, i.e. fewer errors, shorter reaction-times and less intra-individual reaction-time variability than children of the ADHD-group. Furthermore, we predict that the effect of congruency on N2 amplitude as well as Ne- and Pe amplitudes were higher in controls compared to ADHD. In order to differentiate effects from partial overlap of phenotypes, nonaffected siblings of ADHD patients were included in analyses regarding the endophenotype concept. If the parameter in question reflects the phenotype, nonaffected siblings should display the same difference compared to ADHD-patients as unrelated controls did. On the other hand, since nonaffected siblings share half of their genes with ADHD patients, according to the QTL model also susceptibility genes and therefore impairments should be shared to that extent. Hence, the respective parameter should decrease as a linear function of genetic concordance with ADHD across groups (controls 0%, nonaffected siblings 50%, children with ADHD 100%) without a residual component ( 78– 80) and may thus constitute an endophenotype. Subjects Recruitment of ADHD sib pairs was conducted as part of the International Multi-centre ADHD Gene study (IMAGE ( 81; 82)). For this analysis, European Caucasian subjects, all aged 8 to 15 years with an estimated full-scale IQ above 80 ( 83; 84) and no known child psychiatric disorder that may mimic ADHD were included. They belonged to one of three subgroups: - Children with DSM-IV diagnosis of ADHD combined type having at least one biological sibling.
- Nonaffected siblings of children with DSM-IV diagnosis of ADHD combined type, without any clinical diagnosis of ADHD.
- Unrelated healthy control-subjects without a clinical diagnosis or a known family history of ADHD.
Children of groups 1 & 2 were recruited by child psychiatry clinics from Goettingen, Germany and Zurich, Switzerland. The control group was recruited from regular schools in Goettingen only. Ethical approval was obtained from local ethical review boards. Detailed information sheets were provided and informed consent from children and parents were obtained. Children taking stimulant treatment were off medication for at least 48h before testing. All children earned small prizes; parents did not receive any financial reward except travel expense reimbursements. The diagnostic assessment was performed with long versions of Conners’ rating scales ( 85; 86) and Strengths and Difficulties Questionnaires (SDQ ( 87; 88)) for parents and teacher. If T scores on Conners ADHD scales (L, M, N) exceeded 62 and scores on SDQ Hyperactivity scale exceeded the 90 th percentile, a semi-structured clinical interview (PACS ( 89– 93)) was applied by trained investigators in order to verify ADHD diagnosis according to DSM-IV and to confine symptoms from other child psychiatric disorders ( 94; 95). To ensure that control subjects were free of susceptibility for ADHD, children with T-scores exceeding 60 on both parent and teacher scales of the Conners total symptoms scale were excluded from that group. Since female subjects in our ADHD sample were outnumbered and considerably younger, only datasets from 125 males (14 from Zürich and 111 from Göttingen) were analysed here. All had normal or corrected to normal vision and understood task instructions as verified during practice blocks. Due to excessive artefacts in the EEG or too few errors or correct responses, seventeen subjects had to be excluded (three controls, two nonaffected siblings and 12 subjects with ADHD; reflecting comparable exclusion-ratio across groups, χ2(2)=0.41, p=.82). Groups were matched for age (F (2, 105)=.1, p=.90) and there was only a trend for different estimated total IQs (F (2, 105)=2.9, p=.06, see Table 1 for further sample characteristics). In the ADHD-group, PACS interview yielded susceptibility for mood disorder (N=7), tourette’s syndrome (N=2), substance abuse (N=1), obsessive compulsive disorder (N=3), anxiety disorder (N=34), oppositional defiant disorder (ODD, N=46) and conduct disorder (CD, N=14). Procedure Assessments of children were carried out on two days. The neurophysiological took place before the neuropsychological testing or vice versa, following a randomization scheme. Neurophysiological test-sessions were carried out in video-controlled, noise-shielded and slightly dimmed rooms. Subjects sat on a comfortable seat during electrode attachment and task-performance. The flanker-task was administered after 6 minutes of resting EEG followed by a Continous Performance Test lasting 11 minutes and, if desired, a short break. Stimuli and Task The flanker-task consisted of ten blocks á 40 trials each, modelled after Kopp et al. ( 75) (). Columns of black arrowheads (equilateral triangles with 18 mm edge length at 3 positions with 23mm distance centre to centre) were presented in the centre of a 17″ CRT monitor with 800*600 points resolution against light grey background at 120cm viewing-distance. On every trial, a fixation mark in the centre of the screen was replaced by the stimuli. Initially, only flankers (two arrowheads pointing to the same direction above and below the position of the fixation mark) were presented for 100ms, before the target arrowhead also appeared for 150ms between the flankers. Subjects had to press response buttons with the index-finger of their hand corresponding to the direction indicated by the target. The standard serial mouse used to record responses caused a response-trigger delay of approximately 35 ms which was corrected for in the analyses ( 96). On congruent trials, flanker and target arrowheads pointed in the same and on incongruent trials into opposite directions. A trial was presented every 1650ms, and total task duration was approximately 13 min. The features congruent vs. incongruent and target pointing to the left vs. right were balanced and randomized. Written feedback was given at the end of each block. If more than 10% errors on congruent or more than 40% errors on incongruent trials were made, it was instructed to be more accurate. In case of less than 10% errors in the congruent and less than 40% errors in incongruent trials, it was stressed to respond faster; otherwise it was told to go on the same way. Feedback was introduced in order to control for accuracy, which may influence error processing ( 38; 39). Two practice blocks with 24 trials each were administered first. Electrophysiological recording and processing For subjects from Göttingen, the electroencephalogram was recorded with Ag/AgCl electrodes and Abralyt 2000 electrode cream from 23 sites according to an extended 10–20 system using a BrainAmp amplifier. The electrooculogram was recorded from two electrodes placed above and below the right eye and at the outer canthi. EEG and EOG were recorded simultaneously using FCz as recording reference at a sampling rate of 500Hz with low and high cutoff filters set to 0.016Hz and 100Hz respectively and a 50Hz notch filter. The ground electrode was placed at the forehead. In Zürich, the EEG was recorded from additional channels using a Neuroscan SynAmps amplifier with reference at Fpz and a ground electrode placed at the forehead. The EOG was recorded from electrodes below the left and right eye. Sampling rate was 500Hz and filter settings were 0.1 to 70 Hz. Impedances were kept below 10 kΩ. Postprocessing ensured full compatibility. Altogether 24 common sites were analysed here. After downsampling to 256 Hz the EEG was re-referenced to the average and filtered offline with 0.1 – 15 Hz, 24 dB/oct Butterworth filters. Occular artifacts were corrected using the method of Gratton and Coles without raw average subtraction ( 97). If the amplitude at any EEG-electrode exceeded ±100 μV, a section −100 to +800 ms was excluded from further analyses. Response locked (−500 ms to +1000 ms relative to the button press) and stimulus-locked (−200 to +1825 ms around target-onset) segments were subsequently checked and averaged. To avoid distortion of ERP topography, no baseline subtraction was applied. Averages of stimulus-locked waveforms to congruent and incongruent correct responded trials contained at least 40 sweeps, response-locked averages to incongruent trials contained at least 25 sweeps for errors and 40 sweeps for correct responses. Consideration of signal to noise ratios revealed group-differences only for waveforms stimulus-locked to congruent correct responded trials at site Cz (F(2, 105)=3.2, p=.04) and response-locked to errors in incongruent trials at Pz (F(2, 105)=4.8, p=.01). Analyses Effects of “congruency” (congruent vs. incongruent trials) and “group” (controls vs. nonaffected siblings vs. ADHD) on number of errors, reaction-time of correct responses and reaction-time variability of correct responses (intra-individual standard deviation of reaction times with sum of squares computed separately for each block to exclude potential reaction-time differences between blocks) were assessed using repeated-measure analyses of variance (ANOVAs). Additional univariate ANOVAs were conducted to explore interactions and further details. If effects reached significance, additional post-hoc tests adjusted for multiple comparisons following Sidak were conducted. Inspection of the grand average waveforms revealed that both the effect of congruency on N2 components and the error-related negativity (Ne) were maximal at frontocentral electrodes (see and ). Stimulus-locked N2 peaks scored at FCz 200–400ms after the stimulus-onset of correct responded trials were subject to an ANOVA with factors “congruency”, “site” (Fz, FCz, Cz) and “group”. Violations from sphericity were corrected following Greenhouse-Geisser, ε and adjusted p-values are reported along with original degrees-of-freedom. Ne measured at FCz was defined as the most negative peak 0 to150ms post erroneous response on incongruent trials with respect to the preceding positivity (PNe, −100 to 20ms) in order to obtain a more robust measure of this component ( 44; 68; 98). Amplitudes and latencies of error negativity were analysed using repeated-measure ANOVAs with factors “peak” (Ne vs. PNe) and “group”. The plateau-like Pe on incongruent error trials maximal at centro-parietal electrodes was analysed using the mean amplitude in time window 200 to 500ms after an error in an ANOVA with factors “site” (Cz, Pz) and “group”. Since Pe may be confounded with stimulus-locked components, the P3 to incongruent error trials was scored 350–650ms after target onset at site Cz and its mean amplitude at Cz and Pz was entered subsequently as a covariate. Both Ne and Pe were specific for errors. For each dependent variable, contrasts over the three groups were computed to clarify which measures directly reflected genetic concordance with ADHD. Additional correlations between electrophysiological and behavioural parameters were tested for the total sample to clarify functional significance of ERP findings. All analyses remained stable when subjects from Zürich were excluded. To differentiate effects of comorbid ODD/CD, analyses were subsequently conducted with patients possibly suffering from ODD/CD excluded. Performance Data More errors were committed in incongruent than congruent trials (F (1, 105)=495.2, p<.01, Table 2), which was more pronounced in the group of controls compared to ADHD (F (2, 105)=3.8, p=.03). Furthermore, groups differed only regarding error-rates of congruent (F (2, 105)=5.4, p=.01, controls permitted less errors than ADHD), but not incongruent stimuli (F (1, 105)=.6, p=.53). If subjects with ODD/CD were excluded, the interaction “congruency*group” vanished and only a trend towards group-differences on error-rate for the congruent condition was found (F (2, 59)=2.5, p=.09). Reaction times of correct responses were generally slower for incongruent compared to congruent trials (F(1, 105)=753.9, p<.01). Groups differed in their reaction times (F(2, 105)=3.8, p=.03), with controls responding faster than individuals with ADHD for both congruent and incongruent correct trials. Nonaffected siblings did not differ in response speed from boys with ADHD nor from controls. Contrasts revealed a linear trend between reaction-times and genetic concordance with ADHD (F(1, 105)=7.3, p<.01) in absence of a significant residual (F(1, 105)=0.3, p=.58). With subjects suffering from ODD/CD excluded, the main effect of group was diminished to a trend (F(2, 59)=2.9, p=.06), but results of trend analyses remained stable. Although congruent and incongruent correct trials yielded similar intra-individual reaction-time variability (F (1, 105)=1.4, p=.23), group-differences were found (F (2, 105)=10.1, p<.01): controls revealed lower RT-variability than boys with ADHD in both conditions ( Table 2). Nonaffected siblings did not differ from controls or ADHD. Contrasts between RT-variability and genetic concordance with ADHD again detected a linear trend (F (1, 105)=19.1, p<.01) without a residual (F (1, 105)=1.1, p=.31). These effects persisted if subjects with ODD/CD were excluded. ERP Data N2 peaked at about 330ms relative to target-onset ( Table 3 and ). No effects of any independent variable were found on N2 latency (all F <1.1, p>.35). | Table 3Stimulus-locked effects of conflict on electrophysiological parameters |
N2 amplitude was enhanced by incongruent compared to congruent items (F(1, 105)=50.8, p<.01), and was generally higher at Fz and FCz compared to Cz (F(2, 210)=102.2, p<.01). N2 enhancement was also highest at Fz and FCz (“congruency*site”, F(2, 210)=17.5, p<.01). Furthermore, the N2 congruency effect (i.e. the mean difference of N2 amplitude across sites Fz, FCz, Cz) differed between groups (“congruency*group”, F(2, 105)=4.1, p=.02), being more pronounced in controls compared to ADHD, while nonaffected siblings displayed no differences to both other groups. Contrasts between the N2 congruency effect and genetic concordance with subjects suffering from ADHD showed a linear trend (F(1, 105)=7.7,<.01) and no significant residual (F(1, 105)=0.5, p=.47). The effects persisted when subjects suffering from ODD/CD were excluded. Mean N2 enhancement across electrodes Fz, FCz and Cz was correlated with faster and less variable reaction-times in both congruent and incongruent trials (all r≥.25, p<.01) and lower error-rate in the congruent condition (r=.34, p<.01), but also with higher congruency effect on error rate (increased error-rate in incongruent compared to congruent trials, r=−.31, p<.01). The whole complex of PNe and Ne had a similar mean latency for all groups (F (2, 105)=.7, p=.51) but was more widespread for controls compared to ADHD (“peak*group”, F (2, 105)=4.7, p=.01, Table 4 and ). | Table 4Response-locked electrophysiological data of error processing |
Ne amplitude measured peak-to-peak was higher in controls compared to ADHD (“peak*group”, F(2, 105)=5.7, p<.01). There was a linear trend (F(1, 105)=10.9, p<.01), but no significant residual (F(1, 105)=0.5, p=.50) between genetic concordance with ADHD and Ne amplitude peak-to-peak. Higher peak-to-peak Ne amplitude was correlated similar to N2-enhancement with faster and less variable reaction-times as well as lower error-rate in the congruent condition (all r≥.32, p<.01), but also with higher increase in error-rate in incongruent compared to congruent trials (r=−.26, p<.01). Ne (r=.33, p<.01), but not Pe were correlated with N2-enhancement. When subjects with ODD/CD were excluded, effects on the peak-to-peak Ne amplitude remained stable. A strong effect of stimulus-locked P3 amplitude to incongruent error trials on Pe was found (F(1, 104)=315.0, p<.01, part. η2=.75), but no group-differences were detected irrespectively whether P3 amplitude was taken as covariate or not. Higher Pe amplitude was correlated with lower error-rate in both congruent and incongruent conditions and lower RT-variability in both congruent and incongruent conditions (all r<−.22, p<.03). In this study, we examined neuropsychological and neurophysiological aspects of action monitoring and error processing as candidates for endophenotypes of ADHD. Since nonaffected siblings were contrasted with children suffering from ADHD and unrelated controls, effects that go beyond differences in the phenotype as reflected by increased ADHD prevalence among family members of patients ( 99– 101) can be detected. The adaptive feedback-procedure used in this version of the flanker-task prompted subjects to respond with similar accuracy, thus confounds with speed-accuracy tradeoff and possible task-induced differences in motivation could be avoided. Therefore groups differed mainly in reaction-time and intra-individual reaction-time variability. As expected ( 3; 11; 12; 15), boys with ADHD performed worse than unrelated healthy controls. However, ADHD boys’ performance deficit did not increase under conflict. Nonaffected siblings of subjects suffering from ADHD – despite sharing the same phenotype with unrelated healthy controls - neither differed from ADHD subjects as controls did nor from controls. There was a reliable linear trend between genetic concordance with children suffering from ADHD and reaction-time as well as RT-variability without significant residuals. This agrees with recent papers concluding that state-regulation as indexed by RT-variability is probably an endophenotype for ADHD ( 9; 92). Incongruent compared to congruent stimuli yielded the typical N2 amplitude enhancement ( 24; 25) which is correlated with faster and less variable reaction-times in both congruent and incongruent conditions and with reduced error-rates only in the congruent. This is in line with the notion that N2 is an index for a more general monitoring process triggered in this case by incongruent stimuli features. Since the magnitude of diminished accuracy due to incongruent trials is additionally correlated with higher magnitude of N2 enhancement, modulations in N2 amplitude do not reflect activity of response-inhibitory processes which should control for conflicting impact and should thus lead to an inverse correlation. N2-enhancement was found to be higher in unrelated controls, but not in nonaffected siblings compared to boys with ADHD. It followed a pure linear trend for genetic concordance with ADHD over groups, which indicates that conflict-monitoring as indexed by N2-enhancement might be a specific biological basis for behavioural endophenotypes like RT-SD as described above. Furthermore, this flanker-task evoked clear fronto-central error negativity in children. We found reduced Ne amplitude in ADHD compared to unrelated controls which may reflect impairments in fronto-striatal networks as advocated by several cognitive theories of ADHD ( 11– 13). This finding is also in agreement with other clinical studies ( 70; 71), but not with selective Pe reduction in a Go-NoGo task ( 73), or with unexpected Ne enhancement in a simple discrimination task presumably reflecting compensatory processes ( 74). There was also a linear relation between genetic concordance and Ne amplitude, and nonaffected siblings did not differ from both other groups but had intermediate scores, which again points out that Ne might index an endophenotype ( 6). Since both N2 and Ne are highly correlated and share sources in ACC, a common dopaminergic dysfunction may underlie these findings. Thus, it might be fruitful to search for associations between the reported endophenotypes and risk alleles related to dopaminergic pathways ( 102). No such relations were found for Pe, which did not differ between groups irrespectively whether amplitude of potentially confounded stimulus-locked P3 was controlled for or not. This is similar to what was reported in a study with patients suffering from Parkinson’s Disease ( 67), which supports the notion, that Pe unlike Ne does not depend on the dopaminergic system. The findings reported may be compromised by confounding comorbid disorders. Concerning mood disorders, anxiety and obsessive compulsive disorder, an effect of Ne enhancement is widely reported ( 57– 59) which would have diminished the effect of ADHD. On the other hand, comorbid oppositional defiant or conduct disorder might have led to reduced Ne ( 31), but effects remain stable even when subjects possibly suffering from that were excluded. Another limitation of this study is, that we administered the clinical interview only if susceptibility for ADHD was given, thus cases of potentially comorbid ODD/CD may not have been detected in controls and nonaffected siblings. However, SDQ scores of Conduct Problems did not differentiate these groups. Thus, we think that results reported are not compromised by comorbidities. Group differences in ERP parameters may origin due to differences in data quality. Thus we analysed signal to noise ratios for each examined waveform. It turned out, that differences in SNR emerged only for waveforms in which no significant group-differences were found, and therefore rejections of the Null-hypotheses are not compromised by data quality. The authors thank all children and their families for participation. Christa Dahlmann, Renate Kolle and Antonia Seitz conducted the ERP-recordings; Renate Drechsler, Anke Fillmer-Otte, Anne Reiners and Nicola Woestmann performed IQ-testings and conducted further neuropsychological testings. Daniel Brandeis received support from the Swiss National Science Foundation grant 32-109591. Recruitment of ADHD sib pairs was supported by NIMH-grant R01MH062873 to Steve Faraone. | | ACC | anterior cingulate cortex | | | ADHD | Attention deficit/Hyperactivity Disorder | | | ERP | event related potential | | | Ne | error negativity or error related negativity | | | Pe | error positivity |
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