J. J. van der Meere

ERP correlates of impaired error monitoring in children with ADHD

Summary.Objective: The purpose of the current study was to elaborate on error monitoring in children with Attention Deficit Hyperactivity Disorder (ADHD) using the ERP methodology. Method: Children with ADHD executed a visual Go/No-Go task with 25 percent No-Go trials; and a two stimulus reaction time task wherein a neutral warning signal (S1) was presented to inform the child to prepare for an imperative stimulus (S2). Results: In both tasks, children with ADHD responded as fast as controls but made twice as many errors. In addition, they failed to adjust their speed of responding after making an error. Exploring the error-related potentials revealed that the error-related negativity (ERN) was the same for the two groups, but that children with ADHD showed a diminished error positivity (Pe). Conclusions: Based on these findings, we conclude that children with ADHD are normal in early error monitoring processes related to error detection, but show abnormal response strategy adjustments and are deviant in later error monitoring processes associated with the subjective/emotional, conscious evaluation of the error.

LATE POSITIVE COMPONENTS AND STIMULUS EVALUATION TIME

The amplitude and latency of late positive components were, together with reaction time (RT), studied in a task which combines visual and memory search. The visual display contained either one, two or four letters, as did the memory set. Six load combinations, resulting in one, four, eight and 16 comparisons, were examined. The reaction time data indicated a self-terminating search process. Three late positive components were present in the evoked potential: one at 375 msec after the onset of the display, one at 375 msec after the offset of the display and one around 600 msec. Only the latter component appeared to be sensitive to the number of comparisons. Adaptive averaging was applied to this latter component. The latency of this P300 suggested, in contrast to the RT data, an exhaustive search process. In addition there was a negligible correlation between the response latency and P300 latency at single trial level. Several hypotheses are suggested for what P300 could have to tell us.

The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ

BACKGROUND Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. METHOD Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

Behaviour and school achievement in patients with early and continuously treated phenylketonuria

Thirty patients with early and continuously treated phenylketonuria (PKU) between 8 and 20 years of age were compared with 30 controls, matched individually for age, sex, and educational level of both parents, on behaviour rating scales for parents and teachers as well as a school achievement scale. PKU patients, as a group, demonstrated more problems in task-oriented behaviour and average academic performance than did matched controls. Interestingly, whereas male PKU patients were rated significantly lower on introversion by their teachers, female patients were rated significantly higher on introversion and lower on extraversion than matched controls. This sex difference was also reflected in the relationship between measures of dietary control and the behaviour clusters, suggesting that male and female patients respond differently to elevated Phe levels or the stress associated with PKU. The teacher rating on average academic performance of the PKU patients was associated with recent level of dietary control, which suggests that it might be improved by more strict adherence to the diet. In addition, academic performance correlated negatively with the behaviour cluster negative task orientation. Further studies are recommended to obtain a more complete evaluation of this relationship and to replicate the current findings on larger samples.

Separation of genetic influences on attention deficit hyperactivity disorder symptoms and reaction time performance from those on IQ

BACKGROUND Attention deficit hyperactivity disorder (ADHD) shows a strong phenotypic and genetic association with reaction time (RT) variability, considered to reflect lapses in attention. Yet we know little about whether this aetiological pathway is shared with other affected cognitive processes in ADHD, such as lower IQs or the generally slower responses (mean RTs). We aimed to address the question of whether a shared set of genes exist that influence RT variability, mean RT, IQ and ADHD symptom scores, or whether there is evidence of separate aetiological pathways. METHOD Multivariate structural equation modelling on cognitive tasks data (providing RT data), IQ and ADHD ratings by parents and teachers collected on general population sample of 1314 twins, at ages 7-10 years. RESULTS Multivariate structural equation models indicated that the shared genetic influences underlying both ADHD symptom scores and RT variability are also shared with those underlying mean RT, with both types of RT data largely indexing the same underlying liability. By contrast, the shared genetic influences on ADHD symptom scores and RT variability (or mean RT) are largely independent of the genetic influences that ADHD symptom scores share with IQ. CONCLUSIONS The finding of unique aetiological pathways between IQ and RT data, but shared components between mean RT, RT variability and ADHD symptom scores, illustrates key influences in the genetic architecture of the cognitive and energetic processes that underlie the behavioural symptoms of ADHD. In addition, the multivariate genetic model fitting findings provide valuable information for future molecular genetic analyses.

ERP correlates of error monitoring in adult ADHD

The purpose of the current study was to evaluate whether error monitoring difficulties persist in adults with attention deficit hyperactivity disorder (ADHD) using the event-related potential (ERP) methodology. Adults with ADHD and age-matched healthy controls executed a visual Go/No-Go task with 25% No-Go trials. Performance and ERP correlates of error monitoring were compared between groups. At the performance level no difference was noted between groups. However, exploring the error-related potentials revealed that the error-related negativity (ERN) was the same for both groups, but that adults with ADHD showed a smaller error positivity (Pe). Based on these findings, we conclude that adults with ADHD are normal in early automatic error detection, but are deviant in later conscious evaluation of the error. The findings add to the increasing evidence supporting disturbances in error monitoring in ADHD and show that these problems may persist in adulthood ADHD.

Prefrontal dysfunction in early and continuously treated phenylketonuria

In this study, we tested the hypothesis that patients with early and continuously treated phenylketonuria (PKU) are selectively impaired in cognitive functions dependent on the prefrontal cortex (PFC) over a wide age range. Thirty-six patients with PKU between 8 and 20 years of age and 36 controls matched for age, sex, and educational level of both parents performed computerized versions of tests shown to be sensitive to PFC functions. To assess specificity, we selected within each test measures shown to be specifically impaired by PFC damage as well as measures not specifically impaired by damage to the PFC (control measures). A contrast sensitivity test was administered to obtain additional and independent evidence for the mechanism proposed to underlie the specific PFC deficits. Patients with early and continuously treated PKU demonstrated impairments on 3 of the 4 PFC measures but not on any of the control measures. Furthermore, they were found to be significantly less sensitive to contrast than were the matched controls. Together, these results seem to confirm that specific deficits in PFC functions persist in older patients with early and continuously treated PKU. The results with respect to the biochemical mechanism underlying these deficits were less clear. They do suggest, however, that some of the deficits may be ameliorated by stricter dietary treatment.

HFA and ADHD: A direct comparison on state regulation and response inhibition

This study examined whether children with high-functioning autism (HFA) are easily overaroused/activated and whether children with attention-deficit/hyperactivity disorder (ADHD) are easily underaroused/activated. This double dissociation was tested using a go/no-go paradigm with computer-paced fast and slow conditions and a self-paced condition. In the HFA group, a performance decline in the fast condition and slow performance in the self-paced condition were expected. In the ADHD group, a performance decline in the slow condition and fast performance in the self-paced condition were expected. No difference was found between groups for state regulation and response inhibition. Findings are discussed in the light of development, comorbidity, and subtypes.

The Separation of ADHD Inattention and Hyperactivity-Impulsivity Symptoms: Pathways from Genetic Effects to Cognitive Impairments and Symptoms

Both shared and unique genetic risk factors underlie the two symptom domains of attention deficit hyperactivity disorder (ADHD): inattention and hyperactivity-impulsivity. The developmental course and relationship to co-occurring disorders differs across the two symptom domains, highlighting the importance of their partially distinct etiologies. Familial cognitive impairment factors have been identified in ADHD, but whether they show specificity in relation to the two ADHD symptom domains remains poorly understood. We aimed to investigate whether different cognitive impairments are genetically linked to the ADHD symptom domains of inattention versus hyperactivity-impulsivity. We conducted multivariate genetic model fitting analyses on ADHD symptom scores and cognitive data, from go/no-go and fast tasks, collected on a population twin sample of 1,312 children aged 7–10. Reaction time variability (RTV) showed substantial genetic overlap with inattention, as observed in an additive genetic correlation of 0.64, compared to an additive genetic correlation of 0.31 with hyperactivity-impulsivity. Commission errors (CE) showed low additive genetic correlations with both hyperactivity-impulsivity and inattention (genetic correlations of 0.17 and 0.11, respectively). The additive genetic correlation between RTV and CE was also low and non-significant at −0.10, consistent with the etiological separation between the two indices of cognitive impairments. Overall, two key cognitive impairments phenotypically associated with ADHD symptoms, captured by RTV and CE, showed different genetic relationships to the two ADHD symptom domains. The findings extend a previous model of two familial cognitive impairment factors in combined subtype ADHD by separating pathways underlying inattention and hyperactivity-impulsivity symptoms.

Genetic analysis of reaction time variability: room for improvement?

Background Increased reaction time variability (RTV) on cognitive tasks requiring a speeded response is characteristic of several psychiatric disorders. In attention deficit hyperactivity disorder (ADHD), the association with RTV is strong phenotypically and genetically, yet high RTV is not a stable impairment but shows ADHD-sensitive improvement under certain conditions, such as those with rewards. The state regulation theory proposed that the RTV difference score, which captures change from baseline to a rewarded or fast condition, specifically measures ‘state regulation’. By contrast, the interpretation of RTV baseline (slow, unrewarded) scores is debated. We aimed to investigate directly the degree of phenotypic and etiological overlap between RTV baseline and RTV difference scores. Method We conducted genetic model fitting analyses on go/no-go and fast task RTV data, across task conditions manipulating rewards and event rate, from a population-based twin sample (n=1314) and an ADHD and control sibling-pair sample (n=1265). Results Phenotypic and genetic/familial correlations were consistently high (0.72–0.98) between RTV baseline and difference scores, across tasks, manipulations and samples. By contrast, correlations were low between RTV in the manipulated condition and difference scores. A comparison across two different go/no-go task RTV difference scores (slow-fast/slow-incentive) showed high phenotypic and genetic/familial overlap (r = 0.75–0.83). Conclusions Our finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV. Given the statistical shortcomings of difference scores, we recommend the use of RTV baseline scores for most analyses, including genetic analyses.