The burden of parenting children with frontal lobe epilepsy.

OBJECTIVE: Caring for a child with a chronic illness adds stress to the typical parenting stress in healthy developing children. This stress can place a heavy burden on parents and may increase when a child displays problem behavior. In general, parenting and child's behavior problems are associated. Furthermore, externalizing (more outgoing) behavior is reported frequently in children with frontal lobe epilepsy (FLE). Therefore, in this study, we first investigated the burden of parents of children with FLE, and second, we investigated the relation between the experienced burden and reported behavioral problems. The validity of parents' reports on proxy measures as well as duration of epilepsy is taken into account. METHODS: Thirty-one parents of children with FLE completed validated questionnaires about behavioral problems and burden of parenting. To examine if parents tend to be inconsistent or unusually negative, we used the two validity scales of the Behavioral Rating Inventory of Executive Function (BRIEF) (Negativity and Inconsistency). RESULTS: Only parents of children with FLE who have had epilepsy for 5 years or longer report more problems on the Nijmeegse Vragenlijst voor de Opvoedingssituatie (NVOS) subscales 'Able to manage', 'Child is a burden', and 'Good Interaction' compared with the healthy controls. The subscale 'Child is a burden' significantly predicts scores in about 20% to 49% on the main scales of the Child Behavior Checklist (CBCL), the Global Executive Composite (GEC), and Behavioral Regulation Index (BRI) of the BRIEF. Only 6% of parents scored in the clinical range of the negativity scale of the BRIEF. For the inconsistency scale, this was 45%. CONCLUSION: Parents of children with FLE do not report excessive parental burden. Longer duration of epilepsy might be a risk factor in experiencing burden. The findings suggest a link between parental burden and behavioral problems in children with FLE. Externalizing behavioral problems are the most marked behavioral problems, which relate to the parental burden. Parents tend to be inconsistent in their ratings.

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.

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.

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.

Methylphenidate, interstimulus interval, and reaction time performance of children with attention deficit/hyperactivity disorder: a pilot study.

Thirteen children with attention deficit/hyperactivity disorder (ADHD: DSM-IV-TR) participated in the pilot study. They carried out a Go/No-Go test with a short (2 seconds) and long (6 seconds) interstimulus interval (ISI) when on placebo and a therapeutic dose of methylphenidate (MPH). For the long-ISI placebo condition the responses were slow and inaccurate. This pattern of response may be due to underactivation of the readiness-to-respond state that is not fully controlled by effort allocation. Speed of response and accuracy were enhanced during the short-ISI placebo condition and the long-ISI MPH condition. However, the combined effect (short ISI and MPH) resulted in a fast but inaccurate response style. This pattern of response may be due to overactivation of the readiness-to-respond state. The data of the pilot study support the stimulus shift hypothesis: MPH administration result in deterioration on tests on which children had previously done well (short ISI plus placebo versus short ISI plus MPH). In addition, the data support the idea that ADHD is associated with poor state regulation rather than motivational (delay aversion) theories or temporal-processing/time-estimation theories of ADHD. The pilot study defined empirically an issue for further study with the larger controlled sample.

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.

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.

ERP correlates of impaired error monitoring in children with ADHD.

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.

State regulation and response inhibition in children with ADHD and children with early- and continuously treated phenylketonuria: an event-related potential comparison.

BACKGROUND: The presentation rate of stimuli plays an important role in explaining the performance inefficiency in children with ADHD. In general, children with ADHD have been found to perform more poorly in conditions of relatively slow event rates as compared with fast and moderate event rates. The state regulation hypothesis states that these children have problems in correcting their energetic state necessary to counteract a performance decrement, which requires extra effort allocation. In this study, we investigated state regulation in children with ADHD and used children with early- and continuously treated phenylketonuria (PKU) as a clinical contrast group. METHOD: We measured the parietal P3 during a Go/No-Go task that incorporated a condition with a fast and a slow presentation rate. RESULTS: We were able to show that children with ADHD, relative to controls, responded more slowly and more variably in the slow condition only, which was accompanied by a smaller P3, suggesting less effort allocation. In contrast, the children with PKU did not show a state regulation deficit. The PKU group showed prolonged stimulus evaluation processing, as indexed by P3 latency, compared to controls and children with ADHD. In addition, they made more errors of commission than the controls and the ADHD group. CONCLUSIONS: Our electrophysiological data support the state regulation hypothesis of ADHD. Only the children with PKU had more problems in inhibiting pre-potent responding than controls, which is in accord with the prefrontal dysfunction hypothesis of PKU.

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. Over the years a number of studies have examined behaviour and school achievement in patients with early treated phenylketonuria (PKU; McKusick 261600). In general, these studies have found that despite early treatment with a phenylalanine (Phe)-restricted diet, PKU patients demonstrate more behavioural and school problems than do healthy controls. The behaviour problems include both internalizing symptoms (e.g. solitary, unresponsive, anxious, depressed mood: Pietz et al 1997; Smith et al 1988; Weglage et al 1992) and externalizing symptoms (e.g. hyperactive, talkative, impulsive, restless: Hendrikx et al 1994; Kalverboer et al 1994; Realmuto et al 1986; Smith et al 1988), but not antisocial or socially negative symptoms (e.g. lying, teasing, disobedience: Kalverboer et al 1994; Pietz et al 1997; Smith et al 1988). With respect to school achievement, studies have shown that patients with early treated PKU more often repeat classes or need special tutoring (Berry et al 1979; Brunner et al 1983; Koch et al 1987; Rey et al 1996; Verkerk 1995), have to work harder than healthy controls to achieve the same results (Weglage et al 1993), or have specific deficits in arithmetic achievement scores (Azen et al 1991; Berry et al 1979; Fishler et al 1987; Koch et al 1987; Weglage et al 1993). Nevertheless, many questions regarding the behavioural and school problems of patients with early treated PKU remain unanswered. For instance, the relationship between behavioural and school problems on the one hand and levels of dietary control on the other is still relatively unclear. The few studies that examined this relationship, have focused primarily on children in primary school (Azen et al 1991; Koch et al 1987; Smith et al 1988). Furthermore, although several psychological studies have shown that the pattern of behavioural problems varies by sex (see Prior et al 1999a for a discussion), so far very few studies have examined this issue in PKU patients and results are contradictory (Kalverboer et al 1994; Pietz et al 1997; Smith et al 1988; Weglage et al 1992). In addition, so far no study has actually examined whether there is a relationship between the behavioural problems and school difficulties of PKU patients, even though this relationship has been well documented in the psychological literature (Prior et al 1999b; Richards et al 1995). The aim of the present study is therefore to examine these issues in patients with early and continuously treated PKU over a wide age range and in relation to dietary control. More specifically, school achievement as well as social and task-oriented behaviour (at home

Sustained attention problems in children with early treated congenital hypothyroidism.

Sustained attention was studied in 48 children with early treated congenital hypothyroidism and 35 healthy controls, using a computer-paced and a self-paced continuous performance task. The performance of the patients, particularly those in the low T4 group (38 patients with T4 levels < 50 nmol/l at neonatal screening), declined in the final stage of the computer-paced task, suggesting a problem in remaining attentive over time. The performance of all children declined in the first and improved in the final stage of the self-paced task. This pattern was most pronounced in the low T4 group, reflecting greater variability in their task performance over time, again indicating a problem in sustaining attention. No correlation was found between onset of treatment and sustained attention. The small size of the intermediate T4 group (10 patients with T4 levels > or = 50 nmol/l at neonatal screening) made the results more difficult to interpret and may have concealed a problem with sustained attention in this group.

Information processing in patients with early and continuously-treated phenylketonuria.

UNLABELLED: A total of 33 patients with early and continuously-treated phenylketonuria (PKU) between 7 and 16 years of age and 33 matched controls participated in a study examining perceptual, central, and response-related mechanisms of information processing. The specific mechanisms studied were: perceptual filtering, memory search, response selection, response execution, and motor presetting. In addition, groups were compared on mean intelligence level and task oriented behaviour. The performance of the PKU patients practically matched that of the controls on all three tasks, suggesting that PKU patients who are continuously maintained on a well-controlled phenylalanine-restricted diet are not impaired in the elementary mechanisms of information processing. Furthermore, groups did not differ in mean IQ or task-oriented behaviour. CONCLUSION: These results underline the importance of continued, well-controlled dietary treatment. Further studies are recommended to obtain a more complete evaluation of the potential of PKU patients under these stricter dietary treatment conditions.

Information processing deficits in children with early and continuously treated phenylketonuria?

Thirty-three patients with early and continuously treated classical phenylketonuria (PKU) and 33 controls matched for age, gender, and educational level of both parents, participated in a chronometric study exploring elementary mechanisms of information processing. Subjects performed speeded performance tasks designed to systematically vary the load on perceptual, central, and output-related mechanisms of information processing. A preliminary analysis of the data indicated that the overall performance of patients with early and continuously treated PKU practically matched that of the controls on all three tasks. Although this finding must be interpreted with caution as it is based on only a preliminary analysis of the data, it suggests that PKU patients who are continuously maintained on a well-controlled phenylalanine-restricted diet are not deficient in the elementary mechanisms of processing. Given the more recent findings indicating that young children with early-treated classical PKU have specific cognitive deficits in the executive function skills, despite relatively strict dietary control, the authors suggest that future studies should focus on these higher-order cognitive processes.

Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment.

Although neonatal thyroid screening programs have been of value in preventing cerebral damage, it is still controversial whether patients with congenital hypothyroidism achieve normal motor and cognitive skills. We studied the motor and cognitive skills of 72 children with early-treated congenital hypothyroidism and 35 control subjects at the ages of 7 1/2 and 9 1/2 years. The relative influence of cause, blood thyroxine concentration at the time of screening, and age at the start of thyroxine replacement therapy on motor and cognitive development was investigated. Despite having received treatment at a mean age of 23 days, children with low neonatal thyroxine concentrations (< 50 nmol/L) at screening, particularly children with thyroid agenesis, had significant motor problems and borderline intelligence scores as late as 9 1/2 years of age. Balance and gross motor functions seemed to decline between 7 1/2 and 9 1/2 years of age, whereas language and memory functions seemed to be maintained. Significant correlations between the start of therapy and both motor scores and performance IQ scores at the age of 7 1/2 years in children with severe hypothyroidism show the importance of early treatment for these patients.

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.