Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

BACKGROUND: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE). METHODS: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses. RESULTS: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, ß = 0.088, p = 0.02) but not for CE (R2 = 0.011, ß = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10). CONCLUSIONS: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

The risk of eating disorders comorbid with attention-deficit/hyperactivity disorder: A systematic review and meta-analysis.

OBJECTIVE: There has been interest in whether people with Attention-Deficit/Hyperactivity Disorder (ADHD) are at higher risk of developing an Eating Disorder (ED). The aim of this study was estimate the size of this association with a meta-analysis of studies. METHODS: We retrieved studies following PRISMA guidelines from a broad range of databases. RESULTS: Twelve studies fitted our primary aim in investigating ED in ADHD populations (ADHD = 4,013/Controls = 29,404), and five exploring ADHD in ED populations (ED = 1,044/Controls = 11,292). The pooled odds ratio of diagnosing any ED in ADHD was increased significantly, 3.82 (95% CI:2.34-6.24). A similar level of risk was found across all ED syndromes [Anorexia Nervosa = 4.28 (95% CI:2.24-8.16); Bulimia Nervosa = 5.71 (95% CI: 3.56-9.16) and Binge Eating Disorder = 4.13 (95% CI:3-5.67)]. The risk was significantly higher if ADHD was diagnosed using a clinical interview [5.89 (95% CI:4.32-8.04)] rather than a self-report instrument [2.23 (95% CI:1.23-4.03)]. The pooled odds ratio of diagnosing ADHD in participants with ED was significantly increased, 2.57 (95% CI:1.30-5.11). Subgroup analysis of cohorts with binge eating only yielded a risk of 5.77 (95% CI:2.35-14.18). None of the variables examined in meta-regression procedures explained the variance in effect size between studies. DISCUSSION: People with ADHD have a higher risk of comorbidity with an ED and people with an ED also have higher levels of comorbidity with ADHD. Future studies should address if patients with this comorbidity have a different prognosis, course and treatment response when compared to patients with either disorder alone. RESUMEN OBJETIVO: Ha habido interés en saber si la gente con Trastorno por Déficit de Atención e Hiperactividad (TDAH) están en mayor riesgo de desarrollar un Trastorno de la Conducta Alimentaria (TCA). El objetivo de este estudio fue estimar el tamaño de esta asociación con un meta-análisis de los estudios. Métodos: Recuperamos estudios de una amplia gama base de datos,  que siguen los lineamientos PRISMA. Resultados: Doce estudios encajaron con nuestro objetivo primario de investigar los TCA en poblaciones con TDAH (TDAH = 4,013/Controles = 29,404), y 5 exploraron TDAH en poblaciones con TCA (TCA = 1,044/Controles = 11,292). El odds ratio (OR) agrupado de diagnosticar cualquier TCA en el TDAH se incrementó significativamente, 3.82 (95% CI:2.34-6.24). Un nivel de riesgo similar fue encontrado en todos los síndromes de TCA [Anorexia Nervosa = 4.28 (95% CI:2.24-8.16); Bulimia Nervosa = 5.71 (95% CI:3.56-9.16) y Trastorno por Atracón = 4.13 (95% CI: 3-5.67)]. El riesgo fue significativamente mayor si el TDAH fue diagnosticado utilizando una entrevista clínica [5.89 (95% CI:4.32-8.04)] en lugar de un instrumento de auto-reporte [2.23 (95% CI:1.23-4.03)]. El odds ratio (OR) agrupado de diagnosticar TDAH en participantes con TCA fue significativamente incrementado, 2.57 (95% CI:1.30-5.11). El análisis de los subgrupos de cohort con atracones solamente produjo un riesgo de 5.77 (95% CI:2.35-14.18). Ninguna de las variables examinadas en los procedimientos de meta-regresión explicaron la varianza en el tamaño del efecto entre los estudios. Discusión: La gente con TDAH tiene un mayor riesgo de comorbilidad con un TCA y la gente con un TCA también tiene niveles altos de comorbilidad con TDAH. Los estudios futuros deberán abordar si los pacientes con esta comorbilidad tienen diferente pronóstico, curso y respuesta a tratamiento cuando son comparados con pacientes que solamente tienen uno de los trastornos.  © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016) © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:1045-1057).

Neurocognitive predictors of substance use disorders and nicotine dependence in ADHD probands, their unaffected siblings, and controls: a 4-year prospective follow-up.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a risk factor for substance use disorders (SUDs) and nicotine dependence (ND). Neurocognitive deficits may predict the increased risk of developing SUDs and nicotine dependence. METHODS: This study comprised three groups derived from the Dutch part of the International Multicenter ADHD Genetics (IMAGE) study: ADHD probands (n = 294), unaffected siblings (n = 161), and controls (n = 214). At baseline (age = 12.2), a range of neurocognitive functions was assessed including executive functions (inhibition, working memory, timing), measures of motor functioning (motor timing and tracking) and IQ. After a mean follow-up of 4.2 years, SUDs and ND were assessed. RESULTS: None of the neurocognitive functions predicted later SUDs or ND in ADHD probands, even after controlling for medication use and conduct disorder. Slower response inhibition predicted later nicotine dependence in unaffected siblings (OR = 2.06, 95% CI = 1.22-3.48), and lower IQ predicted increased risk for SUDs in controls (OR = 1.96, 95% CI = 1.12-3.44). CONCLUSIONS: Cold executive functions, motor functioning, and IQ did not predict the elevated risk of SUDs and ND in ADHD. Future studies should target 'hot' executive functions such as reward processing as risk factors for SUDs or ND.

Multilevel analysis of ADHD, anxiety and depression symptoms aggregation in families.

A strong genetic role in the etiology of attention-deficit hyperactivity disorder (ADHD) has been demonstrated by several studies using different methodologies. Shortcomings of genetic studies often include the lack of golden standard practices for diagnosis for ADHD, the use of categorical instead of a dimensional approach, and the disregard for assortative mating phenomenon in parents. The current study aimed to overcome these shortcomings and analyze data through a novel statistical approach, using multilevel analyses with Bayesian procedures and a specific mathematical model, which takes into account data with an elevated number of zero responses (expected in samples with few or no ADHD symptoms). Correlations of parental clinical variables (ADHD, anxiety and depression) to offspring psychopathology may vary according to gender and type of symptoms. We aimed to investigate how those variables interact within each other. One hundred families, comprising a proband child or adolescent with ADHD or a typically developing child or adolescent were included and all family members (both biological parents, the proband child or adolescent and their sibling) were examined through semi-structured interviews using DSM-IV criteria. Results indicated that: (a) maternal clinical variables (ADHD, anxiety and depression) were more correlated with offspring variables than paternal ones; (b) maternal inattention (but not hyperactivity) was correlated with both inattention and hyperactivity in the offspring; (c) maternal anxiety was correlated with offspring inattention; on the other hand, maternal inattention was correlated with anxiety in the offspring. Although a family study design limits the possibility of revealing causality and cannot disentangle genetic and environmental factors, our findings suggest that ADHD, anxiety and depression are variables that correlate in families and should be addressed together. Maternal variables significantly correlated with offspring variables, but the paternal variables did not.

Influence of attention-deficit/hyperactivity disorder on binge eating behaviors and psychiatric comorbidity profile of obese women.

OBJECTIVE: Previous studies have reported higher prevalence rates of attention-deficit/hyperactivity disorder (ADHD) both in eating disorders (ED) and in obese patients. We compared the psychiatric comorbidity profile of obese ADHD women with non-ADHD obese women and how ADHD symptoms impact in binge eating behaviors. DESIGN: Cross-sectional study of a clinical sample. SUBJECTS: 171 adult women were evaluated at a specialized clinic in obesity and ED. MEASUREMENTS: Participants complete a semi-structured interview and psychopathology rating scales. A hierarchical regression model was employed to predict binge eating behavior. RESULTS: Obese ADHD patients had a larger number of psychiatric comorbidities (p<0.001), especially Substance Abuse Disorders, and higher scores on psychopathology rating scales (p<0.05). The highest prediction for binge eating in the regression model was the presence of depressive symptoms, followed by ADHD inattention symptoms and trait-impulsivity. CONCLUSION: ADHD should be routinely evaluated in obese since it is related with more severe psychopathology. Depressive symptoms can predict the presence of binge eating in obese patients.

Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity.

Low birth weight is associated with increased risk for Attention-Deficit/Hyperactivity Disorder (ADHD); however, the etiological underpinnings of this relationship remain unclear. This study investigated if genetic variants in angiogenic, dopaminergic, neurotrophic, kynurenine, and cytokine-related biological pathways moderate the relationship between birth weight and ADHD symptom severity. A total of 398 youth from two multi-site, family-based studies of ADHD were included in the analysis. The sample consisted of 360 ADHD probands, 21 affected siblings, and 17 unaffected siblings. A set of 164 SNPs from 31 candidate genes, representing five biological pathways, were included in our analyses. Birth weight and gestational age data were collected from a state birth registry, medical records, and parent report. Generalized Estimating Equations tested for main effects and interactions between individual SNPs and birth weight centile in predicting ADHD symptom severity. SNPs within neurotrophic (NTRK3) and cytokine genes (CNTFR) were associated with ADHD inattentive symptom severity. There was no main effect of birth weight centile on ADHD symptom severity. SNPs within angiogenic (NRP1 & NRP2), neurotrophic (NTRK1 & NTRK3), cytokine (IL16 & S100B), and kynurenine (CCBL1 & CCBL2) genes moderate the association between birth weight centile and ADHD symptom severity. The SNP main effects and SNP × birth weight centile interactions remained significant after adjusting for multiple testing. Genetic variability in angiogenic, neurotrophic, and inflammatory systems may moderate the association between restricted prenatal growth, a proxy for an adverse prenatal environment, and risk to develop ADHD.

Stimulant treatment for attention-deficit hyperactivity disorder and risk of developing substance use disorder.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is linked to increased risk for substance use disorders and nicotine dependence. AIMS: To examine the effects of stimulant treatment on subsequent risk for substance use disorder and nicotine dependence in a prospective longitudinal ADHD case-control study. METHOD: At baseline we assessed ADHD, conduct disorder and oppositional defiant disorder. Substance use disorders, nicotine dependence and stimulant treatment were assessed retrospectively after a mean follow-up of 4.4 years, at a mean age of 16.4 years. RESULTS: Stimulant treatment of ADHD was linked to a reduced risk for substance use disorders compared with no stimulant treatment, even after controlling for conduct disorder and oppositional defiant disorder (hazard ratio (HR) = 1.91, 95% CI 1.10-3.36), but not to nicotine dependence (HR = 1.12, 95% CI 0.45-2.96). Within the stimulant-treated group, a protective effect of age at first stimulant use on substance use disorder development was found, which diminished with age, and seemed to reverse around the age of 18. CONCLUSIONS: Stimulant treatment appears to lower the risk of developing substance use disorders and does not have an impact on the development of nicotine dependence in adolescents with ADHD.

Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents.

BACKGROUND: Medication is an important element of therapeutic strategies for ADHD. While medications for ADHD are generally well-tolerated, there are common, although less severe, as well as rare but severe adverse events AEs during treatment with ADHD drugs. The aim of this review is to provide evidence- and expert-based guidance concerning the management of (AEs) with medications for ADHD. METHODS: For ease of use by practitioners and clinicians, the article is organized in a simple question and answer format regarding the prevalence and management of the most common AEs. Answers were based on empirical evidence from studies (preferably meta-analyses or systematic reviews) retrieved in PubMed, Ovid, EMBASE and Web of Knowledge through 30 June 2012. When no empirical evidence was available, expert consensus of the members of the European ADHD Guidelines Group is provided. The evidence-level of the management recommendations was based on the SIGN grading system. RESULTS: The review covers monitoring and management strategies of loss of appetite and growth delay, cardiovascular risks, sleep disturbance, tics, substance misuse/abuse, seizures, suicidal thoughts/behaviours and psychotic symptoms. CONCLUSION: Most AEs during treatment with drugs for ADHD are manageable and most of the times it is not necessary to stop medication, so that patients with ADHD may continue to benefit from the effectiveness of pharmacological treatment.

Comorbid anxiety and neurocognitive dysfunctions in children with ADHD.

Previous research established that children with ADHD and comorbid anxiety have a later age of ADHD onset, show less off-task and hyperactive behavior, and have more school problems than children with ADHD alone. Comorbid anxiety appears to ameliorate behavioral inhibition deficits, worsen working memory problems, and lengthen reaction times in ADHD. This study investigated the effect of comorbid anxiety on a broad range of neurocognitive functions and includes child-, parent- and teacher reports of anxiety. The sample consisted of 509 children in the age range 5-19 years, including 238 children with a diagnosis of ADHD combined subtype and 271 normal control children. Children were tested on a broad battery of neurocognitive tasks that proved highly sensitive to ADHD in previous work. Linear Structural Equation Modeling (SEM) was used to estimate the effect of comorbid anxiety on the neurocognitive functions. Child reported anxiety was associated with slower motor speed and response speed and better behavioral inhibition. Teacher reported anxiety was related to worse time production. Parent reported anxiety was not significantly associated with any of the neurocognitive functions. Compared to parent and teacher reports of anxiety, child reported comorbid anxiety shows foremost the largest associations with the neurocognitive dysfunctions observed in children with ADHD. This stresses the importance of including child self-reported anxiety assessments in clinical and research practice.

Aetiology for the covariation between combined type ADHD and reading difficulties in a family study: the role of IQ.

BACKGROUND: Twin studies using both clinical and population-based samples suggest that the frequent co-occurrence of attention deficit hyperactivity disorder (ADHD) and reading ability/disability (RD) is largely driven by shared genetic influences. While both disorders are associated with lower IQ, recent twin data suggest that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genetic influences contributing to general cognitive ability. The current study aimed to extend the previous findings that were based on rating scale measures in a population sample by examining the generalisability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. This study investigated the familial relationships between ADHD, reading difficulties and IQ in a sample of individuals diagnosed with ADHD combined type, their siblings and control sibling pairs. METHODS: Multivariate familial models were run on data from 1,789 individuals at ages 6-19. Reading difficulties were measured with both rating scale and an objective task. IQ was obtained using the Wechsler Intelligence Scales (WISC-III/WAIS-III). RESULTS: Significant phenotypic (.2-.4) and familial (.3-.5) correlations were observed among ADHD, reading difficulties and IQ. Yet, 53%-72% of the overlapping familial influences between ADHD and reading difficulties were not shared with IQ. CONCLUSIONS: Our finding that familial influences shared with general cognitive ability, although present, do not account for the majority of the overlapping familial influences on ADHD and reading difficulties extends previous findings from a population-based study to a clinically ascertained sample with combined type ADHD.

The hierarchical factor model of ADHD: invariant across age and national groupings?

OBJECTIVE: To examine the factor structure of attention-deficit/hyperactivity disorder (ADHD) in a clinical sample of 1,373 children and adolescents with ADHD and their 1,772 unselected siblings recruited from different countries across a large age range. Hierarchical and correlated factor analytic models were compared separately in the ADHD and sibling samples, across three different instruments and across parent and teacher informants. Specific consideration was given to factorial invariance analyses across different ages and different countries in the ADHD sample. METHOD: A sample of children and adolescents between 5 and 17 years of age with ADHD and their unselected siblings was assessed. Participants were recruited from seven European countries and Israel. ADHD symptom data came from a clinical interview with parents Parental Account of Childhood Symptoms and questionnaires from parents and teachers (Conners Parent and Teacher). RESULTS: A hierarchical general factor model with two specific factors best represented the structure of ADHD in both the ADHD and unselected sibling groups, and across informants and instruments. The model was robust and invariant with regard to age differences in the ADHD sample. The model was not strongly invariant across different national groups in the ADHD sample, likely reflecting severity differences across the different centers and not any substantial difference in the clinical presentation of ADHD. CONCLUSIONS: The results replicate previous studies of a model with a unitary ADHD component and separable specific traits of inattention and hyperactivity/impulsivity. The unique contribution of this study was finding support for this model across a large developmental and multinational/multicultural sample and its invariance across ages.

Neuropsychological correlates of emotional lability in children with ADHD.

BACKGROUND: Emotional lability (EL) is commonly seen in patients with attention-deficit/hyperactivity disorder (ADHD). The reasons for this association remain currently unknown. To address this question, we examined the relationship between ADHD and EL symptoms, and performance on a range of neuropsychological tasks to clarify whether EL symptoms are predicted by particular cognitive and/or motivational dysfunctions and whether these associations are mediated by the presence of ADHD symptoms. METHODS: A large multi-site sample of 424 carefully diagnosed ADHD cases and 564 unaffected siblings and controls aged 6-18 years performed a broad neuropsychological test battery, including a Go/No-Go Task, a warned four-choice Reaction Time task, the Maudsley Index of Childhood Delay Aversion and Digit span backwards. Neuropsychological variables were aggregated as indices of processing speed, response variability, executive functions, choice impulsivity and the influence of energetic and/or motivational factors. EL and ADHD symptoms were regressed on each neuropsychological variable in separate analyses controlling for age, gender and IQ, and, in subsequent regression analyses, for ADHD and EL symptoms respectively. RESULTS: Neuropsychological variables significantly predicted ADHD and EL symptoms with moderate-to-low regression coefficients. However, the association between neuropsychological parameters on EL disappeared entirely when the effect of ADHD symptoms was taken into account, revealing that the association between the neuropsychological performance measures and EL is completely mediated statistically by variations in ADHD symptoms. Conversely, neuropsychological effects on ADHD symptoms remained after EL symptom severity was taken into account. CONCLUSIONS: The neuropsychological parameters examined, herein, predict ADHD more strongly than EL. They cannot explain EL symptoms beyond what is already accounted for by ADHD symptom severity. The association between EL and ADHD cannot be explained by these cognitive or motivational deficits. Alternative mechanisms, including overlapping genetic influences (pleiotropic effects) and/or alternative neuropsychological processes need to be considered.

Cardiovascular considerations of attention deficit hyperactivity disorder medications: a report of the European Network on Hyperactivity Disorders work group, European Attention Deficit Hyperactivity Disorder Guidelines Group on attention deficit hyperactivity disorder drug safety meeting.

Regulatory decisions regarding attention deficit hyperactivity disorder drug licensing and labelling, along with recent statements from professional associations, raise questions of practice regarding the evaluation and treatment of patients with attention deficit hyperactivity disorder. To address these issues for the European community, the European Network for Hyperkinetic Disorders, through its European Attention Deficit Hyperactivity Disorder Guidelines Group, organised a meeting between attention deficit hyperactivity disorder specialists, paediatric cardiovascular specialists, and representatives of the major market authorisation holders for attention deficit hyperactivity disorder medications. This manuscript represents their consensus on cardiovascular aspects of attention deficit hyperactivity disorder medications. Although sudden death has been identified in multiple young individuals on attention deficit hyperactivity disorder medication causing regulatory concern, when analysed for exposure using currently available data, sudden death does not appear to exceed that of the general population. There is no current evidence to suggest an incremental benefit to electrocardiography assessment of the general attention deficit hyperactivity disorder patient. Congenital heart disease patients have an increased prevalence of attention deficit hyperactivity disorder, and can benefit from attention deficit hyperactivity disorder therapies, including medication. The attention deficit hyperactivity disorder specialist is the appropriate individual to evaluate benefit and risk and recommend therapy in all patients, although discussion with a heart specialist is reasonable for congenital heart disease patients. For attention deficit hyperactivity disorder patients with suspected heart disease or risk factor/s for sudden death, assessment by a heart specialist is recommended, as would also be the case for a non-attention deficit hyperactivity disorder patient. The identification of risk factors for sudden death should not automatically exclude the use of attention deficit hyperactivity disorder medication.

Neuropsychological intra-individual variability explains unique genetic variance of ADHD and shows suggestive linkage to chromosomes 12, 13, and 17.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder that is usually accompanied by neuropsychological impairments. The use of heritable, psychometrically robust traits that show association with the disorder of interest can increase the power of gene-finding studies. Due to the robust association of intra-individual variability with ADHD on a phenotypic and genetic level, intra-individual variability is a prime candidate for such an attempt. We aimed to combine intra-individual variability measures across tasks into one more heritable measure, to examine the relatedness to other cognitive factors, and to explore the genetic underpinnings through quantitative trait linkage analysis. Intra-individual variability measures from seven tasks were available for 238 ADHD families (350 ADHD-affected and 195 non-affected children) and 147 control families (271 children). Intra-individual variability measures from seven different tasks shared common variance and could be used to construct an aggregated measure. This aggregated measure was largely independent from other cognitive factors related to ADHD and showed suggestive linkage to chromosomes 12q24.3 (LOD = 2.93), 13q22.2 (LOD = 2.36), and 17p13.3 (LOD = 2.00). A common intra-individual variability construct can be extracted from very diverse neuropsychological tasks; this construct taps into unique genetic aspects of ADHD and may relate to loci conferring risk for ADHD (12q24.3 and 17p13.3) and possibly autism (12q24.3). Given that joining of data across sites boosts the power for genetic analyses, our findings are promising in showing that intra-individual variability measures are viable candidates for across site analyses where different tasks have been used.

Neuropsychological endophenotype approach to genome-wide linkage analysis identifies susceptibility loci for ADHD on 2q21.1 and 13q12.11.

ADHD linkage findings have not all been consistently replicated, suggesting that other approaches to linkage analysis in ADHD might be necessary, such as the use of (quantitative) endophenotypes (heritable traits associated with an increased risk for ADHD). Genome-wide linkage analyses were performed in the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 nonaffected siblings. Eight candidate neuropsychological ADHD endophenotypes with heritabilities > 0.2 were used as quantitative traits. In addition, an overall component score of neuropsychological functioning was used. A total of 5407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. Two significant genome-wide linkage signals were found, one for Motor Timing on chromosome 2q21.1 (LOD score: 3.944) and one for Digit Span on 13q12.11 (LOD score: 3.959). Ten suggestive linkage signals were found (LOD scores > or = 2) on chromosomes 2p, 2q, 3p, 4q, 8q, 12p, 12q, 14q, and 17q. The suggestive linkage signal for the component score that was found at 2q14.3 (LOD score: 2.878) overlapped with the region significantly linked to Motor Timing. Endophenotype approaches may increase power to detect susceptibility loci in ADHD and possibly in other complex disorders.

ERPs associated with monitoring and evaluation of monetary reward and punishment in children with ADHD.

BACKGROUND: Several models of attention-deficit hyperactivity disorder (ADHD) propose abnormalities in the response to behavioural contingencies. Using event-related potentials (ERPs), the present study investigated the monitoring and subsequent evaluation of performance feedback resulting in either reward or punishment in children with ADHD (N = 18) and normal controls (N = 18) aged 8 to 12 years. METHODS: Children performed a time production task, in which visual performance feedback was given after each response. To manipulate its motivational salience, feedback was coupled with monetary gains, losses or no incentives. RESULTS: Performance feedback signalling omitted gains as well as omitted losses evoked a feedback-related negativity (FRN) in control children. The FRN, however, was entirely absent in children with ADHD in all conditions. Moreover, while losses elicited enhanced amplitudes of the late positive potential (LPP) in controls, omitted rewards had this effect in ADHD. CONCLUSIONS: The lack of modulation of the FRN by contingencies in ADHD suggests deficient detection of environmental cues as a function of their motivational significance. LPP findings suggest diminished response to punishment, but oversensitivity to the loss of desired rewards. These findings suggest that children with ADHD have problems assigning relative motivational significance to outcomes of their actions.

Auditory conflict processing in ADHD.

BACKGROUND: Impaired cognitive control has been implicated as an important developmental pathway to attention deficit/hyperactivity disorder (ADHD). Cognitive control is crucial to suppress interference resulting from conflicting information and can be measured by Stroop-like tasks. This study was conducted to gain insight into conflict processing in children with ADHD. METHODS: Event-related potentials (ERPs) were recorded in an auditory Stroop task. Twenty-four children with ADHD were compared with 24 control children (aged 8-12 years). RESULTS: No deficit in interference control was found on the auditory Stroop task in children with ADHD. Children with ADHD responded more slowly, less accurately and more variably compared to controls. No differences between the groups occurred in the early conflict-related ERPs. However, the difference between the congruent and the incongruent condition in the 450-550 ms time window was absent in the ADHD group compared to controls. In addition, the conflict sustained potential was found frontally in the ADHD group but parietally in the control group. CONCLUSIONS: These ERP findings suggest that children with ADHD evaluate conflict to a lesser extent and differ in the way their brains select appropriate responses during conflict compared with controls.

Pre-attentive processing in children with early and continuously-treated PKU. Effects of concurrent Phe level and lifetime dietary control.

Sixty-four children, aged 7 to 14 years, with early-treated PKU, were compared with control children on visual evoked potential (VEP) amplitudes and latencies and auditory mismatch negativity (MMN) amplitudes. It was further investigated whether indices of dietary control would be associated with these evoked potentials parameters. There were no significant differences between controls and children with PKU in VEP- and MMN-indices. However, higher lifetime Phe levels were, in varying degree and stronger than concurrent Phe level, related to increased N75 amplitudes, suggesting abnormalities in attention, and longer P110 latencies, indicating a reduction in speed of neural processing, possibly due to deficits in myelination or reduced dopamine levels in brain and retina. Similarly, higher lifetime Phe levels and Index of Dietary Control (IDC) were associated with decreased MMN amplitudes, suggesting a reduced ability to respond to stimulus change and poorer triggering of the frontally mediated attention switch. In summary, the present study in children with PKU investigated bottom-up information processing, i.e., triggered by external events, a fundamental prerequisite for the individual's responsiveness to the outside world. Results provide evidence that quality of dietary control may affect the optimal development of these pre-attentive processes, and suggest the existence of windows of vulnerability to Phe exposure.

The impact of study design and diagnostic approach in a large multi-centre ADHD study. Part 1: ADHD symptom patterns.

BACKGROUND: The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with the combined type of attention deficit/hyperactivity disorder (ADHD-CT) and 1446 'unselected' siblings. The aim was to analyse the IMAGE sample with respect to demographic features (gender, age, family status, and recruiting centres) and psychopathological characteristics (diagnostic subtype, symptom frequencies, age at symptom detection, and comorbidities). A particular focus was on the effects of the study design and the diagnostic procedure on the homogeneity of the sample in terms of symptom-based behavioural data, and potential consequences for further analyses based on these data. METHODS: Diagnosis was based on the Parental Account of Childhood Symptoms (PACS) interview and the DSM-IV items of the Conners' teacher questionnaire. Demographics of the full sample and the homogeneity of a subsample (all probands) were analysed by using robust statistical procedures which were adjusted for unequal sample sizes and skewed distributions. These procedures included multi-way analyses based on trimmed means and winsorised variances as well as bootstrapping. RESULTS: Age and proband/sibling ratios differed between participating centres. There was no significant difference in the distribution of gender between centres. There was a significant interaction between age and centre for number of inattentive, but not number of hyperactive symptoms. Higher ADHD symptom frequencies were reported by parents than teachers. The diagnostic symptoms differed from each other in their frequencies. The face-to-face interview was more sensitive than the questionnaire. The differentiation between ADHD-CT probands and unaffected siblings was mainly due to differences in hyperactive/impulsive symptoms. CONCLUSIONS: Despite a symptom-based standardized inclusion procedure according to DSM-IV criteria with defined symptom thresholds, centres may differ markedly in probands' ADHD symptom frequencies. Both the diagnostic procedure and the multi-centre design influence the behavioural characteristics of a sample and, thus, may bias statistical analyses, particularly in genetic or neurobehavioral studies.

The impact of study design and diagnostic approach in a large multi-centre ADHD study: Part 2: Dimensional measures of psychopathology and intelligence.

BACKGROUND: The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with ADHD and 1446 unselected siblings. The aim was to describe and analyse questionnaire data and IQ measures from all probands and siblings. In particular, to investigate the influence of age, gender, family status (proband vs. sibling), informant, and centres on sample homogeneity in psychopathological measures. METHODS: Conners' Questionnaires, Strengths and Difficulties Questionnaires, and Wechsler Intelligence Scores were used to describe the phenotype of the sample. Data were analysed by use of robust statistical multi-way procedures. RESULTS: Besides main effects of age, gender, informant, and centre, there were considerable interaction effects on questionnaire data. The larger differences between probands and siblings at home than at school may reflect contrast effects in the parents. Furthermore, there were marked gender by status effects on the ADHD symptom ratings with girls scoring one standard deviation higher than boys in the proband sample but lower than boys in the siblings sample. The multi-centre design is another important source of heterogeneity, particularly in the interaction with the family status. To a large extent the centres differed from each other with regard to differences between proband and sibling scores. CONCLUSIONS: When ADHD probands are diagnosed by use of fixed symptom counts, the severity of the disorder in the proband sample may markedly differ between boys and girls and across age, particularly in samples with a large age range. A multi-centre design carries the risk of considerable phenotypic differences between centres and, consequently, of additional heterogeneity of the sample even if standardized diagnostic procedures are used. These possible sources of variance should be counteracted in genetic analyses either by using age and gender adjusted diagnostic procedures and regional normative data or by adjusting for design artefacts by use of covariate statistics, by eliminating outliers, or by other methods suitable for reducing heterogeneity.