Working memory training in children with neuropsychiatric disorders and mild to borderline intellectual functioning, the role of coaching; a double-blind randomized controlled trial.

BACKGROUND: Working memory training (WMT) has been shown to offer therapeutic benefits to both patients with Attention-Deficit Hyperactivity Disorder (ADHD) and patients with mild to borderline Intellectual Disabilities (MBID; 60 < IQ < 85). However, robust evidence for transfer effects and treatment benefits of WMT over placebo training are lacking. Owing to the nature of double-blind research designs in RCTs, children have received non-specific coaching not based on their actual training performance. Active coaching based on individual training results (such as in clinical practice) might enhance the efficacy of Cogmed WMT. Furthermore, clinical experience and the general treatment approach to these vulnerable children has shown that the intensity and duration of WMT is often too stressful. This study therefore investigated the efficacy of a less intensive, but more prolonged Cogmed WMT (including active personalized coaching and feedback) in reducing behavioral symptoms and improving neurocognitive functioning and academic achievements in children with MBID and neuropsychiatric disorders. METHODS/DESIGN: A double-blind RCT with children (age 10.0-13.11) with neuropsychiatric disorders (ADHD and/or autism spectrum disorder (ASD)) and MBID (IQ: 60 < IQ < 85). Two groups (each n = 26) will receive Cogmed WMT (version R/M) at home or at school for 8 weeks, 4 days a week, at 30 min a day. One group will receive active personalized coaching and feedback based on their actual individual performance during Cogmed training. The other group will only receive general non-personalized coaching (i.e. no receive personalized coaching and feedback). Both groups will undergo a neurocognitive assessment (working memory, executive functioning, academic achievements) before and after training and complete several questionnaires (behavioral problems, parenting style) with a 6 months follow-up. DISCUSSION: This study will add to the literature since the role of coaching in Cogmed WMT has not been studied before. It will also provide opportunities to investigate an alternative version of WMT in a large group of vulnerable children, for whom few evidence-based treatments are available. Ultimately, this will allow us to advise mental health care professionals and special education schools about the use of this type of intervention for children with MBID and neuropsychiatric disorders. TRIAL REGISTRATION: Dutch Trial Register. NTR5223 . Registration date 06-09-2015.

Lower white matter microstructure in the superior longitudinal fasciculus is associated with increased response time variability in adults with attention-deficit/ hyperactivity disorder.

BACKGROUND: Response time variability (RTV) is consistently increased in patients with attention-deficit/hyperactivity disorder (ADHD). A right-hemispheric frontoparietal attention network model has been implicated in these patients. The 3 main connecting fibre tracts in this network, the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF) and the cingulum bundle (CB), show microstructural abnormalities in patients with ADHD. We hypothesized that the microstructural integrity of the 3 white matter tracts of this network are associated with ADHD and RTV. METHODS: We examined RTV in adults with ADHD by modelling the reaction time distribution as an exponentially modified Gaussian (ex-Gaussian) function with the parameters µ, σ and τ, the latter of which has been attributed to lapses of attention. We assessed adults with ADHD and healthy controls using a sustained attention task. Diffusion tensor imaging-derived fractional anisotropy (FA) values were determined to quantify bilateral microstructural integrity of the tracts of interest. RESULTS: We included 100 adults with ADHD and 96 controls in our study. Increased τ was associated with ADHD diagnosis and was linked to symptoms of inattention. An inverse correlation of τ with mean FA was seen in the right SLF of patients with ADHD, but no direct association between the mean FA of the 6 regions of interest with ADHD could be observed. LIMITATIONS: Regions of interest were defined a priori based on the attentional network model for ADHD and thus we might have missed effects in other networks. CONCLUSION: This study suggests that reduced microstructural integrity of the right SLF is associated with elevated τ in patients with ADHD.

Does EEG-neurofeedback improve neurocognitive functioning in children with attention-deficit/hyperactivity disorder? A systematic review and a double-blind placebo-controlled study.

BACKGROUND: The number of placebo-controlled randomized studies relating to EEG-neurofeedback and its effect on neurocognition in attention-deficient/hyperactivity disorder (ADHD) is limited. For this reason, a double blind, randomized, placebo-controlled study was designed to assess the effects of EEG-neurofeedback on neurocognitive functioning in children with ADHD, and a systematic review on this topic was performed. METHODS: Forty-one children (8-15 years) with a DSM-IV-TR diagnosis of ADHD were randomly allocated to EEG-neurofeedback or placebo-neurofeedback treatment for 30 sessions, twice a week. Children were stratified by age, electrophysiological state of arousal, and medication use. Neurocognitive tests of attention, executive functioning, working memory, and time processing were administered before and after treatment. Researchers, teachers, children and their parents, with the exception of the neurofeedback-therapist, were all blind to treatment assignment. Outcome measures were the changes in neurocognitive performance before and after treatment. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov: NCT00723684. RESULTS: No significant treatment effect on any of the neurocognitive variables was found. A systematic review of the current literature also did not find any systematic beneficial effect of EEG-neurofeedback on neurocognitive functioning. CONCLUSION: Overall, the existing literature and this study fail to support any benefit of neurofeedback on neurocognitive functioning in ADHD, possibly due to small sample sizes and other study limitations.

Working memory training in young children with ADHD: a randomized placebo-controlled trial.

BACKGROUND: Until now, working memory training has not reached sufficient evidence as effective treatment for ADHD core symptoms in children with ADHD; for young children with ADHD, no studies are available. To this end, a triple-blind, randomized, placebo-controlled study was designed to assess the efficacy of Cogmed Working Memory Training (CWMT) in young children with ADHD. METHODS: Fifty-one children (5-7 years) with a DSM-IV-TR diagnosis of ADHD (without current psychotropic medication) were randomly assigned to the active (adaptive) or placebo (nonadaptive) training condition for 25 sessions during 5 weeks. The compliance criterion (>20 sessions) was met for 47 children. The primary outcome measure concerned the core behavioural symptoms of ADHD, measured with the ADHD Rating Scale IV (ADHD-RS). Secondary outcome measures were neurocognitive functioning, daily executive functioning, and global clinical functioning. The influence of the increase in difficulty level (Index-Improvement) for the treatment group was also analysed. Clinical trial registration information - 'Working Memory Training in Young ADHD Children'; www.clinicaltrials.gov; NCT00819611. RESULTS: A significant improvement in favour of the active condition was found on a verbal working memory task (p = .041; adapted Digit Span WISC-III, backward condition). However, it did not survive correction for multiple testing. No significant treatment effect on any of the primary or other secondary outcome measurements was found. The Index-Improvement significantly contributed to ADHD-RS and the Behavior Rating Inventory of Executive Function, both rated by the teacher, but revealed no significant group difference. CONCLUSIONS: This study failed to find robust evidence for benefits of CMWT over the placebo training on behavioural symptoms, neurocognitive, daily executive, and global clinical functioning in young children with ADHD.

Response time variability and response inhibition predict affective problems in adolescent girls, not in boys: the TRAILS study.

The present study examines the relationship between neurocognitive functioning and affective problems through adolescence, in a cross-sectional and longitudinal perspective. Baseline response speed, response speed variability, response inhibition, attentional flexibility and working memory were assessed in a cohort of 2,179 adolescents (age 10-12 years) from the TRacking Adolescents' Individual Lives Survey (TRAILS). Affective problems were measured with the DSM-oriented Affective Problems scale of the Youth Self Report at wave 1 (baseline assessment), wave 2 (after 2.5 years) and wave 3 (after 5 years). Cross-sectionally, baseline response speed, response time variability, response inhibition and working memory were associated with baseline affective problems in girls, but not in boys. Longitudinally, enhanced response time variability predicted affective problems after 2.5 and 5 years in girls, but not in boys. Decreased response inhibition predicted affective problems after 5 years follow-up in girls, and again not in boys. The results are discussed in light of recent insights in gender differences in adolescence and state-trait issues in depression.

Facilitated attentional disengagement from negative information in relation to self-reported depressive symptoms of Dutch female undergraduate students.

Prior research has shown that depressive symptoms are associated with an enhanced attention toward negative stimuli and difficulty of disengaging attention from negative stimuli. The current study was an extension of a 2005 study by Koster and colleagues. A different stimulus presentation time and word set were used. The whole range of depressive symptoms was included in this sample instead of creating dichotomized groups. The Exogenous Cueing Task with negative, positive, and neutral cues was administered to 85 female undergraduate university students. Participants completed the Beck's Depression Inventory-II-NL questionnaire to measure self-reported depression. Contrary to previous findings, depressive symptoms were related to a facilitated rather than impaired attentional disengagement from negative stimuli. An explanation for the discrepancy with findings from Koster, et al. may be the different stimulus presentation time (1000 msec. instead of 500 or 1500 msec.).

Effects of maternal and paternal smoking on attentional control in children with and without ADHD.

Maternal smoking during pregnancy is a risk factor for attention-deficit/hyperactivity disorder (ADHD), but data on its adverse effects on cognitive functioning are sparse and inconsistent. Since the effect of maternal smoking during pregnancy may be due to correlated genetic risk factors rather than being a pure environmental effect, we examined the effect of prenatal exposure to smoking on attentional control, taking into account the effects of both maternal and paternal smoking, and examined whether these effects were genetically mediated by parental genotypes. We further examined whether the effect of prenatal exposure to smoking on attentional control interacted with genotypes of the child. Participants were 79 children with ADHD, ascertained for the International Multi-centre ADHD Gene project (IMAGE), and 105 normal controls. Attentional control was assessed by a visual continuous performance task. Three genetic risk factors for ADHD (DRD4 7-repeat allele of the exon 3 variable number of tandem repeats (VNTR), DAT1 10/10 genotype of the VNTR located in the 3' untranslated region, and the DAT1 6/6 genotype of the intron 8 VNTR) were included in the analyses. Paternal smoking had a negative effect on attentional control in children with ADHD and this effect appeared to be mediated by genetic risk factors. The prenatal smoking effect did not interact with genotypes of the child. Maternal smoking had no main effect on attentional control, which may be due to lower smoking rates. This study suggests that the effects of paternal smoking on attentional control in children with ADHD should be considered a proxy for ADHD and/or smoking risk genes. Future studies should examine if the results can be generalized to other cognitive domains.

The dopamine receptor D4 7-repeat allele and prenatal smoking in ADHD-affected children and their unaffected siblings: no gene-environment interaction.

BACKGROUND: The dopamine receptor D4 (DRD4) 7-repeat allele and maternal smoking during pregnancy are both considered as risk factors in the aetiology of attention deficit hyperactivity disorder (ADHD), but few studies have been conducted on their interactive effects in causing ADHD. The purpose of this study is to examine the gene by environment (GxE) interaction of the DRD4 7-repeat allele and smoking during pregnancy on ADHD and oppositional behavior in families from the International Multicenter ADHD Genetics project; and further, to test the hypothesis that the direction of effect of the DRD4 7-repeat allele differs between ADHD affected and unaffected children. METHODS: Linear mixed models were used to assess main and interactive effects of the DRD4 7-repeat allele and smoking during pregnancy in 539 ADHD-affected children and their 407 unaffected siblings, aged 6-17 years. RESULTS: There was some evidence pointing to differential effects of the DRD4 7-repeat allele on ADHD and oppositional symptoms in the affected (fewer symptoms) and unaffected children (increasing ADHD symptoms of teacher ratings). Affected children were more often exposed to prenatal smoking than unaffected children. There were limited main effects of prenatal smoking on severity of symptoms. Given the number of tests performed, no indication was found for GxE interactions. CONCLUSION: Despite the large sample size, no GxE interactions were found. The impact of the DRD4 7-repeat allele might differ, depending on affected status and rater. This finding is discussed in terms of differences in the activity of the dopaminergic system and of different genes involved in rater-specific behaviors.

Family-genetic study of executive functioning in attention-deficit/hyperactivity disorder: Evidence for an endophenotype?

This study examined familiality of attentional control and mental flexibility in multiplex attention-deficit/hyperactivity disorder (ADHD) families. The authors hypothesized that siblings of ADHD probands, although not behaviorally expressing ADHD, have deficits in these executive functions and that the performance of probands, unaffected siblings, and control participants are on a continuum. Participants (aged 6 to 17) were 25 ADHD probands with a family history of ADHD, their 25 unaffected siblings, and 48 control participants. The unaffected siblings did not differ from the ADHD probands on attentional control or on some measures of mental flexibility. Linear changes in performance across the groups reflected an intermediate position of the unaffected siblings between the probands and control participants. These results suggest that these executive functions may be suitable endophenotypes of ADHD.

fMRI Neurofeedback Training for Increasing Anterior Cingulate Cortex Activation in Adult Attention Deficit Hyperactivity Disorder. An Exploratory Randomized, Single-Blinded Study.

Attention Deficit Hyperactivity Disorder (ADHD) is characterized by poor cognitive control/attention and hypofunctioning of the dorsal anterior cingulate cortex (dACC). In the current study, we investigated for the first time whether real-time fMRI neurofeedback (rt-fMRI) training targeted at increasing activation levels within dACC in adults with ADHD leads to a reduction of clinical symptoms and improved cognitive functioning. An exploratory randomized controlled treatment study with blinding of the participants was conducted. Participants with ADHD (n = 7 in the neurofeedback group, and n = 6 in the control group) attended four weekly MRI training sessions (60-min training time/session), during which they performed a mental calculation task at varying levels of difficulty, in order to learn how to up-regulate dACC activation. Only neurofeedback participants received continuous feedback information on actual brain activation levels within dACC. Before and after the training, ADHD symptoms and relevant cognitive functioning was assessed. Results showed that both groups achieved a significant increase in dACC activation levels over sessions. While there was no significant difference between the neurofeedback and control group in clinical outcome, neurofeedback participants showed stronger improvement on cognitive functioning. The current study demonstrates the general feasibility of the suggested rt-fMRI neurofeedback training approach as a potential novel treatment option for ADHD patients. Due to the study's small sample size, potential clinical benefits need to be further investigated in future studies. TRIAL REGISTRATION: ISRCTN12390961.

Motor flexibility problems as a marker for genetic susceptibility to attention-deficit/hyperactivity disorder.

BACKGROUND: Since many children with attention-deficit/hyperactivity disorder (ADHD) have fine visuomotor problems that are already evident at a young age, motor dysfunctioning is investigated in family-genetic perspective. We hypothesized that if fine motor problems may be a marker for genetic susceptibility to ADHD, nonaffected siblings of ADHD probands would experience motor problems similar to those of their ADHD siblings. METHODS: Twenty-five carefully phenotyped ADHD probands with a family history of ADHD, their nonaffected siblings (n = 25), and 48 normal control subjects (aged 6 to 17) completed a motor fluency task and a motor flexibility task. The motor fluency task involved completion of a familiar, automatized trajectory, whereas the motor flexibility task required continuous adjustment of movement to complete an unpredictable random trajectory. RESULTS: On the motor fluency task, the performance of the nonaffected children was significantly better than that of the ADHD probands; strikingly, on the motor flexibility task, they performed as well as their ADHD siblings. CONCLUSIONS: Nonaffected siblings experience complex motor problems similar to their ADHD siblings but only in nonautomatized movements that require controlled processing. The results suggest that higher-order controlled motor deficits in ADHD may be associated with genetic susceptibility for ADHD.

Familial clustering of executive functioning in affected sibling pair families with ADHD.

OBJECTIVE: To investigate familial clustering of executive functioning (i.e., response inhibition, fine visuomotor functioning, and attentional control) in attention-deficit/hyperactivity disorder (ADHD)-affected sibling pairs. METHOD: Fifty-two affected sibling pairs aged 6 to 18 years and diagnosed with ADHD according to DSM-IV performed the Stroop test, go/no-go task, two different fine visuomotor tracking tasks, and a sustained-, divided-, and focused attention task. RESULTS: Significant correlations (r = 0.4) were found between siblings for response inhibition and attentional control and for fine visuomotor skills that made high demands on executive functioning. CONCLUSIONS: Response inhibition, higher order controlled fine visuomotor functioning, and attentional control seem to cluster in ADHD-affected siblings. This suggests that these aspects of executive dysfunctioning may reflect an endophenotype of ADHD. Measurement of these executive functions may facilitate the identification of genes involved in ADHD by forming more homogeneous subgroups.

Sustained attention and executive functioning performance in attention-deficit/hyperactivity disorder.

The aim of this study was to further refine the cognitive phenotype of attention-deficit/hyperactivity disorder (ADHD), with respect to the ability to sustain attention and executive functioning. Participants were 34 boys with ADHD (combined type) and 28 normal controls. The groups were closely matched for age and IQ. All participants were 12 years of age. Both groups performed a computerized sustained attention task and a response interference task. Measures related to speed, accuracy, and time on task were collected. We found that children with ADHD performed slower, less accurately, more impulsively, and with less stability than controls. Both groups produced more errors with increasing time on task, reflecting reduced vigilance. Importantly, no interaction with time on task was found. The overall pattern of results suggests that measures related to accuracy are more informative than measures related to speed of responding in refining the cognitive phenotype of ADHD.

How the Individual Alpha Peak Frequency Helps Unravel the Neurophysiologic Underpinnings of Behavioral Functioning in Children With Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) has been associated with an elevated resting-state theta/beta power ratio and elevated theta power. However, the potential confounding effect of a low individual alpha peak frequency (IAPF) on the theta-power estimate has often been disregarded when studying the relationship between ADHD and the theta/beta power ratio or theta power alone. The aim of the present study was to assess whether the theta/beta power ratio and relative theta power are correlated with behavioral functioning in children with ADHD, as expected from previous studies. Subsequently, the influence of IAPF and the amount of supposed overlap between the individually determined alpha-band and the fixed theta-band were studied. For 38 children (aged 8-15 years), electroencephalographic (EEG) and investigator-scored ADHD Rating Scale IV data were available. Additional neurocognitive data were available for 32 children. As expected, the theta/beta power ratio and theta were positively related to the ADHD core symptoms. This relationship strengthened when controlling for IAPF, although correlations did not significantly differ from one another. Eight of 38 children (21%) showed a supposed overlap between their individually determined alpha band and the theta band. Neurocognitive performance did not show any relationship with the theta/beta power ratio or theta. The results of this study confirm that the theta/beta power ratio and theta power are indeed correlated with behavioral symptoms in children with ADHD and underscore the relevance of taking the IAPF into account.

Cognitive heterogeneity in adult attention deficit/hyperactivity disorder: A systematic analysis of neuropsychological measurements.

Attention Deficit/Hyperactivity Disorder (ADHD) in childhood is associated with impaired functioning in multiple cognitive domains: executive functioning (EF), reward and timing. Similar impairments have been described for adults with persistent ADHD, but an extensive investigation of neuropsychological functioning in a large sample of adult patients is currently lacking. We systematically examined neuropsychological performance on tasks measuring EF, delay discounting, time estimation and response variability using univariate ANCOVA's comparing patients with persistent ADHD (N=133, 42% male, mean age 36) and healthy adults (N=132, 40% male, mean age 36). In addition, we tested which combination of variables provided the highest accuracy in predicting ADHD diagnosis. We also estimated for each individual the severity of neuropsychological dysfunctioning. Lastly, we investigated potential effects of stimulant medication and a history of comorbid major depressive disorder (MDD) on performance. Compared to healthy adults, patients with ADHD showed impaired EF, were more impulsive, and more variable in responding. However, effect sizes were small to moderate (range: 0.05-0.70) and 11% of patients did not show neuropsychological dysfunctioning. The best fitting model predicting ADHD included measures from distinct cognitive domains (82.1% specificity, 64.9% sensitivity). Furthermore, patients receiving stimulant medication or with a history of MDD were not distinctively impaired. To conclude, while adults with ADHD as a group are impaired on several cognitive domains, the results confirm that adult ADHD is neuropsychologically heterogeneous. This provides a starting point to investigate individual differences in terms of impaired cognitive pathways.

Deficient response inhibition as a cognitive endophenotype of ADHD.

OBJECTIVE: To investigate whether a deficient response inhibition is a cognitive endophenotype of attention-deficit/hyperactivity disorder (ADHD). The authors hypothesized that nonaffected siblings of ADHD probands would have a response inhibition between that of ADHD probands and normal controls, although they resembled the controls at a behavioral level. METHOD: Participants were 25 ADHD probands with a family history of ADHD, their nonaffected siblings (n = 25), and 48 normal controls matched for age and IQ. All participants were between 6 and 17 years of age. The nonaffected siblings were compared with their ADHD siblings and with controls on measures reflecting different types of response inhibition. RESULTS: The nonaffected siblings had results similar to those of the ADHD probands, who differed from the controls on all inhibition measures (p <.05). CONCLUSIONS: Siblings of ADHD probands, while not behaviorally expressing the disorder, have ADHD-associated deficits in response inhibition. This suggests that subtyping based on measures of response inhibition can help identify genetic susceptibility to ADHD. Children with a genetic vulnerability to ADHD may have hidden cognitive deficits in the absence of manifest behavioral symptoms. Therefore, they should be monitored to detect possible learning problems.

What future research should bring to help resolving the debate about the efficacy of EEG-neurofeedback in children with ADHD.

In recent years a rising amount of randomized controlled trials, reviews, and meta-analyses relating to the efficacy of electroencephalographic-neurofeedback (EEG-NF) in children with attention-deficit/hyperactivity disorder (ADHD) have been published. Although clinical reports and open treatment studies suggest EEG-NF to be effective, double blind placebo-controlled studies as well as a rigorous meta-analysis failed to find support for the efficacy of EEG-NF. Since absence of evidence does not equate with evidence of absence, we will outline how future research might overcome the present methodological limitations. To provide conclusive evidence for the presence or absence of the efficacy of EEG-NF in the treatment of ADHD, there is a need to set up a well-designed study that ensures optimal implementation and embedding of the training, and possibly incorporates different forms of neurofeedback.

A randomized placebo-controlled trial of electroencephalographic (EEG) neurofeedback in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: A double-blind, randomized, placebo-controlled study was designed to assess the efficacy and safety of electroencephalographic (EEG) neurofeedback in children with attention-deficit/hyperactivity disorder (ADHD). The study started in August 2008 and ended in July 2012 and was conducted at Karakter Child and Adolescent Psychiatry University Centre in Nijmegen, The Netherlands. METHOD: Forty-one children (aged 8-15 years) with a DSM-IV-TR diagnosis of ADHD were randomly assigned to treatment with either EEG neurofeedback (n = 22) or placebo neurofeedback (n = 19) for 30 sessions, given as 2 sessions per week. The children were stratified by age, electrophysiologic state of arousal, and medication use. Everyone involved in the study, except the neurofeedback therapist and the principal investigator, was blinded to treatment assignment. The primary outcome was severity of ADHD symptoms on the ADHD Rating Scale IV, scored at baseline, during treatment, and at study end. Clinical improvement as measured by the Clinical Global Impressions-Improvement scale (CGI-I) was a secondary outcome. RESULTS: While total ADHD symptoms improved over time in both groups (F1,39 = 26.56, P < .001), there was no significant treatment effect, ie, group × time interaction (F1,39 = 0.36, P = .554); the same was true for clinical improvement as measured by the CGI-I (P = .092). No clinically relevant side effects were observed. Among the children and their parents, guessing treatment assignment was not better than chance level (P = .224 for children, P = .643 for parents). CONCLUSION: EEG neurofeedback was not superior to placebo neurofeedback in improving ADHD symptoms in children with ADHD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00723684.

Grasping motor impairments in autism: not action planning but movement execution is deficient.

Different views on the origin of deficits in action chaining in autism spectrum disorders (ASD) have been posited, ranging from functional impairments in action planning to internal models supporting motor control. Thirty-one children and adolescents with ASD and twenty-nine matched controls participated in a two-choice reach-to-grasp paradigm wherein participants received cueing information indicating either the object location or the required manner of grasping. A similar advantage for location cueing over grip cueing was found in both groups. Both accuracy and reaction times of the ASD group were indistinguishable from the control group. In contrast, movement times of the ASD group were significantly delayed in comparison with controls. These findings suggest that movement execution rather than action planning is deficient in ASD, and that deficits in action chaining derive from impairments in internal action models supporting action execution.

The dopamine receptor D4 7-repeat allele influences neurocognitive functioning, but this effect is moderated by age and ADHD status: an exploratory study.

OBJECTIVES: Evidence suggests the involvement of the dopamine D4 receptor gene (DRD4) in the pathogenesis of ADHD, but the exact mechanism is not well understood. Earlier reports on the effects of DRD4 polymorphisms on neurocognitive and neuroimaging measures are inconsistent. This study investigated the functional consequences of the 7-repeat allele of DRD4 on neurocognitive endophenotypes of ADHD in the Dutch subsample of the International Multicenter ADHD Genetics study. METHODS: Participants were 350 children (5-11.5 years) and adolescents (11.6-19 years) with ADHD and their 195 non-affected siblings. An overall measure of neuropsychological functioning was derived by principal component analysis from five neurocognitive and five motor tasks. The effects of DRD4 and age were examined using Linear Mixed Model analyses. RESULTS: The analyses were stratified for affected and non-affected participants after finding a significant three-way interaction between ADHD status, age and the 7-repeat allele. Apart from a main effect of age, a significant interaction effect of age and DRD4 was found in non-affected but not in affected participants, with non-affected adolescent carriers of the 7-repeat allele showing worse neuropsychological performance. In addition, carrying the 7-repeat allele of DRD4 was related to a significantly worse performance on verbal working memory in non-affected siblings, independent of age. CONCLUSIONS: These results might indicate that the effect of the DRD4 7-repeat allele on neuropsychological functioning is dependent on age and ADHD status.