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BackgroundMisconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base.MethodsWe reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder.ResultsWe generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents.ConclusionsMany findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Neuroanatomic heterogeneity limits our understanding of ADHD's etiology. This study aimed to parse heterogeneity of ADHD and to determine whether patient subgroups could be discerned based on subcortical brain volumes.MethodsUsing the large ENIGMA-ADHD Working Group dataset, four subsamples of 993 boys with and without ADHD and to subsamples of 653 adult men, 400 girls, and 447 women were included in analyses. We applied exploratory factor analysis (EFA) to seven subcortical volumes in order to constrain the complexity of the input variables and ensure more stable clustering results. Factor scores derived from the EFA were used to build networks. A community detection (CD) algorithm clustered participants into subgroups based on the networks.ResultsExploratory factor analysis revealed three factors (basal ganglia, limbic system, and thalamus) in boys and men with and without ADHD. Factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, of which one was absent in healthy men. Significant case-control differences of subcortical volumes were observed within communities in boys, often with stronger effect sizes compared to the entire sample. As in the entire sample, none were observed in men. Affected men in two of the communities presented comorbidities more frequently than those in other communities. There were no significant differences in ADHD symptom severity, IQ, and medication use between communities in either boys or men.ConclusionsOur results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case-control differences appear more pronounced at least in some of the subgroups.

Objective: Growing evidence suggests digital interventions may provide neurocognitive benefits for children with ADHD. This study aimed to investigate the efficacy of a digital attention intervention in children with ADHD. Method: In this double-blind randomized controlled trial 55 children with ADHD (5–9 years) were allocated to the intervention (N = 28) or control program (N = 27). Both programs were delivered via touchscreen tablets at home 5 days a week for 5 weeks. The primary outcome was change in the Test of Variables of Attention (TOVA) Attention Comparison Score (ACS) from pre- to post-intervention. Results: Participants who received the intervention had significantly greater improvements in the TOVA ACS from pre- to post-intervention than those in the control (p <.044). No intervention effects were observed on secondary outcomes assessing executive functioning, ADHD symptoms, or functional impairment. Conclusion: Collectively these findings provide insufficient evidence for the implementation of digital attention interventions for children with ADHD. [ABSTRACT FROM AUTHOR]

Background: Despite the known benefits of accurate and timely diagnosis for children with attention-deficit hyperactivity disorder and autism spectrum disorders (autism), for some children this goal is not always achieved. Existing research has explored diagnostic delay for autism and attention-deficit hyperactivity disorder only, and when attention-deficit hyperactivity disorder and autism co-occur, autism has been the focus. No study has directly compared age at diagnosis and diagnostic delay for males and females across attention-deficit hyperactivity disorder, autism and specifically, attention-deficit hyperactivity disorder + autism. Methods: Australian caregivers (N = 677) of children with attention-deficit hyperactivity disorder, autism or attention-deficit hyperactivity disorder + autism were recruited via social media (n = 594) and the Monash Autism and ADHD Genetics and Neurodevelopment Project (n = 83). Caregivers reported on their child's diagnostic process. Diagnostic delay was the mean difference between general initial developmental concerns and the child's attention-deficit hyperactivity disorder and autism diagnosis. Results: Children with autism were significantly younger at autism diagnosis than the attention-deficit hyperactivity disorder + autism group (ηp2 = 0.06), whereas children with attention-deficit hyperactivity disorder were significantly older at attention-deficit hyperactivity disorder diagnosis than the attention-deficit hyperactivity disorder + autism group (ηp2 = 0.01). Delay to attention-deficit hyperactivity disorder and autism diagnosis was significantly longer in the attention-deficit hyperactivity disorder + autism group compared to attention-deficit hyperactivity disorder (ηp2 = 0.02) and autism (η2 = 0.04) only. Delay to autism diagnosis for females with autism (η2 = 0.06) and attention-deficit hyperactivity disorder + autism (η2 = 0.04) was longer compared to males. Conclusions: Having attention-deficit hyperactivity disorder + autism and being female were associated with longer delays to diagnosis. The reasons for these delays and possible adverse effects on outcomes require further study. [ABSTRACT FROM AUTHOR]

Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the willingness to engage in cognitively or physically effortful behavior. However, the degree to which effort sensitivity is impaired in ADHD has rarely been tested, and the efficacy of stimulant medication in ameliorating any such impairments is unclear. Here, we tested 20 individuals with ADHD (11 males, 9 females) who were managed with amphetamine-based medication (dexamfetamine, lisdexamfetamine), and 24 controls (8 males, 16 females). Individuals with ADHD were tested over two counterbalanced sessions, ON and OFF their usual amphetamine-based medication. In each session, participants performed an effortbased decision-making task, in which they were required to choose how much cognitive or physical effort they were willing to engage in return for reward. Our results revealed three main findings. First, individuals with ADHD had lower motivation relative to controls to invest effort in both the cognitive and physical domains. Second, amphetamine increased motivation uniformly across both domains. Finally, the net effect of amphetamine treatment was to mostly restore motivation across both domains of effort relative to healthy controls. These data provide clear evidence for a heightened sensitivity to both cognitive and physical effort in ADHD, and reveal the efficacy of amphetamine-based drugs in restoring effort sensitivity to levels similar to controls. These findings confirm the existence of reduced motivational drive in ADHD, and more broadly provide direct causal evidence for a domain-general role of catecholamines in motivating effortful behavior. [ABSTRACT FROM AUTHOR]

Objective: To investigate the longitudinal associations between COVID-19 induced stress (related to COVID-19 restrictions/changes), attention-deficit/hyperactivity disorder (ADHD) symptoms, oppositional symptoms, and mental health outcomes (negative affect, anxiety, depression, and irritability) in children with ADHD during the COVID-19 pandemic. Method: Parents of 140 Australian children with ADHD (aged 5–17 years) completed an online survey in May 2020 during stay-at-home restrictions and 12-months later. Results: Baseline COVID-19 stress was associated with increased total ADHD symptom severity (β =.21, p =.007) and hyperactivity/impulsivity symptoms (β =.23, p =.002) at 12-months, after accounting for covariates (i.e., child age, gender, ADHD medication, socio-economic status, and baseline symptoms). Despite some indication of associations between baseline COVID-19 stress and 12-month oppositional symptoms and negative affect, these were attenuated when adjusting for baseline symptoms. Conclusions: The study provides initial evidence of the medium-term impacts of pandemic-related stress for children with ADHD. [ABSTRACT FROM AUTHOR]

Objective: Previous studies at child and youth mental health services (CYMHS) suggest that children with ADHD have poorer outcomes compared to those with other diagnoses. This study investigates this in more detail. Methods: Children with ADHD were compared to those with ASD and those with emotional disorders, on routinely collected outcomes at CYMHS in Australia (N = 2,513) and the Netherlands (N = 844). Results: Where the emotional disorders group reached a similar level of emotional symptoms at the end-of-treatment as the ADHD and ASD groups, the latter two groups still had higher scores on ADHD and ASD symptoms (attention and peer problems). The poorer outcomes were mainly explained by higher severity at baseline. In Australia, an ADHD and/or ASD diagnosis also independently contributed to worse outcomes. Conclusion: Those with neurodevelopmental disorders within both countries had poorer outcomes than those with emotional disorders. Services should aim to optimize treatment to ensure best possible outcomes. [ABSTRACT FROM AUTHOR]

Difficulty with sustaining attention to a task is a hallmark of ADHD. It would be useful to know which measures of sustained attention best predict a diagnosis of ADHD. Participants were 129 children with a diagnosis of ADHD and 129 matched controls who completed the fixed Sustained Attention to Response Task (SART). The number of commission and omission errors, standard deviation of response time (SDRT), tau, fast and slow frequency variability, d-prime, and mu were able to successfully classify children with and without ADHD. The mean response time, criterion, and sigma were not able to classify participants. The best classifiers were d-prime (0.75 Area Under the Receiver Operated Characteristic), tau (.74), SDRT (0.74), omission errors (0.72), commission errors (0.71), and SFAUS (0.70). This list of the best classifier measures derived from the SART may prove useful for the planning of future studies. [ABSTRACT FROM AUTHOR]

Objectives: Attention deficit hyperactivity disorder (ADHD) frequently co-occurs with other neurodevelopmental diagnoses, such as autism spectrum disorder (autism), which can make clinical decision making around symptom management challenging for clinicians. There is a paucity of research examining pharmacotherapeutic management of children who have ADHD with co-occurring diagnoses. We aimed to report on the co-occurring diagnoses and symptom profile of children, and report on medication use, stratified by ADHD, autism and ADHD + autism diagnoses. Methods and Materials: Caregivers of 505 children (2-18 years) with ADHD (n = 239), autism (n = 117), and co-occurring ADHD + autism (n = 149) completed a questionnaire on current medication use and clinical rating scales about their child's symptoms, as part of a broader project investigating diagnosis and management of symptoms in children with ADHD or autism. Results: The parents of the ADHD group reported a higher proportion of their children had learning disorders (17.15%) and speech and language disorders (4.60%) compared to the parents of the autism and ADHD + autism groups. Parents of the ADHD + autism group reported higher proportions of intellectual disability (5.37%), oppositional defiant disorder (20.13%), anxiety (38.93%), depression (6.71%) and genetic conditions (3.36%) in their children, in comparison to the parents of the ADHD and autism groups. Children with ADHD were reported to be taking a higher proportion of psychotropic medication (90%), followed by ADHD + autism (86%) and autism (39%). The parents of children with ADHD + autism reported a higher proportion of non-stimulant ADHD medication (25.5%), antipsychotic (18.79%), antidepressant (22.15%) and melatonin (31.54%) use by their children, compared to the parents of the ADHD and autism groups. Conclusions: A similar proportion of children with ADHD + autism and ADHD were reported to be taking medication. However, the types of medication taken were different, as expected with reported co-occurring diagnoses. The complexity of symptoms and diagnoses in ADHD + autism warrants targeted research to optimize management and therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Objective: This review aimed to understand the broader community's attitudes toward ADHD, which could facilitate public health interventions to improve outcomes for individuals with ADHD. Methods: A standardized protocol identified peer-reviewed studies focusing on attitudes of broader community samples, published from January 2014 to February 2020 (inclusive). Results: A total of 1,318 articles were screened and 10 studies were included, examining attitudes of broader community samples from Australia, Sweden, Germany, Finland, Korea, Indonesia, and the United States. Findings revealed that broader community samples displayed varying degrees of ADHD-related knowledge, negative attitudes (that ADHD is over-diagnosed; that pharmacological treatment is not acceptable; that those with ADHD are more likely to exhibit poor behavior), and a desire for maintaining social distance from individuals with ADHD. Conclusion: Findings suggest that community attitudes are generally negative toward those with ADHD. Targeted mental health literacy could provide an important avenue for improving the broader community's attitudes toward those with ADHD. [ABSTRACT FROM AUTHOR]

Objective: To examine the impact of COVID-19 restrictions among children with attention-deficit/hyperactivity disorder (ADHD). Methods: Parents of 213 Australian children (5–17 years) with ADHD completed a survey in May 2020 when COVID-19 restrictions were in place (i.e., requiring citizens to stay at home except for essential reasons). Results: Compared to pre-pandemic, children had less exercise (Odds Ratio (OR) = 0.4; 95% CI 0.3–0.6), less outdoor time (OR = 0.4; 95% 0.3–0.6), and less enjoyment in activities (OR = 6.5; 95% CI 4.0–10.4), while television (OR = 4.0; 95% CI 2.5–6.5), social media (OR = 2.4; 95% CI 1.3–4.5), gaming (OR = 2.0; 95% CI 1.3–3.0), sad/depressed mood (OR = 1.8; 95% CI 1.2–2.8), and loneliness (OR = 3.6; 95% CI 2.3–5.5) were increased. Child stress about COVID-19 restrictions was associated with poorer functioning across most domains. Most parents (64%) reported positive changes for their child including more family time. Conclusions: COVID-19 restrictions were associated with both negative and positive impacts among children with ADHD. [ABSTRACT FROM AUTHOR]

Objective: To determine the financial and non-financial costs of Attention-Deficit/Hyperactivity Disorder (ADHD) across the lifespan. Method: The population costs of ADHD in Australia were estimated for the financial year 2018 to 2019 using a prevalence approach to cost estimation across all ages. Financial (healthcare, productivity, education and justice systems, and deadweight losses) and non-financial costs were measured (Disability Adjusted Life Years (DALYs)). Results: The total social and economic cost of ADHD in 2018 to 2019 were US$12.76 billion (range US$8.40 billion to US$17.44 billion, with per person costs of US$15,664 per year). Productivity costs made up 81% of the total financial costs, followed by deadweight losses (11%), and health system costs (4%). Loss in terms of wellbeing was significant (US$5.31 billion). Conclusion: There is a need to raise public awareness of the considerable socioeconomic impact and burden of ADHD in order to drive investment and policy decisions that improve identification and treatment of ADHD. [ABSTRACT FROM AUTHOR]

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA‐ADHD and ENIGMA‐ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA‐ADHD and ‐ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case–control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case–control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow‐up analyses continue that include more imaging modalities (diffusion MRI and resting‐state functional MRI), collaborations with other large databases, and samples with dual diagnoses. [ABSTRACT FROM AUTHOR]

Objective: We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. Methods: The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Results: Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Conclusion: Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1. [ABSTRACT FROM AUTHOR]

Executive Function (EF) and Effortful Control (EC) have traditionally been viewed as distinct constructs related to cognition and temperament during development. More recently, EF and EC have been implicated in top‐down self‐regulation ‐ the goal‐directed control of cognition, emotion, and behavior. We propose that executive attention, a limited‐capacity attentional resource subserving goal‐directed cognition and behavior, is the common cognitive mechanism underlying the self‐regulatory capacities captured by EF and EC. We addressed three related questions: (a) Do behavioral ratings of EF and EC represent the same self‐regulation construct? (b) Is this self‐regulation construct explained by a common executive attention factor as measured by performance on cognitive tasks? and (c) Does the executive attention factor explain additional variance in attention deficit hyperactivity disorder (ADHD) problems to behavioral ratings of self‐regulation? Measures of performance on complex span, general intelligence, and response inhibition tasks were obtained from 136 preadolescent children (M = 11 years, 10 months, SD = 8 months), along with self‐ and parent‐reported EC, and parent‐reported EF, and ADHD problems. Results from structural equation modeling demonstrated that behavioral ratings of EF and EC measured the same self‐regulation construct. Cognitive tasks measured a common executive attention factor that significantly explained 30% of the variance in behavioral ratings of self‐regulation. Executive attention failed to significantly explain additional variance in ADHD problems beyond that explained by behavioral ratings of self‐regulation. These findings raise questions about the utility of task‐based cognitive measures in research and clinical assessment of self‐regulation and psychopathology in developmental samples. [ABSTRACT FROM AUTHOR]

We examined the effect of a single dose of methylphenidate (MPH) on whole brain functional connectivity, assessed using resting state functional MRI (rsfMRI), in young people with ADHD. 16 young people with ADHD participated in two rsfMRI scans in a randomized, placebo-controlled study with an acute dose of MPH (20 mg). 15 typically developing controls also performed the task under placebo conditions. The network-based statistic (NBS) was used to identify differential connectivity patterns between the MPH and placebo conditions in the ADHD group. Mean connectivity of the resulting sub-network was examined in the ADHD and control groups. Resting state functional connectivity (RSFC) analysis revealed significantly reduced connectivity under MPH compared to placebo in young people with ADHD. Findings were robust across a range of thresholds. No sub-networks of increased connectivity were found at any threshold. Mean connectivity of the identified sub-network was significantly higher in ADHD individuals in the placebo condition compared to controls, however there was no difference between MPH condition and controls. We demonstrated a significant MPH-related reduction in RSFC in a large, robust network primarily involving occipital, temporal and cerebellar regions, and visual, executive and default mode networks. These findings suggest that MPH is 'normalising' a higher RSFC in young people with ADHD. This study is a novel addition to the understanding of treatment effects on the brain in ADHD. [ABSTRACT FROM AUTHOR]

Abstract: Converging evidence suggests that right-hemisphere dominant spatial attention systems can be modulated by non-spatial processes such as attentional capacity. The severity of neglect in right-hemisphere stroke patients for example, is correlated with impairments in non-lateralized attention. Evidence also suggests the coexistence of lateralized inattention and reduced capacity in developmental disorders of attention, such as attention deficit hyperactivity disorder (ADHD), which is marked by cognitive impairments suggestive of right hemisphere dysfunction. These lines of evidence argue against a coincident damage hypothesis and suggest instead a direct modulation of spatial attention by non-spatial processes. Here we sought experimental evidence for this relationship in both acquired and developmental disorders of attention. Six adult stroke patients with focal right brain injury and 19 children with ADHD were studied in comparison to control groups of both healthy older adults and typically developing children. The participants were required to detect transient, unilateral visual targets while simultaneously monitoring a stream of alphanumeric characters at fixation. Load at fixation was manipulated by asking participants either to ignore the central stream and focus on the peripheral detection task (no report condition), or to monitor the central stream for a probe item that was defined by either a unique feature (low load condition) or a conjunction of features (high load condition). As expected, in all participants greater load at fixation slowed responses to peripheral targets. Crucially, in right brain injured patients but not older healthy adults left target detection was slowed significantly more than central and right target detection. A qualitatively similar pattern was seen in children with ADHD, but not in typically developing children. The imposition of load at fixation slowed responses to left compared with right targets, and this response time asymmetry was correlated with the severity of ADHD symptoms. These results suggest that a direct manipulation of non-spatial attention can reveal lateralised attention deficits in both acquired and developmental forms of inattention. Our findings support the view that spatial attention networks are tightly integrated with non-lateralized aspects of attention. [Copyright &y& Elsevier]

Pharmacological evidence suggests the importance of noradrenergic and other monoaminergic neurotransmitters in the aetiology and treatment of attention deficit hyperactivity disorder (ADHD). Until recently, the genes of the noradrenergic pathway were not intensively investigated in ADHD compared to dopaminergic and serotonergic candidates. In this study, 91 SNP markers of 14 noradrenergic genes (an average density of one SNP per 4.5 kbp) were examined in ADHD samples from Ireland and Australia. Although suggestive evidence of association (nominal p ≤ 0.05) with the genes SLC6A2, ADRA1A, ADRA1B and ADRA2B was observed, none remained significant after permutation adjustments. In contrast, haplotype analyses demonstrated a significant association between ADHD and a SLC6A2 haplotype comprising the markers rs36009, rs1800887, rs8049681, rs2242447 and rs9930182 (χ = 9.39, p-corrected = 0.019, OR = 1.51). A rare ADRA1B haplotype made of six SNPs (rs2030373, rs6884105, rs756275, rs6892282, rs6888306 and rs13162302) was also associated (χ = 7.79, p-corrected = 0.042 OR = 2.74) with the disorder. These findings provide evidence of a contribution of the noradrenaline system to the genetic aetiology of ADHD. The observed haplotype association signals may be driven by as yet unidentified functional risk variants in or around the associated regions. Functional genomic analysis is warranted to determine the biological mechanism of the observed association. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate a possible association between norepinephrine genes and cardiovascular side effects of the Osmotic Controlled-Release Oral Delivery System–methylphenidate (OROS-MPH) in Korean children with attention-deficit/hyperactivity disorder (ADHD). One hundred and one children with ADHD (8.7 ± 1.7 years) were recruited from child psychiatric centers at six university hospitals in South Korea. All participants were drug-naive ADHD children treated with OROS-MPH for 12 weeks. During the treatment period the investigators titrated the OROS-MPH dosage on the basis of symptom severity and side effects. Resting heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were examined before and after treatment. The percentage change score (post-treatment – pretreatment/pretreatment × 100) of each parameter was calculated. Genotyping of SLC6A2 −3081(A/T) and G1287A, and alpha-2A-adrenergic receptor (ADRA2A) MspI and DraI polymorphisms was performed. Clinically significant changes were not found in cardiovascular monitoring during the course of treatment. An increase of HR after OROS-MPH treatment was found to be statistically significant (t = 3.54, p = 0.001). Changes in SBP and DBP were not significant and no specific change was found in the ECGs. However, an additive regression analysis demonstrated a significant association between SLC6A2 −3081(A/T) and percentage change in HR post-treatment (p = 0.01) after controlling for age, gender, dosage of MPH and response and baseline pulse rate. Children with ADHD having the T/T genotype of SLC6A2 showed a 12.5% increase in HR compared to baseline, whereas children with the A/T or A/A genotype showed a 3.5% and 2.5% increase after OROS-MPH treatment, respectively. There was also a significant association between the ADRA2A MspI genotype and percentage change of DBP post-treatment after controlling for age, gender, dosage of MPH and response and baseline DBP (p = 0.009). Children with ADHD having the C/C genotype of ADRA2A MspI showed an 18.5% increase in DBP compared to baseline, but children with the G/G or G/C genotype showed a 0.2% decrease after OROS-MPH treatment. The overall cardiovascular effects of OROS-MPH were modest. However, our findings show a positive association between norepinephrine-related gene polymorphisms and cardiovascular response induced by MPH in Korean children with ADHD. Consideration must be given to such children oradults with specific norepinephrine-related genotypes, especially if they show significant changes in HR or DBP after OROS-MPH administration. [ABSTRACT FROM PUBLISHER]

A number of genes with function related to synaptic neurochemistry have been genetically associated with attention deficit/hyperactivity disorder. However, susceptibility to the development of common psychiatric disorders by single variants acting alone, can so far only explain a small proportion of the heritability of the phenotype. It has been postulated that the unexplained 'dark heritability' may at least in part be due to epistatic effects, which may account for the small observed marginal associations, and the difficulties with replication of positive findings. We undertook a comprehensive exploration of pair-wise interactions between genetic variants in 24 candidate genic regions involved in monoaminergic catabolism, anabolism, release, re-uptake and signal transmission in a sample of 177 parent-affected child trios using a case-only design and a case-pseudocontrol design using conditional logistic regression. Marker-pairs thresholded on interaction odds ratio (OR) and P-value are presented. We detected a number of interaction ORs >4.0, including an interesting correlation between markers in the ADRA1B and DBH genes in affected individuals, and several further interesting but smaller effects. These effects are no larger than you would expect by chance under the assumption of independence of all pair-wise relations; however, independence is unlikely. Furthermore, the size of these effects is of interest and attempts to replicate these results in other samples are anticipated. [ABSTRACT FROM AUTHOR]

Background: Evidence for a selective attention abnormality in children with attention deficit hyperactivity disorder (ADHD) has been hard to identify using conventional methods from cognitive science. This study tested whether the presence of selective attention abnormalities in ADHD may vary as a function of perceptual load and target lateralisation. Given evidence of right-hemisphere dysfunction in ADHD we predicted increased interference effects for right, but not left-sided target displays, particularly under low perceptual load. Method: Fourteen children with ADHD-C and 14 typically developing children were tested on a modified flanker task under low and high perceptual load. We also sought evidence for our hypothesis in a re-analysis of an independent data set (42 ADHD; 34 typically developing) in which load effects on selective attention in ADHD were previously examined (Huang-Pollock, Nigg, & Carr, 2005). Results: As predicted, all children showed evidence of greater interference by flankers under low compared with high perceptual load conditions. Crucially, however, children with ADHD showed the greatest interference effect for right-sided target displays under low but not high perceptual load. In contrast, typically developing children showed the greatest interference for left-sided target displays. The magnitude of interference for right-sided targets was also positively correlated with ADHD symptom levels. Re-analysis of an independent data set ( Huang-Pollock et al., 2005 ) further confirmed our findings. Conclusions: This study demonstrates that interference effects in children with ADHD and typically developing children are spatially asymmetrical but opposite in direction. The pattern of right-sided interference effects in children with ADHD suggests disruption within right hemisphere attentional networks in ADHD. [ABSTRACT FROM AUTHOR]

Abstract: The ability to detect and correct errors is critical to adaptive control of behaviour and represents a discrete neuropsychological function. A number of studies have highlighted that attention-deficit hyperactivity disorder (ADHD) is associated with abnormalities in behavioural and neural responsiveness to performance errors. One limitation of previous work has been a failure to determine the extent to which these differences are attributable to failures of conscious error awareness, a process that is dependent on the integrity of the frontal lobes. Recent advances in electrophysiological research make it possible to distinguish unconscious and conscious aspects of error processing. This study constitutes an extensive electrophysiological investigation of error awareness and error processing in ADHD. A Go/No-Go response inhibition task specifically designed to assess error awareness was administered to a group of adults diagnosed with ADHD and a group of matched control participants. The ADHD group made significantly more errors than the control group but was less likely to consciously detect these errors. An analysis of event-related potentials elicited by errors indicated that an early performance monitoring component (early positivity) was significantly attenuated in the ADHD group as was a later component that specifically reflects conscious error processing (Pe). Dipole source modelling suggested that abnormal Pe amplitudes were attributable to decreased activation of the anterior cingulate cortex. Decreased electrodermal activity in the ADHD group also suggested a motivational insensitivity to performance errors. Our data provide evidence that neuropsychological deficits associated with ADHD can be exacerbated by error processing abnormalities. Error awareness may represent an important cognitive and physiological phenotype for ADHD. [Copyright &y& Elsevier]

The sequencing of the human genome and the identification of a vast array of DNA polymorphisms has afforded cognitive scientists with the opportunity to interrogate the genetic basis of cognition with renewed vigor. The extant literature on the molecular genetics of sustained and spatial attention is reviewed herein. Advances in our understanding of the neural substrates of sustained and spatial attention arising from the cognitive neurosciences can help guide putative linkages in cognitive genetics. In line with catecholamine models of sustained attention, associations have been reported between sustained attention and allelic variation in the dopamine beta hydroxylase gene (DBH), the dopamine D2 and D4 receptor genes (DRD2; DRD4) and the dopamine transporter gene (DAT1). Much evidence implicates the cholinergic system in spatial attention. Accordingly, individual differences in spatial attention have been associated with variation in an alpha-4 cholinergic receptor gene (CHRNA4). APOE-ℇ4 allele dosage has been shown to influence the speed of attentional reorienting in independent samples of nonaffected individuals. Preliminary evidence in both healthy children and children with attention deficit hyperactivity disorder (ADHD) suggests and association with variants of the DAT1 gene and the control of spatial attention across the hemifields. With the recent development of high-throughput genotyping techniques, such as microarrays, the time seems ripe for a genomewide association study that can identify quantitative trait loci (QTLs) for sustained and spatial attention. The identification of QTLs for attention will provide a range of novel candidate genes for disorders of attention, such as ADHD and schizophrenia, and will drive cognitive neuroscientists to understand how DNA variation influences the neural substrates of attention. [ABSTRACT FROM AUTHOR]

Background: Dopamine beta hydroxylase (DβH) catalyzes the conversion of dopamine to noradrenaline. Attention-deficit/hyperactivity disorder (ADHD) has been associated with the A2 allele of a Taq I polymorphism of the DBH gene. Since catecholamines regulate visual attention, we examined whether participants with ADHD were impaired on a task requiring temporal attention and how DBH genotype influenced temporal attention in ADHD. Methods: Thirty-seven children and adolescents with ADHD and 52 matched, normal control subjects participated. Participants were presented with two visual stimuli, separated in time by either 50, 100, or 200 milliseconds, and were asked to judge the temporal order of their onset. Genotypes for the Taq 1 polymorphism were available for 33 of the ADHD participants. Results: Attention-deficit/hyperactivity disorder participants were more error prone than control subjects, particularly when stimuli were presented close together in time (i.e., at the 50 milliseconds asynchrony). Moreover, ADHD individuals homozygous for the A2 allele performed more poorly than those without this allele, and this difference was accentuated at the 50 milliseconds asynchrony. Conclusions: Attention-deficit/hyperactivity disorder participants have an impaired rate of perceptual processing for rapidly presented visual events. Deficits in the temporal resolution of visual attention in ADHD are associated with the A2 allele of the Taq I DBH polymorphism or another variant with which it is in linkage disequilibrium. [Copyright &y& Elsevier]

A polymorphism of the dopamine transporter gene (DAT1, 10-repeat) is associated with attention-deficit hyperactivity disorder (ADHD) and has been linked to an enhanced response to methylphenidate (MPH). One aspect of the attention deficit in ADHD includes a subtle inattention to left space, resembling that seen after right cerebral hemisphere damage. Since left-sided inattention in ADHD may resolve when treated with MPH, we asked whether left-sided inattention in ADHD was related to DAT1 genotype and the therapeutic efficacy of MPH. A total of 43 ADHD children and their parents were genotyped for the DAT1 3′ variable number of tandem repeats polymorphism. The children performed the Landmark Test, a well-validated measure yielding a spatial attentional asymmetry index (leftward to rightward attentional bias). Parents rated their child's response to MPH retrospectively using a three-point scale (no, mediocre or very good response). Additionally, parents used a symptom checklist to rate behavior while on and off medication. A within-family control design determined whether asymmetry indices predicted biased transmission of 10-repeat parental DAT1 alleles and/or response to MPH. It was found that left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. Our results suggest a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention. MPH may be most efficacious in this group because it ameliorates a DAT1-mediated hypodopaminergic state.Neuropsychopharmacology (2005) 30, 2290–2297. doi:10.1038/sj.npp.1300839; published online 3 August 2005 [ABSTRACT FROM AUTHOR]

Abstract: ADHD is a childhood-onset behavioural disorder with a heterogeneous profile of neuropsychological impairment. Neuropsychological heterogeneity may, in part, reflect underlying genetic differences. Here we examined sustained attention, response variability and spatial attentional asymmetries in a sample of children and adolescents with ADHD (n =22) in relation to dopamine transporter genotype (DAT1) and also controls (n =20). Participants performed the sustained attention to response task (SART) (testing sustained attention and response variability) and the greyscales task (a perceptual measure of attentional bias). The latter has previously been shown to yield a robust leftward attentional asymmetry in healthy subjects. The 10-repeat allele of the DAT1 gene has been associated with ADHD in a number of studies and appears to have biological significance. The ADHD group was sub-divided into those individuals with two copies of the “high-risk” 10-repeat allele (high-risk DAT1) versus those with one or no copies of this allele (low-risk DAT1). The high-risk DAT1 ADHD group displayed greater response variability on the SART than either the low-risk DAT1 group or healthy controls, whereas the latter two groups did not differ. Further, the high-risk DAT1 group showed an attenuated spatial asymmetry, relative to the low-risk DAT1 ADHD group, who showed the typical leftward attentional asymmetry. Our results suggest that the 10-repeat DAT1 allele may mediate neuropsychological impairment in ADHD. The application of molecular genetics may help to define neuropsychological impaired subgroups of ADHD. [Copyright &y& Elsevier]

Abstract: Increased variability in reaction time (RT) has been proposed as a cardinal feature of attention deficit hyperactivity disorder (ADHD). Increased variability during sustained attention tasks may reflect inefficient fronto-striatal and fronto-parietal circuitry; activity within these circuits is modulated by the catecholamines. A disruption to dopamine signaling is suggested in ADHD that may be ameliorated by methylphenidate (MPH). This study investigated the effects of MPH administration on the variability in RT and error performance on a sustained attention task of a group of 31 medication naïve children with ADHD, compared with 22 non-ADHD, non-medicated, control children. All children performed the fixed-sequence sustained attention to response task (SART) at two time-points: at baseline and after six weeks. The children with ADHD were tested when medication naive at baseline and after six weeks of treatment with MPH and whilst on medication. The medication naïve children with ADHD performed the SART with greater errors of commission and omission when compared with the control group. They demonstrated greater standard deviation of RT and fast moment-to-moment variability. They did not differ significantly from the control group in terms of slow variability in RT. MPH administration resulted in reduced and normalised levels of commission errors and fast, moment-to-moment variability in RT. MPH did not affect the rate of omission errors, standard deviation of RT or slow frequency variability in RT. MPH administration may have a specific effect on those performance components that reflect sustained attention and top–down control rather than arousal. [Copyright &y& Elsevier]

• We evaluated saccade, pursuit and fixation ocular motor profiles in ADHD. • Key difficulties relating to saccade inhibition were identified for ADHD. • Other difficulties related to memorizing visual target locations and initiating antisaccades. • These findings highlight potential ocular motor biomarkers for ADHD. Atypical motor coordination and cognitive processes, such as response inhibition and working memory, have been extensively researched in individuals with attention deficit hyperactivity disorder (ADHD). Oculomotor neural circuits overlap extensively with regions involved in motor planning and cognition, therefore studies of oculomotor function may offer unique insights into motor and cognitive control in ADHD. We performed a series of pairwise meta-analyses based on data from 26 oculomotor studies in ADHD to examine whether there were differences in performance on visually-guided saccade, gap, antisaccade, memory-guided, pursuit eye movements and fixation tasks. These analyses revealed oculomotor disturbances in ADHD, particularly for difficulties relating to saccade inhibition, memorizing visual target locations and initiating antisaccades. There was no evidence for pursuit eye movement disturbances or saccade dysmetria. Investigating oculomotor abnormalities in ADHD may provide insight into top-down cognitive control processes and motor control, and may serve as a promising biomarker in ADHD research and clinical practice. [ABSTRACT FROM AUTHOR]

• ADHD occurs in 5.9 % of youth and 2.5 % of adults. • Most cases of ADHD are caused by the combined effects of many genetic and environmental risks. • There are small differences in the brain between people with and without ADHD. • Untreated ADHD can lead to many adverse outcomes. • ADHD costs society hundreds of billions of dollars each year, worldwide. Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma. [ABSTRACT FROM AUTHOR]

Abstract: Atypical asymmetries of spatial attention have been reported in children with attention deficit hyperactivity disorder (ADHD) and may be exacerbated by non-spatial factors such as attentional capacity. Although preliminary evidence suggests that asymmetries of attention in ADHD may be modifiable by the psychostimulant, methylphenidate, further placebo-controlled studies are required. This study first aimed to confirm recent evidence that increasing non-spatial processing load at fixation can unmask a spatial gradient of target detection in children with ADHD but not Controls. Second, we used placebo-controlled randomised trial methodology to ask whether 20mg of methylphenidate (MPH) could remediate any load-dependent asymmetry of spatial attention in adolescents with ADHD. Twelve male adolescents with ADHD were assessed twice in a double-blind, randomized design, under either placebo or an acute dose of methylphenidate. Thirteen typically developing adolescent Controls completed a single session under placebo. Participants completed a computer-based task in which they monitored a centrally presented rapid serial visual presentation stream for a probe stimulus, while also responding to brief peripheral events. The attentional load of the central task was manipulated by varying the target instructions but not the physical stimuli or the frequency of targets. Between-group analyses under placebo conditions indicated that increased attentional load induced a spatial gradient for target detection in the ADHD but not Controls, such that load slowed response times for left, but not, right hemi-field targets. This load-dependent spatial asymmetry in the adolescents with ADHD was abolished by administration of methylphenidate. Methylphenidate may “normalise” target detection between the hemi-fields in ADHD via enhancement of the right-lateralised ventral attention networks that support non-spatial attention. [Copyright &y& Elsevier]

Abstract: The DAT1 gene codes for the dopamine transporter, which clears dopamine from the synaptic cleft, and a variant of this gene has previously been associated with compromised response inhibition in both healthy and clinical populations. This variant has also been associated with ADHD, a disorder that is characterised by disturbed dopamine function as well as problems with response inhibition. In the present study we used fMRI to investigate the role of dopaminergic genetic variation on executive functioning by comparing how activation associated with successful and unsuccessful inhibitions differs based on DAT1-genotype and ADHD-diagnosis in adolescents performing a go/nogo task. The results identify regional specificity concerning which functional differences can be attributed to the possession of the high risk DAT1 genotype, the clinical condition or an interaction between the two. During response inhibition, individuals with two copies of the 10-repeat allele showed increased activation in frontal, medial, and parietal regions, which may indicate that inhibition is more effortful for this group. Conversely, this group displayed a reduced error response in the parahippocampal gyrus, suggestive of reduced learning from errors. There were also a number of frontal, parietal, medial and occipital regions, where the relationship between genotype and fMRI-activation differed between the ADHD group and the typically developing adolescents. Finally, the ADHD group displayed decreased activation in parietal and (pre)frontal regions during response inhibition, and in frontal and medial brain regions on error trials. [Copyright &y& Elsevier]