Alexis C. Wood

Separation of Cognitive Impairments in Attention-Deficit/Hyperactivity Disorder Into 2 Familial Factors

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is associated with widespread cognitive impairments, but it is not known whether the apparent multiple impairments share etiological roots or separate etiological pathways exist. A better understanding of the etiological pathways is important for the development of targeted interventions and for identification of suitable intermediate phenotypes for molecular genetic investigations. OBJECTIVES To determine, by using a multivariate familial factor analysis approach, whether 1 or more familial factors underlie the slow and variable reaction times, impaired response inhibition, and choice impulsivity associated with ADHD. DESIGN An ADHD and control sibling-pair design. SETTING Belgium, Germany, Ireland, Israel, Spain, Switzerland, and the United Kingdom. PARTICIPANTS A total of 1265 participants, aged 6 to 18 years: 464 probands with ADHD and 456 of their siblings (524 with combined-subtype ADHD), and 345 control participants. MAIN OUTCOME MEASURES Performance on a 4-choice reaction time task, a go/no-go inhibition task, and a choice-delay task. RESULTS The final model consisted of 2 familial factors. The larger factor, reflecting 85% of the familial variance of ADHD, captured 98% to 100% of the familial influences on mean reaction time and reaction time variability. The second, smaller factor, reflecting 13% of the familial variance of ADHD, captured 62% to 82% of the familial influences on commission and omission errors on the go/no-go task. Choice impulsivity was excluded in the final model because of poor fit. CONCLUSIONS The findings suggest the existence of 2 familial pathways to cognitive impairments in ADHD and indicate promising cognitive targets for future molecular genetic investigations. The familial distinction between the 2 cognitive impairments is consistent with recent theoretical models--a developmental model and an arousal-attention model--of 2 separable underlying processes in ADHD. Future research that tests the familial model within a developmental framework may inform developmentally sensitive interventions.

Why cognitive performance in ADHD may not reveal true potential: Findings from a large population-based sample

Focusing on symptoms of attention deficit hyperactivity disorder (ADHD) in a sample obtained from the general population, we aimed to investigate the effects of incentives and event rate on reaction time (RT) performance and response inhibition. We assessed 1156 children, at a mean age of 8 years, on their performance on an inhibition task and a RT task under different experimental conditions that manipulated event rate and incentives. Children with high ADHD (ADHD-H) symptoms showed cognitive performance deficits only under some of the experimental conditions compared to a control group. The fast-incentive condition of the RT task succeeded in normalizing the RT variability, as well as the slow overall speed, in the ADHD-H group. Analyses of ADHD symptom scores as a quantitative trait in the total sample were overall consistent with these findings. The findings suggest that at least some cognitive performance deficits in children with high ADHD symptoms do not reflect stable cognitive deficits. The degree to which cognitive impairments in ADHD can be modulated by energetic or motivational factors has important implications for clinical and educational interventions.

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

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

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

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

Is Overactivity a Core Feature in ADHD? Familial and Receiver Operating Characteristic Curve Analysis of Mechanically Assessed Activity Level

OBJECTIVE Symptoms of overactivity form part of the DSM-IV criteria for the combined or hyperactive-impulsive subtypes of attention-deficit/hyperactivity disorder (ADHD); yet little data exist that would quantify the nature of the overactivity component. We aimed to quantify the ability of four different measures of motion sensor data, taken from actigraphs, and the intraindividual variability (IIV) in these measures, to distinguish ADHD cases from controls. Furthermore, we aimed to investigate the degree of shared familial influences on these measures and the ADHD diagnosis. METHOD Receiver operating characteristic analysis and multivariate structural equation modeling were used on actigraph data collected during a cognitive testing session in a sample of 116 ADHD combined-type probands, 119 of their siblings, and 218 control siblings (age range 6-18 years). RESULTS Three measures of actigraph data--the number of movements made, the magnitude of these movements, and the IIV in the magnitude of movement--yielded an area under the curve of up to 0.8, indicating an ability to distinguish between cases and controls. The latter two of these measures showed significant shared familial vulnerability with an ADHD diagnosis, with high ADHD-actigraph familial correlations. CONCLUSIONS The actigraph data support the DSM-IV conceptualization of including overactivity as one of the core features within ADHD combined subtype. The magnitude of movements made, and the IIV of these movements, may be suitable candidates for future molecular genetic studies seeking to identify polymorphisms associated with the risk for ADHD. Further research should investigate if these findings generalize to a more naturalistic, homelike setting.

Rethinking Shared Environment as a Source of Variance Underlying Attention-Deficit/Hyperactivity Disorder Symptoms: Comment on Burt (2009)

Burt (2009) recently published a meta-analysis of twin studies on behaviors associated with childhood psychopathologies, concluding that the finding that traits associated with attention-deficit/hyperactivity disorder (ADHD) were the only behaviors that did not show a significant influence of shared environment (C) was surprising. We agree, highlighting four methodological issues that may account for this finding: (a) the use of nonlinear transformations to normalize skewed data; (b) low power to detect C and the subsequent presentation of reduced models; (c) the negative confounding of dominant genetic (D) and C influences in twin models with data exclusively from monozygotic and dizygotic twin pairs reared together; and (d) the correction used for contrast effects (a form of rater bias), which may lead to an overestimate of additive genetic (A) or D parameters at the expense of C. We offer suggestions for future research to address these issues, and we emphasize the need for additional research to examine possible shared environmental factors related to ADHD.

A genetic study of ADHD and activity level in infancy

It is well known that there are strong genetic influences on attention‐deficit hyperactivity disorder (ADHD), with genetic association studies providing good evidence for the involvement of the dopamine neurotransmitter system in its aetiology. Developmental origins of ADHD represent an interesting area of research to understand the genetics that underlie early appearing individual differences. However, understanding the molecular basis of ADHD requires accurate, unbiased, heritable measures that can be used for molecular genetic association analyses. We take two approaches to examine the genetics of ADHD behaviours in infancy. Using quantitative genetic techniques, we explore the relationship between objective measures of activity level (AL) in both home and laboratory environments as well as with parent ratings of ADHD symptoms in a population sample of 2‐year‐old twins. Molecular association analyses of these measures examine candidate genes previously associated with ADHD. We find that ADHD symptoms, AL in the home and AL in the lab represent heritable phenotypes in 2‐year‐old infants. AL measured in the home has a strong genetic correlation with symptoms of ADHD, whereas AL in the lab correlates only modestly with the same ADHD measure. Genetic correlations suggest that AL in the home is more comparable than AL in the lab to ADHD behaviour and support the separation of all three for molecular analyses. There was modest evidence for association between DAT1, NET1 and ADHD symptom scores, as well as between DAT1 and AL in the lab.

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.

Actigraph data are, reliable, with functional reliability increasing with aggregation

Motion sensor devices such as actigraphs are increasingly used in studies that seek to obtain an objective assessment of activity level. They have many advantages, and are useful additions to research in fields such as sleep assessment, drug efficacy, behavior genetics, and obesity. However, questions still remain over the reliability of data collected using actigraphic assessment. We aimed to apply generalizability theory to actigraph data collected on a large, general-population sample in middle childhood, during 8 cognitive tasks across two body loci, and to examine reliability coefficients on actigraph data aggregated across different numbers of tasks and different numbers of attachment loci. Our analyses show that aggregation greatly increases actigraph data reliability, with reliability coefficients on data collected at one body locus during 1 task (.29) being much lower than that aggregated across data collected on two body loci and during 8 tasks (.66). Further increases in reliability coefficients by aggregating across four loci and 12 tasks were estimated to be modest in prospective analyses, indicating an optimum trade-off between data collection and reliability estimates. We also examined possible instrumental effects on actigraph data and found these to be nonsignificant, further supporting the reliability and validity of actigraph data as a method of activity level assessment.

Inferring Causation from Cross-Sectional Data: Examination of the Causal Relationship between Hyperactivity–Impulsivity and Novelty Seeking

Previous research suggests an association between hyperactivity–impulsivity – one of the two behavioral dimensions that form attention deficit hyperactivity disorder – and the temperament characteristic of novelty seeking. We aimed to examine etiological links underlying the co-occurrence between these behaviors using a general population sample of 668 twin pairs, ages 7–10, for whom we obtained parent ratings in middle childhood; and pilot longitudinal data on 76 children. Structural equation modeling confirmed a shared genetic etiology (genetic correlation, rD = 0.81; 95% confidence intervals = 0.34–1.00) and showed that much (64%) of the covariation can be accounted for by shared genetic effects. In addition, causal paths were modeled between the two behaviors; 12% of the variance in novelty seeking at age 7 was accounted for by hyperactive–impulsive behaviors at the same age. The causal effects model fits with the current characterization of hyperactive–impulsive behaviors reflecting a heightened need for stimulation. This has important implications for the management of hyperactive–impulsive behaviors in clinical settings.