Alysa E. Doyle

Validity of the executive function theory of attention-deficit/ hyperactivity disorder: A meta-analytic review

One of the most prominent neuropsychologic theories of attention-deficit/hyperactivity disorder (ADHD) suggests that its symptoms arise from a primary deficit in executive functions (EF), defined as neurocognitive processes that maintain an appropriate problem-solving set to attain a later goal. To examine the validity of the EF theory, we conducted a meta-analysis of 83 studies that administered EF measures to groups with ADHD (total N = 3734) and without ADHD (N = 2969). Groups with ADHD exhibited significant impairment on all EF tasks. Effect sizes for all measures fell in the medium range (.46-.69), but the strongest and most consistent effects were obtained on measures of response inhibition, vigilance, working memory, and planning. Weaknesses in EF were significant in both clinic-referred and community samples and were not explained by group differences in intelligence, academic achievement, or symptoms of other disorders. ADHD is associated with significant weaknesses in several key EF domains. However, moderate effect sizes and lack of universality of EF deficits among individuals with ADHD suggest that EF weaknesses are neither necessary nor sufficient to cause all cases of ADHD. Difficulties with EF appear to be one important component of the complex neuropsychology of ADHD.

Molecular genetics of attention-deficit/hyperactivity disorder.

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.

Impact of Executive Function Deficits and Attention-Deficit/Hyperactivity Disorder (ADHD) on Academic Outcomes in Children

The association between executive function deficits (EFDs) and functional outcomes were examined among children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants were children and adolescents with (n = 259) and without (n = 222) ADHD, as ascertained from pediatric and psychiatric clinics. The authors defined EFD as at least 2 executive function measures impaired. Significantly more children and adolescents with ADHD had EFDs than did control participants. ADHD with EFDs was associated with an increased risk for grade retention and a decrease in academic achievement relative to (a) ADHD alone, (b) controlled socioeconomic status, (c) learning disabilities, and (d) IQ. No differences were noted in social functioning or psychiatric comorbidity. Children and adolescents with ADHD and EFDs were found to be at high risk for significant impairments in academic functioning. These results support screening children with ADHD for EFDs to prevent academic failure.

Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder

OBJECTIVE Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. METHOD We used data from four projects: a) the Childrens Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. RESULTS No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. CONCLUSIONS Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorders heritability.

Impact of Psychometrically Defined Deficits of Executive Functioning in Adults With Attention Deficit Hyperactivity Disorder

OBJECTIVE The association between deficits in executive functioning and functional outcomes was examined among adults with attention deficit hyperactivity disorder (ADHD). METHOD Subjects were adults who did (N=213) and did not (N=145) meet DSM-IV criteria for ADHD. The authors defined having deficits in executive functioning as having at least two measures of executive functioning with scores 1.5 standard deviations below those of matched comparison subjects. RESULTS Significantly more adults with ADHD had deficits of executive functioning than comparison subjects. Deficits of executive functioning were associated with lower academic achievement, irrespective of ADHD status. Subjects with ADHD with deficits of executive functioning had a significantly lower socioeconomic status and a significant functional morbidity beyond the diagnosis of ADHD alone. CONCLUSIONS Psychometrically defined deficits of executive functioning may help identify a subgroup of adults with ADHD at high risk for occupational and academic underachievement. More efforts are needed to identify cost-effective approaches to screen individuals with ADHD for deficits of executive functioning.

Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder

Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome‐wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome‐wide significant linkage (PSR = 0.00034, POR = 0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes.

Learning disabilities and executive dysfunction in boys with attention-deficit/hyperactivity disorder.

The effect of comorbid reading or arithmetic learning disabilities (LDs) on neuropsychological function in attention-deficit/hyperactivity disorder (ADHD) was studied. Participants were young males diagnosed with ADHD, with and without LD, and non-ADHD, non-LD male controls of similar age. LD was defined by combined regression-based and low-achievement classifications. Analyses adjusted for the effect of psychiatric comorbidity, age, and socioeconomic status on neuropsychological function. Children who had both ADHD and LD were significantly more impaired on both executive and nonexecutive functions than ADHD children without LD. Neuropsychological performance was most impaired in ADHD with combined arithmetic and reading disability. These data indicate that comorbid LD, especially arithmetic disability, significantly increases the severity of executive function impairment in ADHD.

Impact of Gender and Age on Executive Functioning: Do Girls and Boys With and Without Attention Deficit Hyperactivity Disorder Differ Neuropsychologically in Preteen and Teenage Years?

ADHD is known to have neuropsychological correlates, characterized mainly by executive function (EF) deficits. However, most available data are based on studies of boys through age 12. Our goal was to assess whether girls with ADHD express neuropsychological features similar to those found in boys, and whether these impairments are found in both preteen and teen samples. Participants were 101 girls and 103 boys with DSM-–III-–R ADHD, and 109 comparison girls and 70 boys without ADHD, ages 9 to 17 years. Information on neuropsychological performance was obtained in a standardized manner blind to clinical status. Primary regression analyses controlled for age, socioeconomic status, learning disability, and psychiatric comorbidity. Girls and boys with ADHD were significantly more impaired on some measures of EFs than healthy comparisons but did not differ significantly from each other. With the exception of 1 test score there were no significant Sex �× Diagnosis interactions. Moreover, there were no more significant interactions among age, gender, and diagnosis than would be expected by chance. Neuropsychological measures of EFs were comparably impaired in girls compared to boys with ADHD, and these impairments are found at ages 9 to 12 and ages 13 to 17. These findings suggest that executive dysfunctions are correlates of ADHD regardless of gender and age, at least through the late teen years.

Stability of executive function deficits into young adult years: a prospective longitudinal follow-up study of grown up males with ADHD

Objective:  Although individuals with attention deficit‐hyperactivity disorder (ADHD) commonly exhibit deficits in executive functions that greatly increase the morbidity of the disorder, all available information on the subject is cross sectional.

Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis

BACKGROUND Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156. FINDINGS Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohens d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohens d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5). INTERPRETATION With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING National Institutes of Health.