Parsing heterogeneity in attention-deficit hyperactivity disorder using EEG-based subgroups.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous condition for which multiple efforts to characterize brain state differences are underway. The objective of this study was to identify distinct subgroups of resting electroencephalography (EEG) profiles among children with and without ADHD and subsequently provide extensive clinical characterization of the subgroups. METHODS: Latent class analysis was used with resting state EEG recorded from a large sample of 781 children with and without ADHD (N = 620 ADHD, N = 161 Control), aged 6-18 years old. Behavioral and cognitive characteristics of the latent classes were derived from semistructured diagnostic interviews, parent completed behavior rating scales, and cognitive test performance. RESULTS: A five-class solution was the best fit for the data, of which four classes had a defining spectral power elevation. The distribution of ADHD and control subjects was similar across classes suggesting there is no one resting state EEG profile for children with or without ADHD. Specific latent classes demonstrated distinct behavioral and cognitive profiles. Those with elevated slow-wave activity (i.e. delta and theta band) had higher levels of externalizing behaviors and cognitive deficits. Latent subgroups with elevated alpha and beta power had higher levels of internalizing behaviors, emotion dysregulation, and intact cognitive functioning. CONCLUSIONS: There is population-level heterogeneity in resting state EEG subgroups, which are associated with distinct behavioral and cognitive profiles. EEG measures may be more useful biomarkers of ADHD outcome or treatment response rather than diagnosis.

On genome-wide association studies for family-based designs: an integrative analysis approach combining ascertained family samples with unselected controls.

Large numbers of control individuals with genome-wide genotype data are now available through various databases. These controls are regularly used in case-control genome-wide association studies (GWAS) to increase the statistical power. Controls are often "unselected" for the disease of interest and are not matched to cases in terms of confounding factors, making the studies more vulnerable to confounding as a result of population stratification. In this communication, we demonstrate that family-based designs can integrate unselected controls from other studies into the analysis without compromising the robustness of family-based designs against genetic confounding. The result is a hybrid case-control family-based analysis that achieves higher power levels than population-based studies with the same number of cases and controls. This strategy is widely applicable and works ideally for all situations in which both family and case-control data are available. The approach consists of three steps. First, we perform a standard family-based association test that does not utilize the between-family component. Second, we use the between-family information in conjunction with the genotypes from unselected controls in a Cochran-Armitage trend test. The p values from this step are then calculated by rank ordering the individual Cochran-Armitage trend test statistics for the genotype markers. Third, we generate a combined p value with the association p values from the first two steps. Simulation studies are used to assess the achievable power levels of this method compared to standard analysis approaches. We illustrate the approach by an application to a GWAS of attention deficit hyperactivity disorder parent-offspring trios and publicly available controls.

Brain growth rate abnormalities visualized in adolescents with autism.

Autism spectrum disorder is a heterogeneous disorder of brain development with wide ranging cognitive deficits. Typically diagnosed before age 3, autism spectrum disorder is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared with those of typically developing children and adolescents. Using tensor-based morphometry, we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and seven typically developing boys (mean age/interscan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (P = 0.03, corrected), especially in the parietal (P = 0.008), temporal (P = 0.03), and occipital lobes (P = 0.02). We also visualized abnormal overgrowth in autism in gray matter structures such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. Tensor-based morphometry revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects.

Rethinking a right hemisphere deficit in ADHD.

INTRODUCTION: Early observations from lesion studies suggested right hemisphere (RH) dysfunction in ADHD. However, a strictly right-lateralized deficit has not been well supported. An alternatively view suggests increased R > L asymmetry of brain function and abnormal interhemispheric interaction. If true, RH pathology in ADHD should reflect interhemispherically networked and overactivated functioning. The authors evaluated these assertions. METHOD: Four elements of lateralized brain function were measured: LH specialized, RH specialized, LH with interhemispheric processing (LH/IH), and RH with interhemispheric processing (RH/IH). Next, the authors tested their association with cognitive ability, psychiatric comorbidity, and sibling correlations in 79 children with ADHD. RESULTS: RH/IH processing was uniquely associated with other outcome measures. There were no associations for independent RH or LH function alone. CONCLUSION: Interhemispherically networked RH processing is critical in ADHD. In addition, lack of association between LH specialized processing and cognitive ability (especially for verbal cognitive tasks) supports increased RH mediation of task processing.

Mindfulness and attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a disorder characterized by attentional difficulties. Mindfulness is a receptive attention to present experience. Both ADHD and mindfulness are associated with attention and personality. This study tests whether individuals with ADHD have lower mindfulness scores than controls and, if true, whether personality contributes to these differences. One hundred and five adults (half with ADHD) were assessed for mindfulness, using the Kentucky Inventory of Mindfulness Skills, and personality, using the Tridimensional Character Inventory. Individuals with ADHD report themselves as less mindful than non-ADHD controls and more novelty-seeking, less self-directed, and more self-transcendent. Mindfulness is negatively associated with ADHD and positively associated with self-directedness and self-transcendence. Analyses of subscales of mindfulness suggest that ADHD is associated most with the "Acting in Awareness" dimension, perhaps because of shared items reflecting attentional variability. The current findings support that a large portion of variability in trait mindfulness can be explained by ADHD status and personality traits of self-directedness and self-transcendence. It further suggests that interventions that increase mindfulness might improve symptoms of ADHD and increase self-directedness and/or self-transcendence.

Social functioning difficulties in ADHD: association with PDD risk.

Although social difficulties are a common feature of Attention-Deficit Hyperactivity Disorder (ADHD), little is known about the diversity of social problems, their etiology, or their relationship to disorders of social behavior, such as autism or Pervasive Developmental Disorder (PDD). In 379 children and adolescents with ADHD, social functioning was assessed using the Child Behavior Checklist (Achenbach, 1991). Factor analysis and structural equation modeling revealed two factors that we labeled Peer Rejection and Social Immaturity. A factor reflecting ;PDD risk' was defined from eight items of a separate screening instrument for PDD and examined for its association with these two social factors. There was a significant association with both factors, but the association was much stronger for the Social Immaturity (Standardized Beta [beta ] = .51) than Peer Rejection (beta = .29) factors. Social Immaturity was also associated with a greater number of hyperactive symptoms while high Peer Rejection was associated with increased aggression and lower IQ in the ADHD children.

Cognitive functioning in affected sibling pairs with ADHD: familial clustering and dopamine genes.

BACKGROUND: This paper examines familiality and candidate gene associations of cognitive measures as potential endophenotypes in attention-deficit/hyperactivity disorder (ADHD). METHODS: The sample consists of 540 participants, aged 6 to 18, who were diagnosed with ADHD from 251 families recruited for a larger genetic study of ADHD. All members of the family underwent psychiatric interviews and children were administered a large battery of cognitive tasks. Subjects were genotyped for several dopaminergic candidate genes (DAT1, DRD4, and DRD5). RESULTS: Performance on measures of intelligence, working memory, and set-shifting had the highest sibling correlations and exhibited significant familial clustering. The 7-repeat allele of the dopamine receptor D4 (DRD4) gene was associated with poor performance on measures of intelligence, color naming, interference control, and working memory. There were no significant associations with DAT1 and DRD5. CONCLUSIONS: Sibling correlations, familial clustering and candidate gene associations provide strong support for verbal working memory as a candidate endophenotype for ADHD. More complex models of, and larger sample sizes for, genetic association with cognitive functions are encouraged for future study.

Mindfulness meditation training in adults and adolescents with ADHD: a feasibility study.

OBJECTIVE: ADHD is a childhood-onset psychiatric condition that often continues into adulthood. Stimulant medications are the mainstay of treatment; however, additional approaches are frequently desired. In recent years, mindfulness meditation has been proposed to improve attention, reduce stress, and improve mood. This study tests the feasibility of an 8-week mindfulness training program for adults and adolescents with ADHD. METHOD: Twenty-four adults and eight adolescents with ADHD enrolled in a feasibility study of an 8-week mindfulness training program. RESULTS: The majority of participants completed the training and reported high satisfaction with the training. Pre-post improvements in self-reported ADHD symptoms and test performance on tasks measuring attention and cognitive inhibition were noted. Improvements in anxiety and depressive symptoms were also observed. CONCLUSION: Mindfulness training is a feasible intervention in a subset of ADHD adults and adolescents and may improve behavioral and neurocognitive impairments. A controlled clinical study is warranted.

Preliminary report of familial clustering of EEG measures in ADHD.

The purpose of the present study is to examine the familiality of electroencephalographic (EEG) measures among affected sibling pairs with Attention-Deficit Hyperactivity Disorder (ADHD). EEG was recorded during baseline (eyes open and eyes closed) and cognitive activation conditions on a sample of 58 children with ADHD (27 multiplex families), ages 6-18. EEG power in three frequency bands: theta (4-7 Hz), alpha (8-12 Hz) and beta (12-20 Hz) was tested for sibling correlation, familial co-segregation and association with behavioral task performance on a sustained attention task. Sibling correlation for EEG measures was moderate during baseline conditions and significantly higher for the cognitive activation condition. Familial clustering of frontal and parietal alpha power was evident, but only during the cognitive activation condition. Theta and alpha power correlated significantly with CPT response variability and omission errors, respectively. Cognitive task performance did not exhibit familial clustering in our sample. EEG measures (i.e., alpha power) recorded during cognitive activation is a strongly familial trait in ADHD and may be a putative endophenotype for ADHD.

Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder affecting some 5-10% of children and 4-5% of adults. The cannabinoid receptor gene (CNR1) is a positional candidate gene due to its location near an identified ADHD linkage peak on chromosome 6, its role in stress and dopamine regulation, its association with other psychiatric disorders that co-occur with ADHD, and its function in learning and memory. We tested SNP variants at the CNR1 gene in two independent samples-an unselected adolescent sample from Northern Finland, and a family-based sample of trios (an ADHD child and their parents). In addition to using the trios for association study, the parents (with and without ADHD) were used as an additional case/control sample of adults for association tests. ADHD and its co-morbid psychiatric disorders were examined. A significant association was detected for a SNP haplotype (C-G) with ADHD (P = 0.008). A sex by genotype interaction was observed as well with this haplotype posing a greater risk in males than females. An association of an alternative SNP haplotype in this gene was found for post-traumatic stress disorder (PTSD) (P = 0.04 for C-A, and P = 0.01 for C-G). These observations require replication, however, they suggest that the CNR1 gene may be a risk factor for ADHD and possibly PTSD, and that this gene warrants further investigation for a role in neuropsychiatric disorders.

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 (P(SR) = 0.00034, P(OR) = 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.

ADHD symptoms and subtypes: relationship between childhood and adolescent symptoms.

OBJECTIVE: To study attention-deficit/hyperactivity disorder (ADHD) symptoms and DSM-IV subtypes in childhood and adolescence. METHOD: A total of 457 adolescents ages 16 to 18 years from the Northern Finland Birth Cohort 1986 participated in an epidemiological survey for ADHD. After assessment with a diagnostic interview those with current or childhood ADHD were classified using DSM-IV criteria. Childhood diagnosis of ADHD was set according to retrospective recall. The characteristics and relationships in ADHD symptomatology in childhood and adolescence were studied in relation to behavioral problems and parental history of attentional problems. RESULTS: ADHD was reported more commonly in childhood than in adolescence and variations in subtype classification occurred. Those with childhood and adolescent diagnosis had endorsed specific inattentive symptoms more commonly, had greater comorbid major depression and/or oppositional defiant disorder, and had fathers with more reported attentional problems than those with only childhood diagnosis. In childhood, ADHD subtypes differed along symptom severity, but by adolescence these differences were no longer significant. CONCLUSIONS: The persistence of ADHD from childhood to adolescence may be common. Specific inattentive symptoms, certain psychiatric comorbidity, and family history of attention problems (fathers specifically) contribute to the risk of persistent ADHD. ADHD subtype differences reflect symptom severity differences in childhood that are negligible by adolescence.

Subtypes versus severity differences in attention-deficit/hyperactivity disorder in the Northern Finnish Birth Cohort.

OBJECTIVE: To investigate whether behaviors of inattention, hyperactivity, and impulsivity among adolescents in Northern Finland reflect qualitatively distinct subtypes of ADHD, variants along a single continuum of severity, or of severity differences within subtypes. METHOD: Latent class models, exploratory factor models, and factor mixture models were applied to questionnaire data of ADHD behaviors obtained from the Northern Finland Birth Cohort (NFBC). Latent class models correspond to qualitatively distinct subtypes, factor analysis corresponds to severity differences, and factor mixture analysis allows for both subtypes and severity differences within subtypes. RESULTS: A comparison of the different models shows that models that distinguish between a low scoring majority class (unaffecteds) and a high scoring minority class (affecteds), and allow for two factors (inattentive, hyperactive-impulsive) with severity differences provide the best fit. CONCLUSIONS: The analysis provides support that a high-scoring minority group (8.8% of males and 6.8% of females) likely reflects an ADHD group in the Northern Finland Birth Cohort, whereas the majority of the population falls into a low-scoring group of unaffecteds. Distinct factors composed of items of inattention and hyperactivity-impulsivity are evident for both sexes with considerable variability in severity within each class.

Executive functioning among Finnish adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: The present study examined cognitive functioning in a population sample of adolescents with and without attention-deficit/hyperactivity disorder (ADHD) from the Northern Finland Birth Cohort 1986. METHOD: The sample consisted of 457 adolescents ages 16 to 18 who were assessed using a battery of cognitive tasks. Performance according to diagnostic group (control, behavior disorder, and ADHD) and sex was compared. Then, the effect of executive function deficit (EFD) was assessed by diagnostic group status on behavioral and cognitive measures. RESULTS: When compared to non-ADHD groups, adolescents with ADHD exhibited deficits on almost all of the cognitive measures. The behavior disorder group obtained scores that were generally intermediate between the ADHD and control groups, but exhibited deficits in intelligence and executive function similar to the ADHD group. Approximately half the ADHD sample had EFD; however, the type and presence of EFDs were not differentially related to cognitive performance as a function of diagnosis. CONCLUSIONS: These findings indicate that EFDs are more frequent in ADHD than control or behavior disorder groups. EFDs are a general risk factor for poor cognitive functioning across multiple domains, irrespective of diagnostic status.

ADHD candidate gene study in a population-based birth cohort: association with DBH and DRD2.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset disorder with a significant impact on public health. Although a genetic contribution to risk is evident, predisposing genetic determinants remain largely unknown despite extensive research. So far, the most promising candidate genes have been those involved in dopamine and serotonin pathways. This study tests a series of allelic variants within such candidate genes to determine their potential influence on ADHD susceptibility. METHOD: We used a population sample ascertained from a birth cohort of a subpopulation of Finland, characterized by founder effect and isolation, thus minimizing genetic heterogeneity. The subjects were systematically ascertained using DSM-IV diagnostic criteria for ADHD from the Northern Finland Birth Cohort 1986 of more than 9,000 individuals, resulting in the study sample of 188 ADHD cases and 166 controls. We genotyped markers in 13 candidate genes, including critical components of dopamine and serotonin pathways. RESULTS: We report evidence for association of ADHD with allelic variants of the dopamine beta-hydroxylase (DBH) and dopamine receptor D2 (DRD2) genes. CONCLUSIONS: Our study supports the involvement of the dopamine pathway in the etiology of ADHD; specifically the genes DBH and DRD2 deserve more attention in further studies.

Prevalence and psychiatric comorbidity of attention-deficit/hyperactivity disorder in an adolescent Finnish population.

OBJECTIVE: The purpose of the study was to estimate the prevalence of attention-deficit/hyperactivity disorder (ADHD) and its clinical characteristics in the Northern Finland Birth Cohort 1986. METHOD: A general population Northern Finland Birth Cohort 1986 of 9,432 children followed prospectively from the early fetal period was surveyed at adolescence (ages 16-18) for ADHD behaviors. Among 6,622 respondents to the survey, a subset of 457 likely cases and controls were evaluated for ADHD and other psychiatric disorders. Chi-square and descriptive statistics were used to examine clinical characteristics of ADHD in the subset, and logistic regression was used to estimate prevalence by weighted extrapolation in the larger cohort. RESULTS: The estimated prevalence of ADHD among adolescents in the Northern Finland Birth Cohort 1986 is 8.5% with a male/female ratio of 5.7:1. The distribution of ADHD subtypes among the ADHD adolescents is 28% Combined, 64% Inattentive, and 8% Hyperactive-Impulsive. A lifetime diagnosis of a broadly defined ADHD (probable or definite) had a prevalence of 18.2% with a male/female odds ratio (OR) of 3.2. This lifetime diagnosis of ADHD is significantly associated with anxiety (OR 2.4), mood (OR 2.9), and disruptive behavioral disorders (OR 17.3) in the cohort. CONCLUSIONS: ADHD is a common neurobehavioral disorder among Northern Finnish adolescents and significantly associated with psychiatric comorbidity in adolescence.

Effects of source of DNA on genotyping success rates and allele percentages in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS).

OBJECTIVE: In children diagnosed with attention-deficit/hyperactivity disorder (ADHD) and their parents, who were participants of the Preschool ADHD Treatment Study (PATS), we assessed the effect of source of DNA (from buccal or blood cells) on the genotyping success rate and allele percentages for the five polymorphisms in three candidate genes (DAT1, DRD4, and SNAP 25) investigated in the PATS pharmacogenetic study of response to stimulant medication. METHOD: At baseline assessment, 241 individuals (113 probands and 128 parents) consented to participate; 144 individuals (52 probands and 92 parents) provided blood samples from venipuncture, and 97 individuals (61 probands and 36 parents) provided buccal samples from cheek swab as specimens for isolation of DNA. Three types of polymorphisms-variable number of tandem repeat (VNTR) polymorphism, tandem duplication polymorphism (TDP), and single nucleotide polymorphism (SNP)-were evaluated, including the DRD4 gene 48-bp VNTR in exon III, the DAT1 gene 40-bp VNTR in 3'-untranslated region, the DRD4 gene TDP 120-bp duplication in the promoter region, the SNAP-25 gene TC-1069 SNP, and the SNAP-25 gene TG-1065 SNP. Standard procedures were used to genotype individuals for each of these five polymorphisms. RESULTS: Using the methods available in 2004, the genotyping success rate was on the average much greater for DNA from blood cells than buccal cells (e.g., 91% vs. 54% in probands). For some polymorphisms (DRD4-VNTR, DRD4-TDP, and SNAP25-TC SNP), allele proportion also varied by blood versus buccal source of DNA (e.g., 26.5% vs. 18.6% for the 7-repeat allele of the DRD4 gene). CONCLUSIONS: The much lower success rate for genotyping based on DNA from buccal than blood cells is likely due to the quality of DNA derived from these two sources. The observed source differences in allele proportion may be due to self-selection related to choice of how specimens were collected (from cheek swab or venipuncture), or to a selective detection of some alleles based on differences in DNA quality.

Familial association and frequency of learning disabilities in ADHD sibling pair families.

In a sample of 235 families with at least two children with Attention-Deficit/ Hyperactivity Disorder (ADHD), the frequency and familial association of learning disabilities (LD) were assessed. Familiality was examined both between sibling pairs and between parents and their children. Two methods for defining LD, a discrepancy-based and a low-achievement model, were employed to examine the occurrence of LD in this sample. The specific types of LD examined included Reading Disability (RD), Math Disability (MD), and Writing Disability (WD). The prevalence rates were highest for RD, followed by WD then MD. The two definitions of LD yielded similar prevalence rates but identified different groups of children with vastly different IQ scores. Strong familial association was demonstrated for RD both between sibling pairs and between parents and children, with weaker association for WD. There was evidence of nonrandom mating for LD among parents, but not for ADHD or for ADHD + LD. Despite the high comorbidity of ADHD and LD among parents, the presence of ADHD in the parents did not predict child LD supporting independent familial factors underlying ADHD and LD.

Relationship of family environment and parental psychiatric diagnosis to impairment in ADHD.

OBJECTIVE: Family environmental factors as well as parental attention-deficit/hyperactivity disorder (ADHD) status have shown associations with variability in ADHD. The purpose of the present study was to examine the links among family environment, parental psychiatric diagnosis, and child impairment within a sample of ADHD-affected sibling pairs (ASPs) ages 5 to 18 years. METHOD: Parents in 220 ASP families completed a measure of family functioning, the Family Environment Scale. Children's impairment was measured by clinical ratings of global functioning and by maternal ratings of behavior. RESULTS: Parents of children with ADHD rate their families as higher in conflict and lower in achievement and organization than normative samples. High family conflict is significantly associated with impairment in ADHD ASPs accounting for approximately 40% of the sibling similarity in impairment. Parental psychiatric diagnosis revealed no significant direct link to sibling impairment, but rather a significant indirect link to impairment mediated by family conflict. Direct associations with parental diagnosis depend on birth order of the ASP members despite the comparable mean impairment scores for older and younger ADHD siblings. CONCLUSIONS: There are strong links between impairment in children with ADHD and family environment. Different processes and mechanisms may contribute to impairment in different children in the same family.

Temperament and character profiles and the dopamine D4 receptor gene in ADHD.

OBJECTIVE: This study was designed to investigate the link among attention deficit hyperactivity disorder (ADHD) in adults, novelty-seeking temperament, and the 48-base pair (bp) dopamine D4 receptor (DRD4) gene variant. METHOD: This study drew from a larger molecular genetic study of ADHD in which the ascertainment criterion was having an affected sibling pair with ADHD. Parents (N=171) from 96 families provided data. Of the 171 parents, 56 (33%) had a lifetime history of ADHD, with 28 (50%) continuing to meet DSM-IV criteria (i.e., "persistent" ADHD). Latent variable modeling was used to test whether the DRD4 gene variant or Temperament and Character Inventory factors could predict ADHD. RESULTS: Using latent variable modeling, the authors were able to confirm the first-order factor structure of the Temperament and Character Inventory. Furthermore, novelty seeking predicted ADHD lifetime diagnosis (R(2)=26%), while the DRD4 gene variant independently predicted ADHD (R(2)=5%) but not novelty seeking. CONCLUSIONS: In this unique sample of parents from multiply affected ADHD families, novelty seeking and the 48-bp DRD4 variant were associated with a lifetime history of ADHD. However, the association between novelty seeking and ADHD does not appear to be due to variation in the 48-bp DRD4 variant.