Molly A. Nikolas

Distinct neuropsychological subgroups in typically developing youth inform heterogeneity in children with ADHD

Research and clinical investigations in psychiatry largely rely on the de facto assumption that the diagnostic categories identified in the Diagnostic and Statistical Manual (DSM) represent homogeneous syndromes. However, the mechanistic heterogeneity that potentially underlies the existing classification scheme might limit discovery of etiology for most developmental psychiatric disorders. Another, perhaps less palpable, reality may also be interfering with progress—heterogeneity in typically developing populations. In this report we attempt to clarify neuropsychological heterogeneity in a large dataset of typically developing youth and youth with attention deficit/hyperactivity disorder (ADHD), using graph theory and community detection. We sought to determine whether data-driven neuropsychological subtypes could be discerned in children with and without the disorder. Because individual classification is the sine qua non for eventual clinical translation, we also apply support vector machine-based multivariate pattern analysis to identify how well ADHD status in individual children can be identified as defined by the community detection delineated subtypes. The analysis yielded several unique, but similar subtypes across both populations. Just as importantly, comparing typically developing children with ADHD children within each of these distinct subgroups increased diagnostic accuracy. Two important principles were identified that have the potential to advance our understanding of typical development and developmental neuropsychiatric disorders. The first tenet suggests that typically developing children can be classified into distinct neuropsychological subgroups with high precision. The second tenet proposes that some of the heterogeneity in individuals with ADHD might be “nested” in this normal variation.

Low blood lead levels associated with clinically diagnosed attention-deficit/hyperactivity disorder and mediated by weak cognitive control.

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) and low-level lead exposure are high-prevalence conditions among children, and studies of large populations have suggested that these conditions are related. We examine this relationship in children from a community sample exposed to average background levels of lead who have a diagnosis of ADHD that is established by clinical criteria. METHODS One hundred fifty children ages 8-17 years participated (mean age = 14 years; 53 control subjects, 47 ADHD Predominantly Inattentive type, 50 ADHD-Combined type). Diagnosis was formally established with a semi-structured clinical interview and parent and teacher ratings. Children completed intelligence quotient (IQ) measures and the stop task (a neuropsychological measure). Lead was assayed from whole blood with inductively coupled plasma mass spectrometry. RESULTS Blood lead levels in this sample closely matched US population exposure averages, with a maximum level of 3.4 mug/dL. Blood lead levels were statistically significantly higher in ADHD-combined type than in non-ADHD control (p < .05) children. Blood lead was associated with symptoms of hyperactivity-impulsivity but not inattention-disorganization, after control of covariates. Blood lead levels were linked with a lower IQ (p < .05), but IQ did not account for effects on hyperactivity. Instead, hyperactivity mediated effects of lead on IQ. Effects of blood lead on hyperactivity-impulsivity were mediated by poor performance on the stop task. This mediation effect was independent of effects of lead on IQ. CONCLUSIONS Low-level lead exposure might be an important contributor to ADHD. Its effects seem to be mediated by less effective cognitive control, consistent with a route of influence via striatal-frontal neural circuits.

Genetic and environmental influences on ADHD symptom dimensions of inattention and hyperactivity: a meta-analysis.

Behavioral genetic investigations have consistently demonstrated large genetic influences for the core symptom dimensions of attention-deficit/hyperactivity disorder (ADHD), namely inattention (INATT) and hyperactivity (HYP). Yet little is known regarding potential similarities and differences in the type of genetic influence (i.e., additive vs. nonadditive) on INATT and HYP. As these symptom dimensions form the basis of the current Diagnostic and Statistical Manual of Mental Disorders subtype classification system, evidence of differential genetic influences would have important implications for research investigating causal mechanisms for ADHD. The current meta-analysis aimed to investigate the nature of etiological influences for INATT and HYP by comparing the type and magnitude of genetic and environmental influences each. A comprehensive literature search yielded 79 twin and adoption studies of INATT and/or HYP. Of these, 13 samples of INATT and 9 samples of HYP were retained for analysis. Results indicated that both dimensions were highly heritable (genetic factors accounted for 71% and 73% of the variance in INATT and HYP, respectively). However, the 2 dimensions were distinct as to the type of genetic influence. Dominant genetic effects were significantly larger for INATT than for HYP, whereas additive genetic effects were larger for HYP than for INATT. Estimates of unique environmental effects were small to moderate and shared environmental effects were negligible for both symptom dimensions. The pattern of results generally persisted across several moderating factors, including gender, age, informant, and measurement method. These findings highlight the need for future studies to disambiguate INATT and HYP when investigating the causal mechanisms, and particularly genetic influences, behind ADHD.

Confirmation and Extension of Association of Blood Lead with Attention-Deficit/Hyperactivity Disorder (ADHD) and ADHD Symptom Domains at Population-Typical Exposure Levels

BACKGROUND Recent studies have suggested that child attention-deficit/hyperactivity disorder (ADHD) and its symptom domains are related to blood lead level, even at background exposure levels typical in western countries. However, recent studies disagreed as to whether lead was related to inattention or hyperactivity-impulsivity within the ADHD domain. More definitive evaluation of these questions was sought. METHODS Two hundred and thirty-six (236) children aged 6-17 years participated (61 ADHD-Combined type, 47 ADHD Predominantly Inattentive type, 99 non-ADHD control, 29 unclassified borderline, situational, or not otherwise specified (NOS) cases). Formal diagnosis was reliably established by a best estimate procedure based on a semi-structured clinical interview and parent and teacher ratings. Lead was assayed from whole blood using inductively coupled plasma mass spectrometry with a method detection limit of .3 microg/dL. RESULTS Blood lead levels were slightly below United States and Western Europe population exposure averages, with a mean of .73 and a maximum of 2.2 microg/dL. This is the lowest level of blood lead ever studied in relation to ADHD. After statistical control for covariates including IQ and prenatal smoking exposure, blood lead was associated with ADHD-combined type but not inattentive type. Parent and teacher report indicated association of blood lead with Conners cognitive problems, but only teacher report showed effects on DSM-IV inattention symptoms. Blood lead was associated with hyperactivity-impulsivity in parent report regardless of measurement method, whereas teacher report effects depended on child treatment history. CONCLUSIONS These findings confirm that in children with typical US population lead exposure, careful identification of children with ADHD also identifies children with slightly elevated blood lead.

Measured Gene-by-Environment Interaction in Relation to Attention-Deficit/ Hyperactivity Disorder

OBJECTIVE To summarize and evaluate the state of knowledge regarding the role of measured gene-by-environment interactions in relation to attention-deficit/hyperactivity disorder. METHOD A selective review of methodologic issues was followed by a systematic search for relevant articles on measured gene-by-environment interactions; the search yielded 16 studies, which are discussed in qualitative fashion. RESULTS Relatively consistent evidence points to the interaction of genotype with psychosocial factors in the development of attention-deficit/hyperactivity disorder. The next step is to identify the mechanisms on the environment side and the gene combinations on the genetic side accounting for this effect. In contrast, evidence for gene-by-environment interactions involving pre- and perinatal risk factors is generally negative or unreplicated. The aggregate effect size for psychosocial interaction with genotype is more than double that for the interaction of pre- and perinatal risks with genotype. Only a small fraction of candidate environments and gene markers has been studied, and multivariate methods to integrate multiple gene or environment markers have yet to be implemented. CONCLUSIONS Gene-by-environment interaction appears likely to prove fruitful in understanding the etiology of attention-deficit/hyperactivity disorder. Findings to date already suggest new avenues of investigation particularly involving psychosocial mechanisms and their interplay with genotype. Further pursuit of theoretically promising leads is recommended.

The Dopamine Receptor D4 Gene (DRD4) Moderates Family Environmental Effects on ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of gene-by-environment interaction (i.e., G x E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G x E design, we examined whether the DRD4 promoter 120-bp tandem repeat polymorphism, previously associated with ADHD, moderated the effects of inconsistent parenting and marital conflict on ADHD or Oppositional-Defiant Disorder (ODD). Participants were 548 children with ADHD and non-ADHD comparison children and their parents. Homozygosity for the DRD4 promoter 120-bp tandem repeat insertion allele increased vulnerability for ADHD and ODD only in the presence of inconsistent parenting and appeared to increase susceptibility to the influence of increased child self-blame for marital conflict on ADHD inattention. DRD4 genotypes may interact with these proximal family environmental risk factors by increasing the individual’s responsivity to environmental contingencies.

Genotype and neuropsychological response inhibition as resilience promoters for attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder under conditions of psychosocial adversity.

Whereas child personality, IQ, and family factors have been identified as enabling a resilient response to psychosocial adversity, more direct biological resilience factors have been less well delineated. This is particularly so for child attention-deficit/hyperactivity disorder (ADHD), which has received less attention from a resilience perspective than have associated externalizing disorders. Children from two independent samples were classified as resilient if they avoided developing ADHD, oppositional defiant disorder (ODD), or conduct disorder (CD) in the face of family adversity. Two protective factors were examined for their potential relevance to prefrontal brain development: neuropsychological response inhibition, as assessed by the Stop task, and a composite catecholamine genotype risk score. Resilient children were characterized in both samples by more effective response inhibition, although the effect in the second sample was very small. Genotype was measured in Sample 1, and a composite high risk genotype index was developed by summing presence of risk across markers on three genes expressed in prefrontal cortex: dopamine transporter, dopamine D4 receptor, and noradrenergic alpha-2 receptor. Genotype was a reliable resilience indicator against development of ADHD and CD, but not ODD, in the face of psychosocial adversity. Results illustrate potential neurobiological protective factors related to development of prefrontal cortex that may enable children to avoid developing ADHD and CD in the presence of psychosocial adversity.

Personality Mediation of Genetic Effects on Attention-Deficit/Hyperactivity Disorder.

Personality traits may be viable candidates for mediators of the relationship between genetic risk and ADHD. Participants were 578 children (331 boys; 320 children with ADHD) between the ages of six and 18. Parents and teachers completed a comprehensive, multi-stage diagnostic procedure to assess ADHD and comorbid disorders. Mother completed the California Q-Sort to assess child Big Five personality traits. Children provided buccal samples of DNA which were assayed for selected markers on DRD4, DAT1, and ADRA2A. An additive genetic risk composite was associated with ADHD symptoms and maladaptive personality traits; maladaptive personality traits were associated with ADHD symptoms. Low conscientiousness and high neuroticism partially mediated the relationship between genetic risk and ADHD symptoms. Mediation effects for conscientiousness were specific to inattentive symptoms; effects for neuroticism generalized to all disruptive behaviors. High neuroticism and low conscientiousness may be useful as early markers for children at risk for ADHD.

Executive function assessment and adult attention-deficit/hyperactivity disorder: tasks versus ratings on the Barkley deficits in executive functioning scale.

Adults with attention-deficit/hyperactivity disorder (ADHD) exhibit variable impairments on executive function (EF) tasks. Due to this variability, ratings of EF (rather than tasks) have been proposed as an alternative method that better captures symptom severity and impairment among adults with ADHD. However, few studies have jointly examined performance across multiple neuropsychological domains and EF ratings as predictors of severity and impairment among adults with ADHD. Adults (N = 273) ages 18-38 years (M = 22.6 years, 55.3% male, 62.2% with ADHD) completed a comprehensive diagnostic and neurocognitive assessment, which included self and informant ratings of ADHD symptom severity and EF and tasks of arousal/activation, response inhibition, set shifting, interference control, and working memory. Hierarchical linear regression models indicated that tasks of arousal/activation and response inhibition uniquely predicted ADHD symptom dimensions and related impairments. Over and above EF task performance, EF ratings of time management significantly predicted increased inattention (β = .209, p < .001, ΔR² = 3.9%), whereas ratings of restraint predicted increased hyperactivity/impulsivity (β = .259, p < .001, ΔR² = 6.4%). Furthermore, EF ratings of time management, restraint, and emotion regulation incrementally accounted for variance in relationship, professional, and daily living impairments over and above EF task performance (ΔR² range = 1.7-7.7%). Results may help refine neurobiological theories and assessment of adult ADHD.

Factor Structure of the Children’s Perception of Interparental Conflict Scale for Studies of Youths With Externalizing Behavior Problems

The assessment of childrens perception of marital conflict is an important area of research related to family relations, childrens cognitions about self, and the development of psychopathology. The leading instrument in this domain is the Childrens Perception of Interparental Conflict Scale (CPIC; J. H. Grych, M. Seid, & F. D. Fincham, 1992). It has 48 items organized into 9 conceptual designed subscales, with reports of 3-factor higher order structure to the 9 subscales. However, the 3-factor solution does not capture all 9 subscales well. Further, items have never been subjected to factor analysis to evaluate the best fitting factor structure at the item level. Doing so is particularly important when bringing the scale into new populations such as children with attention-deficit/hyperactivity disorder (ADHD) or disruptive behavior disorders. In the present study, 2 samples of children (total N = 1,190; ages 6-18 years) completed the CPIC. An exploratory factor analysis in Sample 1 (from a clinical study of ADHD and non-ADHD youths) yielded 4 interpretable factors. A confirmatory factor analysis in Sample 2 (a population sample of twins) confirmed the generalizability of the solution with an acceptable fit, although 1 item was dropped. The final solution used 38 of the 48 items. The 4-factor solution captured a Conflict Properties factor, two appraisal factors labeled Threat to Self and Self-Blame, and a Triangulation/Stability factor that included elements of appraisal and content. The authors concluded that the item-based 4-factor solution to the CPIC is preferable to the 9-factor or 3-factor formulation.