Heidi Aase

Rodent Models of Attention-Deficit/Hyperactivity Disorder

An ideal animal model should be similar to the disorder it models in terms of etiology, biochemistry, symptomatology, and treatment. Animal models provide several advantages over clinical research: simpler nervous systems, easily interpreted behaviors, genetic homogeneity, easily controlled environment, and a greater variety of interventions. Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder of childhood onset that is characterized by inattentiveness, hyperactivity, and impulsiveness. Its diagnosis is behaviorally based; therefore, the validation of an ADHD model must be based in behavior. An ADHD model must mimic the fundamental behavioral characteristics of ADHD (face validity), conform to a theoretical rationale for ADHD (construct validity), and predict aspects of ADHD behavior, genetics, and neurobiology previously uncharted in clinical settings (predictive validity). Spontaneously hypertensive rats (SHR) fulfill many of the validation criteria and compare well with clinical cases of ADHD. Poor performers in the five-choice serial reaction time task and Naples high-excitability rats (NHE) are useful models for attention-deficit disorder. Other animal models either focus on the less important symptom of hyperactivity and might be of limited value in ADHD research or are produced in ways that would not lead to a clinical diagnosis of ADHD in humans, even if ADHD-like behavior is displayed.

Altered reinforcement mechanisms in attention-deficit/hyperactivity disorder.

The present study tested eight boys with attention-deficit/hyperactivity disorder (ADHD) and 12 normal boys (comparison group), aged 7-12 years, to investigate the hypothesis that ADHD is associated with a steeper and shorter delay-of-reinforcement gradient than is normal. A two-component schedule of reinforcement was used to deliver trinkets or coins as reinforcers in a game-like test. One component was marked by a signal. During this period reinforcers (coins or trinkets) were delivered every 30 s. This component is called a 30-s fixed interval (FI) schedule of reinforcement and measures changes in reactivity to reinforcers. The other component was in effect when the signal was turned off. Then no reinforcer was ever delivered. This is called an extinction (EXT) component and measures primarily sustained attention. The ADHD children gradually developed hyperactivity to a large extent consisting of bursts of responses with short interresponse times (IRTs) during both schedule components. The response bursts not only constituted a substantial portion of the ADHD overactivity, but may well be a key component of the behaviour commonly described as impulsiveness, the key behavioural characteristic of ADHD. In addition, the ADHD children showed behaviour during the extinction component that may well be described as a sustained-attention deficit: initially stopping when the signal was turned off and then resuming responding some time thereafter as if the signal had been turned on again. The comparison group ceased responding during extinction and did not show impulsiveness. The findings were in accordance with a steeper and shorter delay gradient in ADHD.

The Spontaneously Hypertensive Rat model of ADHD – the importance of selecting the appropriate reference strain

Although several molecular and genetic manipulations may produce hyperactive animals, hyperactivity alone is insufficient for the animal to qualify as a model of ADHD. Based on a wider range of criteria - behavioral, genetic and neurobiological - the spontaneously hypertensive rat (SHR) obtained from Charles River, Germany (SHR/NCrl) at present constitutes the best validated animal model of ADHD combined subtype (ADHD-C), and the Wistar Kyoto substrain obtained from Harlan, UK (WKY/NHsd) is its most appropriate control. Although other rat strains may behave like WKY/NHsd rats, genetic results indicate significant differences when compared to the WKY/NHsd substrain, making them less suitable controls for the SHR/NCrl. The use of WKY/NCrl, outbred Wistar, Sprague Dawley or other rat strains as controls for SHRs may produce spurious neurobiological differences. Consequently, data may be misinterpreted if insufficient care is taken in the selection of the control group. It appears likely that the use of different control strains may underlie some of the discrepancies in results and interpretations in studies involving the SHR and WKY. Finally, we argue that WKY rats obtained from Charles River, Germany (WKY/NCrl) provide a promising model for the predominantly inattentive subtype of ADHD (ADHD-PI); in this case also the WKY/NHsd substrain should be used as control.

Autism Spectrum Disorder, ADHD, Epilepsy, and Cerebral Palsy in Norwegian Children

BACKGROUND: Numerous studies have investigated the prevalence of neurologic and neurodevelopmental disorders individually, but few have examined them collectively, and there is uncertainty as to what extent they overlap. METHODS: The study has determined the proportions of children aged 0 to 11 years with diagnoses of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), epilepsy, and cerebral palsy (CP) in Norway. The data were obtained from the Norwegian Patient Register, which is nationwide and contains diagnoses assigned by Norwegian specialist health services (hospitals and outpatient clinics). The Norwegian Patient Register started collecting individual-level data in 2008, and the follow-up period for the study is years 2008 through 2010. RESULTS: For ASD, ADHD, and epilepsy, the proportions were highest in the oldest children. At age 11 years, the incidence was 0.7% for ASD, 2.9% for ADHD, and 0.9% for epilepsy. The cumulative incidence is likely to be higher because some cases diagnosed before 2008 were probably missed. For CP, the proportions were ∼0.3% for age ≥5 years. There was considerable overlap between diagnoses. For all disorders, boys had a significantly increased risk. In school-age children (aged 6–11 years) the male/female ratio was 4.3 for ASD, 2.9 for ADHD, 1.2 for epilepsy, and 1.3 for CP. CONCLUSIONS: The findings demonstrate the significant burden of disease associated with neurologic and neurodevelopmental disorders in children and that this burden is disproportionately skewed toward boys.

International Variation in Treatment Procedures for ADHD: Social Context and Recent Trends

OBJECTIVE Scientific and clinical interest in attention-deficit hyperactivity disorder (ADHD) is increasing worldwide. This article presents data from a cross-national workshop and survey related to questions of variability in diagnostic and, particularly, treatment procedures. METHODS Representatives of nine nations (Australia, Brazil, Canada, China, Germany, Israel, the Netherlands, Norway, and the United Kingdom), plus the United States, who attended a 2010 workshop on ADHD, responded to a survey that addressed diagnostic procedures for ADHD; treated prevalence of medication approaches, as well as psychosocial interventions; types of medications and psychosocial treatments in use; payment systems; beliefs and values of the education system; trends related to adult ADHD; and cultural and historical attitudes and influences related to treatment. RESULTS Use of both medication and psychosocial treatment for ADHD varies widely within and across nations. More expensive long-acting formulations of medications are becoming more widespread. Nations with socialized medical care provide a wide array of evidence-based interventions. Economic, historical, and political forces and cultural values are related to predominant attitudes and practices. Strong antipsychiatry and antimedication voices remain influential in many nations. CONCLUSIONS There is considerable variation in implementation of care for ADHD. Recognition of the social context of ADHD is an important step in ensuring access to evidence-based interventions for this prevalent, chronic, and impairing condition.

Moment-to-moment dynamics of ADHD behaviour in South African children

BackgroundThe behaviour of children with Attention-Deficit/Hyperactivity Disorder is characterized by low predictability of responding. Low behavioural predictability is one way of operationalizing intra-individual ADHD-related variability. ADHD-related variability may be caused by inefficient behavioural selection mechanisms linked to reinforcement and extinction, as suggested by the recently published dynamic developmental theory (DDT) of ADHD. DDT argues that ADHD is a basic neurobehavioural disorder, caused by dysfunctioning dopamine systems. For establishing ADHD as a neurobehavioural disorder, findings from studies conducted in Western countries should be replicated in other cultural populations. The present study replicated the study conducted in Norway, with children from the Limpopo province in the Republic of South Africa.MethodsBoys and girls, aged 6–9 yr, from seven ethnic groups participated. Scores by teachers on the Disruptive Behavior Disorders rating scale defined participation in either ADHD-hyperactive/impulsive (-HI), ADHD-predominantly inattentive (-PI), or ADHD-combined (-C) groups. Children below the 86th percentile were matched on gender and age and comprised the non-ADHD group. The children completed a computerized game-like task where mouse clicks on one of two squares on the screen resulted in delivery of a reinforcer according to a variable interval schedule of reinforcement. Reinforcers were cartoon pictures presented on the screen together with a sound. Predictability of response location and timing were measured in terms of explained variance.ResultsOverall, the results replicated findings from Norway. Specifically, the ADHD-C group showed significantly lower predictability of responding than the non-ADHD group, while the ADHD-HI and the ADHD-PI groups were in-between. In accordance with the previous study, response location, but not response timing, was a sensitive behavioural measure. There were no significant gender differences. Cartoon pictures were effective reinforcers as the non-ADHD group showed learning of the task. There was no relation between behavioural predictability and motor functions.ConclusionThe present study makes a strong case for ADHD as a basic, neurobehavioural disorder, not a cultural phenomenon, by replicating findings from a wealthy Western country in a poor province of a developing country. The results were, generally, in line with predictions from the dynamic developmental theory of ADHD by indicating that reinforcers were less efficient in the ADHD group than in the non-ADHD group. Finally, the results substantiated ADHD-related variability as an etiologically important characteristic of ADHD behaviour.

Genome-Wide Analysis of Attention Deficit Hyperactivity Disorder in Norway

Background Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric condition, but it has been difficult to identify genes underlying this disorder. This study aimed to explore genetics of ADHD in an ethnically homogeneous Norwegian population by means of a genome-wide association (GWA) analysis followed by examination of candidate loci. Materials and Methods Participants were recruited through Norwegian medical and birth registries as well as the general population. Presence of ADHD was defined according to DSM-IV criteria. Genotyping was performed using Illumina Human OmniExpress-12v1 microarrays. Statistical analyses were divided into several steps: (1) genome-wide association in the form of logistic regression in PLINK and follow-up pathway analyses performed in DAPPLE and INRICH softwares, (2) SNP-heritability calculated using genome-wide complex trait analysis (GCTA) tool, (3) gene-based association tests carried out in JAG software, and (4) evaluation of previously reported genome-wide signals and candidate genes of ADHD. Results In total, 1.358 individuals (478 cases and 880 controls) and 598.384 autosomal SNPs were subjected to GWA analysis. No single polymorphism reached genome-wide significance. The strongest signal was observed at rs9949006 in the ENSG00000263745 gene (OR=1.51, 95% CI 1.28–1.79, p=1.38E-06). Pathway analyses of the top SNPs implicated genes involved in the regulation of gene expression, cell adhesion and inflammation. Among previously identified ADHD candidate genes, prominent association signals were observed for SLC9A9 (rs1393072, OR=1.46, 95% CI = 1.21–1.77, p=9.95E-05) and TPH2 (rs17110690, OR = 1.38, 95% CI = 1.14–1.66, p=8.31E-04). Conclusion This study confirms the complexity and heterogeneity of ADHD etiology. Taken together with previous findings, our results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, providing targets for further genetic exploration of this complex disorder.

Suboptimal Maternal Iodine Intake Is Associated with Impaired Child Neurodevelopment at 3 Years of Age in the Norwegian Mother and Child Cohort Study

Background: Severe iodine deficiency in pregnancy has major effects on child neurodevelopment, but less is known about the potential consequences of mild-to-moderate deficiency and iodine supplement use.Objective: We explored the associations between maternal iodine intake and child neurodevelopment at 3 y of age and the potential impact of maternal intake of iodine from supplements on the same outcomes.Methods: This population-based prospective observational study included 48,297 mother-child pairs recruited during pregnancy from 2002 to 2008. Maternal iodine intake was calculated based on a validated food-frequency questionnaire answered during midpregnancy that covered mean intake since the beginning of pregnancy. Associations between iodine intake and maternal-reported child language and motor development and behavior problems were explored by multivariable regression analyses.Results: In 33,047 mother-child pairs, excluding iodine supplement users, maternal iodine intake was associated with child language delay (P = 0.024), externalizing and internalizing behavior problems (both P < 0.001), and fine motor skills (P = 0.002) but not gross motor skills or the risk of not walking unaided at 17 mo of age. In 74% of the participants who had an iodine intake <160 μg/d (Estimated Average Requirement), suboptimal iodine intake was estimated to account for ∼5% (95% CI: -5%, 14%) of the cases of language delay, 16% (95% CI: 0%, 21%) of the cases of externalizing behavior problems >1.5 SD, and 16% (95% CI: 10%, 21%) of the cases of internalizing behavior problems >1.5 SD. In 48,297 mother-child pairs, including iodine supplement users, we found no protective effects of supplemental iodine during pregnancy on neurodevelopment.Conclusions: Maternal iodine intake below the Estimated Average Requirement during pregnancy was associated with symptoms of child language delay, behavior problems, and reduced fine motor skills at 3 y of age. The results showed no evidence of a protective effect of iodine supplementation during pregnancy.

Reliability of triclosan measures in repeated urine samples from Norwegian pregnant women

Triclosan (TCS) is a synthetic antibacterial chemical that is used in personal care products and is measurable in urine. Urinary TCS has been associated with allergy in children in Norway and the United States. A reasonable degree of temporal reliability of TCS urinary concentrations has been reported among US children as well as for Puerto Rican pregnant women. We examined the reliability of TCS measures in urine among Norwegian pregnant women. TCS was measured in spot urine samples collected in gestational weeks 17, 23, and 29 from 45 women in The Norwegian Mother and Child Cohort Study (MoBa) enrolled in 2007 and 2008. Spearman’s rank correlation coefficient (rs) and intraclass correlation coefficient (ICC) statistics were calculated. Fifty-six percent of the 45 women had a least one sample with a value above the method limit of detection (2.3 μg/l). The correlation coefficients were 0.61 for TCS concentrations at 17 and 23 weeks and 0.49 for concentrations at 17 and 29 weeks. For the three time points, the ICC was 0.49. The reliability of TCS concentrations in repeated urine samples from pregnant Norwegian women was reasonably good, suggesting a single urine sample can adequately represent TCS exposure during pregnancy.

Measurement of Total and Free Urinary Phenol and Paraben Concentrations over the Course of Pregnancy: Assessing Reliability and Contamination of Specimens in the Norwegian Mother and Child Cohort Study.

Background Exposures to environmental phenols and parabens may be harmful, especially in utero. Prior studies have demonstrated high within-person variability of urinary concentrations across pregnancy. Objectives We sought to measure phenol and paraben biomarker concentrations for the Norwegian Mother and Child Cohort (MoBa) study, assess within-person variability, and investigate any possible external phenol or paraben contamination of specimens. Methods We collected three spot urine samples at approximately 17, 23, and 29 weeks gestation in a hospital setting and added a preservative containing ethyl paraben. We measured urinary concentrations and within-person variability for phenols and parabens in a MoBa sample (n = 45), including a subgroup of 15 participants previously randomly selected for a bisphenol A (BPA) exposure study who had unusually high total BPA concentrations. Additionally, we compared reliability results for total, conjugated, and free concentrations of phenolic compounds. Results We detected total and free BPA, butyl paraben, propyl paraben, and methyl paraben in 100% of samples, total benzophenone-3 in 95% of samples, and infrequently detected free benzophenone-3 and total and free 2,4-dichlorophenol and 2,5-dichlorophenol. Intraclass correlation coefficients (ICCs) for total, conjugated, and free concentrations ranged from relatively low for BPA to moderate for propyl paraben. ICCs were generally similar overall and by subgroup. Conclusions Using conjugated concentrations improved reliability estimates only for BPA. Measuring total and free concentrations, an approach that may be useful for future studies, allowed us to identify likely BPA and butyl paraben contamination of archived MoBa urine specimens. Citation Guidry VT, Longnecker MP, Aase H, Eggesbø M, Zeiner P, Reichborn-Kjennerud T, Knudsen GP, Bertelsen RJ, Ye X, Calafat AM, Engel SM. 2015. Measurement of total and free urinary phenol and paraben concentrations over the course of pregnancy: assessing reliability and contamination of specimens in the Norwegian Mother and Child Cohort Study. Environ Health Perspect 123:705–711; http://dx.doi.org/10.1289/ehp.1408325