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author:("roelse, Nanda")
1.  Altered neural connectivity during response inhibition in adolescents with attention-deficit/hyperactivity disorder and their unaffected siblings 
NeuroImage : Clinical  2015;7:325-335.
Introduction
Response inhibition is one of the executive functions impaired in attention-deficit/hyperactivity disorder (ADHD). Increasing evidence indicates that altered functional and structural neural connectivity are part of the neurobiological basis of ADHD. Here, we investigated if adolescents with ADHD show altered functional connectivity during response inhibition compared to their unaffected siblings and healthy controls.
Methods
Response inhibition was assessed using the stop signal paradigm. Functional connectivity was assessed using psycho-physiological interaction analyses applied to BOLD time courses from seed regions within inferior- and superior frontal nodes of the response inhibition network. Resulting networks were compared between adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and controls (N = 125).
Results
Control subjects showed stronger functional connectivity than the other two groups within the response inhibition network, while subjects with ADHD showed relatively stronger connectivity between default mode network (DMN) nodes. Stronger connectivity within the response inhibition network was correlated with lower ADHD severity, while stronger connectivity with the DMN was correlated with increased ADHD severity. Siblings showed connectivity patterns similar to controls during successful inhibition and to ADHD subjects during failed inhibition. Additionally, siblings showed decreased connectivity with the primary motor areas as compared to both participants with ADHD and controls.
Discussion
Subjects with ADHD fail to integrate activation within the response inhibition network and to inhibit connectivity with task-irrelevant regions. Unaffected siblings show similar alterations only during failed stop trials, as well as unique suppression of motor areas, suggesting compensatory strategies. These findings support the role of altered functional connectivity in understanding the neurobiology and familial transmission of ADHD.
Highlights
•We investigate the neural connectivity during response inhibition using PPI.•We investigate connectivity in participants with ADHD, their siblings and controls.•Participants with ADHD show lower connectivity within the response inhibition network.•Participants with ADHD show higher connectivity with the default mode network.•Unaffected siblings show unique patterns of compensatory activation.
doi:10.1016/j.nicl.2015.01.004
PMCID: PMC4297885  PMID: 25610797
ADHD, attention deficit/hyperactivity disorder; CD, conduct disorder; DMN, default mode network; GEE, generalized estimating equations; ICV, intraindividual coefficient of variance; ODD, oppositional defiant disorder; RD, reading disorder; ROI, region of interest; SSRT, stop-signal reaction time; SST, Stop-signal task; SI, supplementary information; WM, white matter; ADHD; PPI; Connectivity; Siblings; Response inhibition
2.  ADHD is a risk factor for overweight and obesity in children 
Journal of developmental and behavioral pediatrics : JDBP  2013;34(8):10.1097/DBP.0b013e3182a50a67.
Objective
Although hyperactivity would seem to increase energy expenditure, attention deficit/hyperactivity disorder (ADHD) appears to increase the risk for being overweight. The present study examined the Body Mass Index (BMI) in children with ADHD and its relationship with age, gender, ADHD and comorbid symptom severity, inhibitory control, developmental coordination disorder (DCD), sleep duration and methylphenidate use.
Method
Participants were 372 Dutch children with ADHD combined type aged 5–17 years participating in the International Multicenter ADHD Genetics (IMAGE) study. We categorized BMI according to international age- and gender-specific reference values and calculated BMI-standard deviation scores (BMI-SDS). The control population was matched for age, gender and ethnicity and originated from the same birth cohort as the ADHD group. Inhibitory control was measured by the computerized Stop-signal task. Prevalence differences of underweight, overweight and obesity between groups were expressed in odds ratio’s. We used linear regression analyses with gender, age, parent- and teacher-rated ADHD and comorbid scores, inhibitory control, sleep duration, motor coordination and methylphenidate use to predict BMI-SDS.
Results
Boys with ADHD 10–17 and girls 10–12 years of age were more likely to be overweight than children in the general Dutch population. Younger girls and female teenagers, however, seemed to be at lower risk for being overweight. Higher oppositional behavior and social communication problems related to higher BMI-SDS scores, whereas more stereotyped behaviors related to lower BMI-SDS scores. We found no effects of the other examined associated risk factors on BMI-SDS.
Conclusion
ADHD in boys is a risk factor for overweight. In girls with ADHD, the prevalence of overweight is age-dependent and most pronounced in girls 10–12 years of age. They have a fourfold risk of being obese. Higher oppositional and social communication problems pose an increased risk for overweight, whereas sleep duration, motor coordination problems and methylphenidate use do not.
doi:10.1097/DBP.0b013e3182a50a67
PMCID: PMC3859965  PMID: 24131879
ADHD; BMI; DCD; sleep; methylphenidate
3.  Different stability of social-communication problems and negative demanding behaviour from infancy to toddlerhood in a large Dutch population sample 
Background
Little is known about the stability of behavioural and developmental problems as children develop from infants to toddlers in the general population. Therefore, we investigated behavioural profiles at two time points and determined whether behaviours are stable during early development.
Methods
Parents of 4,237 children completed questionnaires with 62 items about externalizing, internalizing, and social-communicative behaviour when the children were 14–15 and 36–37 months old. Factor mixture modelling identified five homogeneous profiles at both time points: three with relatively normal behaviour or with mild/moderate problems, one with clear communication and interaction problems, and another with pronounced negative and demanding behaviour.
Results
More than 85% of infants with normal behaviour or mild problems at 14–15 months were reported to behave relatively typically as toddlers at 36–37 months. A similar percentage of infants with moderate communication problems outgrew their problems by the time they were toddlers. However, infants with severe problems had mild to severe problems as toddlers, and did not show completely normal behaviour. Improvement over time occurred more often in children with negative and demanding behaviour than in children with communication and interaction problems. The former showed less homotypic continuity than the latter.
Conclusions
Negative and demanding behaviour is more often transient and a less specific predictor of problems in toddlerhood than communication and interaction problems.
doi:10.1186/1753-2000-8-19
PMCID: PMC4110065  PMID: 25061477
Factor mixture modelling; Behavioural and developmental profiles and problems; Continuity and stability; Infants and toddlers; General population
4.  Brain Volumetric Correlates of Autism Spectrum Disorder Symptoms in Attention Deficit/Hyperactivity Disorder 
PLoS ONE  2014;9(6):e101130.
Autism spectrum disorder (ASD) symptoms frequently occur in subjects with attention deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural correlates, no study to date has investigated these structural correlates within a framework that robustly accounts for the phenotypic overlap between the two disorders. The presence of ASD symptoms was measured by the parent-reported Children’s Social and Behavioural Questionnaire (CSBQ) in ADHD subjects (n = 180), their unaffected siblings (n = 118) and healthy controls (n = 146). ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners’ ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of ASD symptom scores were analysed by modelling ASD symptom scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. ASD symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. ASD scores were predicted by the interaction between WM and GM volumes. Increasing ASD score was associated with greater GM volume. Equivocal results from previous structural studies in ADHD and ASD may be due to the fact that comorbidity has not been taken into account in studies to date. The current findings stress the need to account for issues of ASD comorbidity in ADHD.
doi:10.1371/journal.pone.0101130
PMCID: PMC4076257  PMID: 24979066
6.  Identification of an age-dependent biomarker signature in children and adolescents with autism spectrum disorders 
Molecular Autism  2013;4:27.
Background
Autism spectrum disorders (ASDs) are neurodevelopmental conditions with symptoms manifesting before the age of 3, generally persisting throughout life and affecting social development and communication. Here, we have investigated changes in protein biomarkers in blood during childhood and adolescent development.
Methods
We carried out a multiplex immunoassay profiling analysis of serum samples from 37 individuals with a diagnosis of ASD and their matched, non-affected siblings, aged between 4 and 18 years, to identify molecular pathways affected over the course of ASDs.
Results
This analysis revealed age-dependent differences in the levels of 12 proteins involved in inflammation, growth and hormonal signaling.
Conclusions
These deviations in age-related molecular trajectories provide further insight into the progression and pathophysiology of the disorder and, if replicated, may contribute to better classification of ASD individuals, as well as to improved treatment and prognosis. The results also underline the importance of stratifying and analyzing samples by age, especially in ASD and potentially other developmental disorders.
doi:10.1186/2040-2392-4-27
PMCID: PMC3751071  PMID: 23915542
Autism; Age; Biomarkers; Molecular profiling; Inflammation; Metabolism
7.  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 generalizability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. We therefore 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
We ran multivariate familial models on data from 1789 individuals at ages 6 to 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 (0.2–0.4) and familial (0.3–0.5) correlations were observed among ADHD, reading difficulties and IQ. Yet 53% to 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, though 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.
doi:10.1111/j.1469-7610.2012.02527.x
PMCID: PMC3414694  PMID: 22324316
ADHD; reading difficulties; IQ; familial; sibling-pair; comorbidity
8.  Linkage to Chromosome 1p36 for Attention Deficit Hyperactivity Disorder Traits in School and Home Settings 
Biological psychiatry  2008;64(7):571-576.
Background
Limited success has been achieved through previous ADHD linkage scans which were all designed to map genes underlying the dichotomous phenotype. The International Multi-centre ADHD Genetics (IMAGE) project performed a whole genome linkage scan specifically designed to map ADHD quantitative trait loci.
Methods
A set of 1,094 single selected Caucasian ADHD nuclear families was genotyped on a highly accurate and informative SNP panel. Two quantitative traits measuring the children’s symptoms in home and school settings were collected and standardized according to a population sample of 8000 children to reflect the developmental nature and gender prevalence difference of ADHD. Univariate linkage test was performed on both traits and their mean score.
Results
A significant common linkage locus was found at chromosome 1p36 with a locus-specific heritability of 5.1% and a genomewide empirical p<0.04. Setting-specific suggestive linkage signals were also found: LOD=2.2 at 9p23 for home trait and LOD=2.6 at 11q21 for school trait.
Conclusions
These results indicate that given large samples with proper phenotypic measures, searching for ADHD genes with a QTL strategy is an important alternative to using the clinical diagnosis. The fact that our linkage region 1p36 overlaps with the dyslexia QTL DYX8 further suggests it is potentially a pleiotropic locus for ADHD and dyslexia.
doi:10.1016/j.biopsych.2008.02.024
PMCID: PMC3589988  PMID: 18439570
9.  Callous–unemotional traits as a cross-disorders construct 
Purpose
Callous–unemotional (CU) traits are currently viewed as the defining signs and symptoms of juvenile psychopathy. It is unclear, however, whether CU traits have validity only in the context of conduct disorder (CD) as proposed by Frick and Moffitt (A proposal to the DSM-V childhood disorders and the ADHD and disruptive behavior disorders work groups to include a specifier to the diagnosis of conduct disorder based on the presence of callous–unemotional traits, American Psychiatric Association, Washington, DC, 2010), or also outside CD, either in combination with other forms of psychopathology or as a stand-alone construct.
Methods
The current review systematically studied the existent literature on CU traits in juveniles to examine their validity inside and outside CD according to the framework regarding the validity of a psychiatric diagnosis provided by Robins and Guze (Am J Psychiatry 126:983–987, 1970).
Results
Inside youth with conduct problems, and CD specifically, it seems that CU traits meet the Robins and Guze criteria. As many of the reviewed studies included youth with ODD and ADHD as well, there are indications the same might be true for ODD and ADHD, although probably to a lesser extent. In other disorders, CU traits may be present as well, but their role is not firmly established. As stand-alone construct, data are lacking or are scarce on all of the above-mentioned criteria.
Conclusions
CU traits are a useful specifier in CD, and possibly also in disruptive behaviour disorders (DBDs) more generally. High CU traits outside DBDs exist but it is as yet unknown if there is a clinical need for defining CU traits as a stand-alone construct.
doi:10.1007/s00127-012-0513-x
PMCID: PMC3496473  PMID: 22570257
Callous–unemotional traits; Juvenile psychopathy; Conduct disorder; Validity
10.  Visual Scanning in Very Young Children with Autism and Their Unaffected Parents 
Autism Research and Treatment  2012;2012:748467.
This study of gaze patterns in very young children with autism and their parents included 23 cases (with 16 fathers and 19 mothers) and 46 controls (with 14 fathers and 28 mothers). Children (mean age 3.3 ± 1.5 years) with autism met DSM-IV and ADOS-G diagnostic criteria. The participants' gaze patterns were recorded while they viewed four simple movies that did not feature people. In children, severity of autism is related to spending more time watching irrelevant regions in one of the four movies. The mothers of children with autism showed an atypical pattern for three movies, whereas the fathers of children with autism did not show an atypical gaze pattern. The gaze pattern of the mothers was positively correlated with that of their children. The atypical viewing pattern of autistic individuals appears not to be restricted to people and social situations but is also seen in other situations, suggesting that there is a perceptual broad autism phenotype.
doi:10.1155/2012/748467
PMCID: PMC3420630  PMID: 22937259
11.  Life before birth: are the dice tossed for the rest of our lives? 
doi:10.1007/s00787-012-0264-y
PMCID: PMC3314808  PMID: 22382495
12.  Perinatal Risk Factors Interacting With Catechol O-Methyltransferase and the Serotonin Transporter Gene Predict ASD symptoms in Children With ADHD 
Background
Symptoms of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) often co-occur. Given the previously found familiality of ASD symptoms in children with ADHD, addressing these symptoms may be useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD.
Methods
We studied the association of the catechol o-methyltransferase (COMT) Val158Met polymorphism and the serotonin transporter (SLC6A4/SERT/5-HTT) 5-HTTLPR insertion/deletion polymorphism with ASD symptoms in children with ADHD, and whether these polymorphisms would interact with pre- and perinatal risk factors, i.e., maternal smoking during pregnancy and low birth weight. Analyses were performed using linear regression in 207 Dutch participants with combined type ADHD of the International Multicenter ADHD Genetics (IMAGE) study, and repeated in an independent ADHD sample (n = 439) selected from the TRracking Adolescents' Individual Lives Survey (TRAILS). Dependent variables were the total and subscale scores of the Children's Social Behavior Questionnaire (CSBQ).
Results
No significant main effects of COMT Val158Met, 5-HTTLPR, maternal smoking during pregnancy and low birth weight on ASD symptoms were found. However, the COMT Val/Val genotype interacted with maternal smoking during pregnancy in increasing stereotyped behavior in the IMAGE sample (p = 0.008); this interaction reached significance in the TRAILS sample after correction for confounders (p = 0.02). In the IMAGE sample, the 5-HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction (p = 0.02), and also interacted with low birth weight, increasing rigid behavior (p = 0.03). Findings for 5-HTTLPR in the TRAILS sample were similar, albeit for related CSBQ subscales.
Conclusions
These findings suggest gene-environment interaction effects on ASD symptoms in children with ADHD.
doi:10.1111/j.1469-7610.2010.02277.x
PMCID: PMC2970704  PMID: 20868372
Attention-deficit/Hyperactivity Disorder; Autism Spectrum Disorder; gene environment; 5-HTT; COMT
13.  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 scans (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 Children’s 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 the 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 SNPs, 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 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 disorder’s heritability.
doi:10.1016/j.jaac.2010.06.008
PMCID: PMC2928252  PMID: 20732625
ADHD; meta-analysis; association; GWAS; genetics
14.  Identifying Loci for the Overlap Between ADHD and ASD Using a Genome-wide QTL Linkage Approach 
Objective
The genetic basis for Autism Spectrum Disorder (ASD) symptoms in children with Attention-Deficit Hyperactivity Disorder (ADHD) was addressed using a genome-wide linkage approach.
Method
Participants of the International Multi-Center ADHD Genetics study comprising 1143 probands with ADHD and 1453 siblings were analyzed. The total and subscale scores of the Social Communication Questionnaire (SCQ) were used as quantitative traits for multipoint regression-based linkage analyses on 5407 autosomal single-nucleotide polymorphisms applying MERLIN-regress software, both without and with inclusion of ADHD symptom scores as covariates.
Results
The analyses without ADHD symptom scores as covariates resulted in 3 suggestive linkage signals, i.e., on chromosomes 15q24, 16p13, and 18p11. Inclusion of ADHD symptom scores as covariates resulted in additional suggestive loci on chromosomes 7q36 and 12q24, whereas the LOD score of the locus on chromosome 15q decreased below the threshold for suggestive linkage. The loci on 7q, 16p, and 18p were found for the SCQ restricted & repetitive subscale, that on 15q was found for the SCQ communication subscale, and that on 12q for the SCQ total score.
Conclusions
Our findings suggest that QTLs identified in this study are ASD specific, although the 15q QTL potentially has pleiotropic effects for ADHD and ASD. This study confirms that genetic factors influence ASD traits along a continuum of severity, as loci potentially underlying ASD symptoms in children with ADHD were identified even though subjects with autism had been excluded from the IMAGE sample, and supports the hypothesis that differential genetic factors underlie the three ASD dimensions.
doi:10.1016/j.jaac.2010.03.015
PMCID: PMC2929476  PMID: 20610137
ADHD; autism spectrum disorder; linkage; comorbidity
15.  Undertreatment of Motor Problems in Children with ADHD 
Background
Motor problems occur in 30% to 50% of children with ADHD, and have a severe impact on daily life. In clinical practice there seems to be little attention for this comorbidity with the possible consequence that these motor problems go undertreated.
Method
Clinical interview and questionnaire survey of treatment by physiotherapy and factors predicting treatment of motor problems in 235 children with ADHD and 108 controls.
Results
Half of motor-affected children had received physiotherapy. Treated children had more severe motor problems, and less frequently presented with comorbid anxiety and conduct disorder. Treated and untreated children were similar in age, and rated similarly on ADHD inattentive and hyperactive-impulsive scales and parental socio-economic status.
Conclusion
Currently, undertreatment of motor problems in ADHD occurs. Behavioural factors play a role in referral and intervention.
doi:10.1111/j.1475-3588.2009.00538.x
PMCID: PMC2850122  PMID: 20376200
ADHD; motor problems; children; developmental coordination disorder questionnaire; comorbidity; physiotherapy
16.  The dopamine receptor D4 7-repeat allele and prenatal smoking in ADHD-affected children and their unaffected siblings: no gene–environment interaction 
Background
The dopamine receptor D4 (DRD4) 7-repeat allele and maternal smoking during pregnancy are both considered as risk factors in the aetiology of attention deficit hyperactivity disorder (ADHD), but few studies have been conducted on their interactive effects in causing ADHD. The purpose of this study is to examine the gene by environment (G×E) interaction of the DRD4 7-repeat allele and smoking during pregnancy on ADHD and oppositional behavior in families from the International Multicenter ADHD Genetics project; and further, to test the hypothesis that the direction of effect of the DRD4 7-repeat allele differs between ADHD affected and unaffected children.
Methods
Linear mixed models were used to assess main and interactive effects of the DRD4 7-repeat allele and smoking during pregnancy in 539 ADHD-affected children and their 407 unaffected siblings, aged 6–17 years.
Results
There was some evidence pointing to differential effects of the DRD4 7-repeat allele on ADHD and oppositional symptoms in the affected (fewer symptoms) and unaffected children (increasing ADHD symptoms of teacher ratings). Affected children were more often exposed to prenatal smoking than unaffected children. There were limited main effects of prenatal smoking on severity of symptoms. Given the number of tests performed, no indication was found for G×E interactions.
Conclusion
Despite the large sample size, no G×E interactions were found. The impact of the DRD4 7-repeat allele might differ, depending on affected status and rater. This finding is discussed in terms of differences in the activity of the dopaminergic system and of different genes involved in raterspecific behaviors.
doi:10.1111/j.1469-7610.2008.01998.x
PMCID: PMC2870715  PMID: 19017022
Dopamine receptor D4 gene; attention deficit hyperactivity disorder (ADHD); maternal smoking during pregnancy; gene by environment interaction
17.  Randomized Controlled Trial of the Focus Parent Training for Toddlers with Autism: 1-Year Outcome 
This randomized controlled trial compared results obtained after 12 months of nonintensive parent training plus care-as-usual and care-as-usual alone. The training focused on stimulating joint attention and language skills and was based on the intervention described by Drew et al. (Eur Child Adolesc Psychiatr 11:266–272, 2002). Seventy-five toddlers with autism spectrum disorder (65 autism, 10 PDD-NOS, mean age = 34.4 months, SD = 6.2) were enrolled. Analyses were conducted on a final sample of 67 children (lost to follow-up = 8). No significant intervention effects were found for any of the primary (language), secondary (global clinical improvement), or mediating (child engagement, early precursors of social communication, or parental skills) outcome variables, suggesting that the ‘Focus parent training’ was not of additional value to the more general care-as-usual.
doi:10.1007/s10803-010-1004-0
PMCID: PMC2980624  PMID: 20440639
Autism; Parent training; Toddler; Early intervention; Randomized controlled trial
18.  A Pilot Study of Abnormal Growth in Autism Spectrum Disorders and Other Childhood Psychiatric Disorders 
The aims of the current study were to examine whether early growth abnormalities are (a) comparable in autism spectrum disorders (ASD) and other childhood psychiatric disorders, and (b) specific to the brain or generalized to the whole body. Head circumference, height, and weight were measured during the first 19 months of life in 129 children with ASD and 59 children with non-ASD psychiatric disorders. Both groups showed comparable abnormal patterns of growth compared to population norms, especially regarding height and head circumference in relation to height. Thus abnormal growth appears to be related to psychiatric disorders in general and is mainly expressed as an accelerated growth of height not matched by an increase in weight or head circumference.
doi:10.1007/s10803-010-1026-7
PMCID: PMC3005115  PMID: 20428954
Autism; Growth; Head circumference; Height; Weight; Endophenotype
19.  Effects of food on physical and sleep complaints in children with ADHD: a randomised controlled pilot study 
European Journal of Pediatrics  2010;169(9):1129-1138.
Attention deficit/hyperactivity disorder (ADHD), a common behavioural disorder in children, may be associated with comorbid physical and sleep complaints. Dietary intervention studies have shown convincing evidence of efficacy in reducing ADHD symptoms in children. In this pilot study, we investigated the effects of an elimination diet on physical and sleep complaints in children with ADHD. A group of 27 children (3.8–8.5 years old), who all met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD, were assigned randomly to either a diet group (15/27) or a control group (12/27). The diet group followed a 5-week elimination diet; the control group adhered to their normal diet. Parents of both groups had to keep an extended diary and had to monitor the behaviour and the physical and sleep complaints of their child conscientiously. The primary endpoint was the clinical response, i.e. a decrease of physical and sleep complaints, at the end of the trial, based on parent ratings on a Physical Complaints Questionnaire. The number of physical and sleep complaints was significantly decreased in the diet group compared to the control group (p < 0.001), with a reduction in the diet group of 77% (p < 0.001, effect size = 2.0) and in the control group of 17% (p = 0.08, effect size = 0.2). Specific complaints that were significantly reduced were in three domains: headaches or bellyaches, unusual thirst or unusual perspiration, and sleep complaints. The reduction of complaints seemed to occur independently of the behavioural changes (p = 0.1). However, the power of this comparison was low. A positive correlation existed between the reduction of physical and behavioural symptoms (p < 0.01). The reduction did not differ between children with or without an atopic constitution (p = 0.7). An elimination diet may be an effective instrument to reduce physical complaints in children with ADHD, but more research is needed to determine the effects of food on (functional) somatic symptoms in children with and without ADHD. This trial was registered as an International Standard Randomised Controlled Trial, ISRCTN47247160.
doi:10.1007/s00431-010-1196-5
PMCID: PMC2908441  PMID: 20401617
ADHD; Children; Elimination diet; Physical complaints; Sleep problems
20.  Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder 
Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders. Evidence indicates both disorders co-occur with a high frequency, in 20–50% of children with ADHD meeting criteria for ASD and in 30-80% of ASD children meeting criteria for ADHD. This review will provide an overview on all available studies [family based, twin, candidate gene, linkage, and genome wide association (GWA) studies] shedding light on the role of shared genetic underpinnings of ADHD and ASD. It is concluded that family and twin studies do provide support for the hypothesis that ADHD and ASD originate from partly similar familial/genetic factors. Only a few candidate gene studies, linkage studies and GWA studies have specifically addressed this co-occurrence, pinpointing to some promising pleiotropic genes, loci and single nucleotide polymorphisms (SNPs), but the research field is in urgent need for better designed and powered studies to tackle this complex issue. We propose that future studies examining shared familial etiological factors for ADHD and ASD use a family-based design in which the same phenotypic (ADHD and ASD), candidate endophenotypic, and environmental measurements are obtained from all family members. Multivariate multi-level models are probably best suited for the statistical analysis.
doi:10.1007/s00787-010-0092-x
PMCID: PMC2839489  PMID: 20148275
Attention-deficit/hyperactivity disorder; Autism spectrum disorder; Molecular genetics; Shared heritability
21.  Improved Diagnostic Validity of the ADOS Revised Algorithms: A Replication Study in an Independent Sample 
Recently, Gotham et al. (2007) proposed revised algorithms for the Autism Diagnostic Observation Schedule (ADOS) with improved diagnostic validity. The aim of the current study was to replicate predictive validity, factor structure, and correlations with age and verbal and nonverbal IQ of the ADOS revised algorithms for Modules 1 and 2 in a large independent Dutch sample (N = 532). Results showed that the improvement of diagnostic validity was most apparent for autism, except in very young or low functioning children. Results for other autism spectrum disorders were less consistent. Overall, these findings support the use of the more homogeneous revised algorithms, with the use of similar items across developmental cells making it easier to compare ADOS scores within and between individuals.
doi:10.1007/s10803-009-0915-0
PMCID: PMC2864898  PMID: 20148299
Autism; ADOS; Algorithm; Sensitivity; Specificity; Diagnosis
22.  Neuropsychological measures probably facilitate heritability research of ADHD 
Abstract
Previous studies, in which cognitive and motor neuropsychological tasks were administered to 816 children from Attention-Deficit/Hyperactivity Disorder (ADHD)- and control-families, showed that various of these measures appeared useful for genetic research in ADHD by forming candidate endophenotypes: underlying, heritable, vulnerability traits that mark an enhanced liability for developing ADHD. The current study extends these findings by showing that six of these ten measures correlate more strongly between siblings than an ADHD composite, suggesting these measures may have a larger heritability than ADHD itself. Significant sibling cross-correlations also suggested that six of ten neuropsychological measures related to similar familial (and heritable) factors as ADHD, suggesting these measures to be useful for ADHD genetic research. An aggregated neuropsychological composite appeared to be the most powerful, since it correlated more strongly between siblings than most individual task measures. These findings suggest heritability research in ADHD will probably be facilitated by including neuropsychological measures.
doi:10.1016/j.acn.2008.06.002
PMCID: PMC3895968  PMID: 18635338
Endophenotype; Phenotype; ADHD; Heritability; Neuropsychology; Siblings
23.  Effects of maternal and paternal smoking on attentional control in children with and without ADHD 
Maternal smoking during pregnancy is a risk factor for attention-deficit/hyperactivity disorder (ADHD), but data on its adverse effects on cognitive functioning are sparse and inconsistent. Since the effect of maternal smoking during pregnancy may be due to correlated genetic risk factors rather than being a pure environmental effect, we examined the effect of prenatal exposure to smoking on attentional control, taking into account the effects of both maternal and paternal smoking, and examined whether these effects were genetically mediated by parental genotypes. We further examined whether the effect of prenatal exposure to smoking on attentional control interacted with genotypes of the child. Participants were 79 children with ADHD, ascertained for the International Multi-centre ADHD Gene project (IMAGE), and 105 normal controls. Attentional control was assessed by a visual continuous performance task. Three genetic risk factors for ADHD (DRD4 7-repeat allele of the exon 3 variable number of tandem repeats (VNTR), DAT1 10/10 genotype of the VNTR located in the 3′ untranslated region, and the DAT1 6/6 genotype of the intron 8 VNTR) were included in the analyses. Paternal smoking had a negative effect on attentional control in children with ADHD and this effect appeared to be mediated by genetic risk factors. The prenatal smoking effect did not interact with genotypes of the child. Maternal smoking had no main effect on attentional control, which may be due to lower smoking rates. This study suggests that the effects of paternal smoking on attentional control in children with ADHD should be considered a proxy for ADHD and/or smoking risk genes. Future studies should examine if the results can be generalized to other cognitive domains.
doi:10.1007/s00787-009-0001-3
PMCID: PMC2718195  PMID: 19288168
ADHD; Genetics; Smoking; Pregnancy; Response time variability
24.  Comorbid Problems in ADHD: Degree of Association, Shared Endophenotypes, and Formation of Distinct Subtypes. Implications for a Future DSM 
We aimed to assess which comorbid problems (oppositional defiant behaviors, anxiety, autistic traits, motor coordination problems, and reading problems) were most associated with Attention-Deficit/Hyperactivity Disorder (ADHD); to determine whether these comorbid problems shared executive and motor problems on an endophenotype level with ADHD; and to determine whether executive functioning (EF)—and motor-endophenotypes supported the hypothesis that ADHD with comorbid problems is a qualitatively different phenotype than ADHD without comorbid problems. An EF—and a motor-endophenotype were formed based on nine neuropsychological tasks administered to 816 children from ADHD—and control-families. Additional data on comorbid problems were gathered using questionnaires. Results indicated that oppositional defiant behaviors appeared the most important comorbid problems of ADHD, followed by autistic traits, and than followed by motor coordination problems, anxiety, and reading problems. Both the EF—and motor-endophenotype were correlated and cross-correlated in siblings to autistic traits, motor coordination problems and reading problems, suggesting ADHD and these comorbid problems may possibly share familial/genetic EF and motor deficits. No such results were found for oppositional defiant behaviors and anxiety. ADHD in co-occurrence with comorbid problems may not be best seen as a distinct subtype of ADHD, but further research is warranted.
Electronic supplementary material
The online version of this article (doi:10.1007/s10802-009-9312-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s10802-009-9312-6
PMCID: PMC2708322  PMID: 19308723
Attention-deficit/Hyperactivity disorder; Comorbidity; Endophenotype; Phenotype; DSM-V
25.  Speed, Variability, and Timing of Motor Output in ADHD: Which Measures are Useful for Endophenotypic Research? 
Behavior Genetics  2007;38(2):121-132.
Attention-Deficit/Hyperactivity Disorder (ADHD) shares a genetic basis with motor coordination problems and probably motor timing problems. In line with this, comparable problems in motor timing should be observed in first degree relatives and might, therefore, form a suitable endophenotypic candidate. This hypothesis was investigated in 238 ADHD-families (545 children) and 147 control-families (271 children). A motor timing task was administered, in which children had to produce a 1,000 ms interval. In addition to this task, two basic motor tasks were administered to examine speed and variability of motor output, when no timing component was required. Results indicated that variability in motor timing is a useful endophenotypic candidate: It was clearly associated with ADHD, it was also present in non-affected siblings, and it correlated within families. Accuracy (under- versus over-production) in motor timing appeared less useful: Even though accuracy was associated with ADHD (probands and affected siblings had a tendency to under-produce the 1,000 ms interval compared to controls), non-affected siblings did not differ from controls and sibling correlations were only marginally significant. Slow and variable motor output without timing component also appears present in ADHD, but not in non-affected siblings, suggesting these deficits not to be related to a familial vulnerability for ADHD. Deficits in motor timing could not be explained by deficits already present in basic motor output without a timing component. This suggests abnormalities in motor timing were predominantly related to deficient motor timing processes and not to general deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD.
doi:10.1007/s10519-007-9186-8
PMCID: PMC2257997  PMID: 18071893
ADHD; Siblings; Endophenotype; Motor timing; Motor speed; Motor variability

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