Evaluating physical activity using accelerometry in children at risk of developmental coordination disorder in the presence of attention deficit hyperactivity disorder

Physical activity (PA) is compromised in children and adolescents with developmental coordination disorder (DCD). Approximately half of all children with DCD suffer from attention-deficit hyperactive disorder (ADHD); a cohort often considered more physically active than typically developing youth. Accelerometry is an effective method of assessing physical activity patterns; although estimates of PA in children with DCD using this quantifiable method have not been attempted. We hypothesize that children with co-morbid DCD/ADHD will be more physically active than children with DCD and healthy peers. Therefore, the purpose of this study was to contrast physical activity (step count and activity energy expenditure using accelerometry [AEE]) between children with DCD, co-morbid DCD and ADHD (DCD/ADHD), and healthy controls. A sample of 110 children with DCD (N = 32), DCD/ADHD (N = 30) and controls (N = 48) age 12-13 years agreed to participate. Co-morbid DCD/ADHD was present in nearly half of the children with DCD (48.4%). Analysis of covariance demonstrated a positive interaction for females step count (F[1,92] = 4.92, p = 0.009). A significant group difference for step count (F[1,92] = 4.43, p = .04) was identified in females. Post hoc comparison tests identified significantly lower step count between males with DCD and controls (p = .004) and males with DCD/ADHD and controls (p = 0.003). Conversely, females with DCD/ADHD had significantly more step counts than their controls (p = .01). Hyperactivity in females with DCD/ADHD appears to contribute to more physical activity, whereas DCD may contribute to decreased activity in males with DCD and DCD/ADHD. Hyperactivity expressed among girls with DCD/ADHD appears to override the hypoactive behavior associated with females with DCD. Conversely, the expression of hyperactivity among boys with DCD/ADHD does not translate as hypothesized. The contrasting expression of physical activity (i.e., step count and AEE) evaluated using accelerometry in boys and girls with DCD, co-morbid DCD/ADHD and healthy peers are intriguing and constitute further investigation in a larger investigation.     

Deficient response inhibition as a cognitive endophenotype of ADHD

OBJECTIVE: To investigate whether a deficient response inhibition is a cognitive endophenotype of attention-deficit/hyperactivity disorder (ADHD). The authors hypothesized that nonaffected siblings of ADHD probands would have a response inhibition between that of ADHD probands and normal controls, although they resembled the controls at a behavioral level. METHOD: Participants were 25 ADHD probands with a family history of ADHD, their nonaffected siblings (n = 25), and 48 normal controls matched for age and IQ. All participants were between 6 and 17 years of age. The nonaffected siblings were compared with their ADHD siblings and with controls on measures reflecting different types of response inhibition. RESULTS: The nonaffected siblings had results similar to those of the ADHD probands, who differed from the controls on all inhibition measures (p <.05). CONCLUSIONS: Siblings of ADHD probands, while not behaviorally expressing the disorder, have ADHD-associated deficits in response inhibition. This suggests that subtyping based on measures of response inhibition can help identify genetic susceptibility to ADHD. Children with a genetic vulnerability to ADHD may have hidden cognitive deficits in the absence of manifest behavioral symptoms. Therefore, they should be monitored to detect possible learning problems.     

Time reproduction in children with ADHD and their nonaffected siblings

OBJECTIVE: Time reproduction is deficient in children with attention-deficit/hyperactivity disorder (ADHD). Whether this deficit is familial and could therefore serve as a candidate endophenotype has not been previously investigated. It is unknown whether timing deficits are also measurable in adolescent children with ADHD and nonaffected siblings. METHOD: These issues were investigated in 226 children with ADHD, 188 nonaffected siblings, and 162 normal controls ages 5 to 19. Children participated in a visual and auditory time reproduction task. They reproduced interval lengths of 4, 8, 12, 16, and 20 seconds. RESULTS: Children with ADHD and their nonaffected siblings were less precise than controls, particularly when task difficulty was systematically increased. Time reproduction skills were familial. Time reproduction deficits were more pronounced in younger children with ADHD than in older children. Children with ADHD could be clearly dissociated from control children until the age of 9. After this age, group differences were somewhat attenuated, but were still present. Differences between nonaffected siblings and controls were constant across the age range studied. Deficits were unaffected by modality. CONCLUSIONS: Time reproduction may serve as a candidate endophenotype for ADHD, predominantly in younger children with (a genetic risk for) ADHD.     

The attenuation of dysfunctional emotional processing with stimulant medication: An fMRI study of adolescents with ADHD

Functional neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) have focused on the neural correlates of cognitive control. However, for many youths with ADHD, emotional lability is an important clinical feature of the disorder. We aimed to identify the neural substrates associated with emotional lability that were distinct from impairments in cognitive control and to assess the effects that stimulants have on those substrates. We used functional magnetic resonance imaging (fMRI) to assess neural activity in adolescents with (N = 15) and without (N = 15) ADHD while they performed cognitive and emotional versions of the Stroop task that engage cognitive control and emotional processing, respectively. The participants with ADHD were scanned both on and off stimulant medication in a counterbalanced fashion. Controlling for differences in cognitive control, we found that during the emotional Stroop task, adolescents with ADHD as compared with controls demonstrated atypical activity in the medial prefrontal cortex (mPFC). Stimulants attenuated activity in the mPFC to levels comparable with controls.     

Parsing the familiality of oppositional defiant disorder from that of conduct disorder: a familial risk analysis

Background

Family risk analysis can provide an improved understanding of the association between attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), attending to the comorbidity with conduct disorder (CD).

Methods

We compared rates of psychiatric disorders in relatives of 78 control probands without ODD and CD (Control, N = 265), relatives of 10 control probands with ODD and without CD (ODD, N = 37), relatives of 19 ADHD probands without ODD and CD (ADHD, N = 71), relatives of 38 ADHD probands with ODD and without CD (ADHD + ODD, N = 130), and relatives of 50 ADHD probands with ODD and CD (ADHD + ODD + CD, N = 170).

Results

Rates of ADHD were significantly higher in all three ADHD groups compared to the Control group, while rates of ODD were significantly higher in all three ODD groups compared to the Control group. Evidence for co-segregation was found in the ADHD + ODD group. Rates of mood disorders, anxiety disorders, and addictions in the relatives were significantly elevated only in the ADHD + ODD + CD group.

Conclusions

ADHD and ODD are familial disorders, and ADHD plus ODD outside the context of CD may mark a familial subtype of ADHD. ODD and CD confer different familial risks, providing further support for the hypothesis that ODD and CD are separate disorders.     

Quick and easy self-rating of Generalized Anxiety Disorder: validity of the Dutch web-based GAD-7, GAD-2 and GAD-SI

Although psychometrically-defined executive function deficits (EFDs) and ecologically valid functional outcomes have been documented among youth with bipolar I (BP-I) disorder, little is known about their association. We hypothesized that EFDs would be associated with significant ecologically valid impairments beyond those predicted by having BP-I disorder. Youth with BP-I disorder were ascertained from psychiatric clinics and community sources. We defined EFDs as having at least two out of eight EF measures impaired from a battery of six tests. Significantly more youth with BP-I disorder had EFDs than controls (45% versus 17%). Comparisons were made between controls without EFDs (N = 81), controls with EFDs (N = 17), BP-I youth without EFDs (N = 76), and BP-I youth with EFDs (N = 62). EFDs were associated with an increased risk for placement in a special class and a decrease in academic achievement (WRAT-3 reading and arithmetic). EFDs in BP-I subjects were associated with an increased risk for speech/language disorder (as assessed in the K-SADS-E) relative to BP-I subjects without EFDs. Youth with BP-I disorder and EFDs are at high risk for significant impairments in academic functioning.     

The behavioural profile of children with attention-deficit/hyperactivity disorder and of their siblings

The behavioural profiles in N = 69 index children with attention-deficit/hyperactivity disorder (ADHD), N = 32 siblings with ADHD, N = 35 siblings without ADHD, and N = 36 normal controls were compared by the use of standardized parent and teacher rating scales. The four groups were matched by age and IQ. The behavioural profiles of the two ADHD groups were very similar not only in the behavioural domains of ADHD, but also in scales measuring emotional and conduct problems. Siblings without ADHD shared more similarities with normal controls except for more emotional problems. These general trends were stronger in the parent compared to the teacher ratings. These findings indicate that not only ADHD-related but also other behaviours show a strong family aggregation. The informant differences may reflect context dependent differences in child behaviour and contrast effects particularly in parental ratings.     

Role of gene-gene/gene-environment interaction in the etiology of eastern Indian ADHD probands

Associations between attention deficit hyperactivity disorder (ADHD) and genetic polymorphisms in the dopamine receptors, transporter and metabolizing enzymes have been reported in different ethnic groups. Gene variants may affect disease outcome by acting synergistically or antagonistically and thus their combined effect becomes an important aspect to study in the disease etiology. In the present investigation, interaction between ten functional polymorphisms in DRD4, DAT1, MAOA, COMT, and DBH genes were explored in the Indo-Caucasoid population. ADHD cases were recruited based on DSM-IV criteria. Peripheral blood samples were collected from ADHD probands (N = 126), their parents (N = 233) and controls (N = 96) after obtaining informed written consent for participation. Genomic DNA was subjected to PCR based analysis of single nucleotide polymorphisms and variable number of tandem repeats (VNTRs). Data obtained was examined for population as well as family-based association analyses. While case-control analysis revealed higher occurrence of DAT1 intron 8 VNTR 5R allele (P = 0.02) in cases, significant preferential transmission of the 7R-T (DRD4 exon3 VNTR-rs1800955) and 3R-T (MAOA-u VNTR-rs6323) haplotypes were noticed from parents to probands (P = 0.02 and 0.002 respectively). Gene-gene interaction analysis revealed significant additive effect of DBH rs1108580 and DRD4 rs1800955 with significant main effects of DRD4 exon3 VNTR, DAT1 3′UTR and intron 8 VNTR, MAOA u-VNTR, rs6323, COMT rs4680, rs362204, DBH rs1611115 and rs1108580 thereby pointing towards a strong association of these markers with ADHD. Correlation between gene variants, high ADHD score and low DBH enzymatic activity was also noticed, especially in male probands. From these observations, an impact of the studied sites on the disease etiology could be speculated in this ethnic group.     

Evidence that genetic variation in the oxytocin receptor (OXTR) gene influences social cognition in ADHD

Some children with ADHD also have social and communication difficulties similar to those seen in children with autistic spectrum disorders and this may be due to shared genetic liability. As the oxytocin receptor (OXTR) gene has been implicated in social cognition and autistic spectrum disorders, this study investigated whether OXTR polymorphisms previously implicated in autism were associated with ADHD and whether they influenced OXTR mRNA expression in 27 normal human amygdala brain samples. The family-based association sample consisted of 450 DSM-IV diagnosed ADHD probands and their parents. Although there was no association with the ADHD phenotype, an association with social cognitive impairments in a subset of the ADHD probands (N = 112) was found for SNP rs53576 (F = 5.24, p = 0.007) with post-hoc tests demonstrating that the AA genotype was associated with better social ability compared to the AG genotype. Additionally, significant association was also found for rs13316193 (F = 3.09, p = 0.05) with post-hoc tests demonstrating that the CC genotype was significantly associated with poorer social ability than the TT genotype. No significant association between genotype and OXTR mRNA expression was found. This study supports previous evidence that the OXTR gene is implicated in social cognition.     

Parental age and assisted reproductive technology in autism spectrum disorders, attention deficit hyperactivity disorder, and Tourette syndrome in a Japanese population

We investigated whether advanced parental age and assisted reproductive technology (ART) are risk factors in autism spectrum disorders (ASDs), attention deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS). Clinical charts of Japanese outpatients with ASD (n = 552), ADHD (n = 87), and TS (n = 123) were reviewed. Parental age of individuals with ASD, ADHD, or TS was compared with parental age in the general population (GP) of Tokyo after adjusting for year of birth. Paternal and maternal ages were significantly higher in persons with ASD and ADHD, but not those with TS. In final steps of stepwise logistic regression analysis, both maternal and paternal age were associated with ASD after controlling for the other parent's age, gender, and birth order. In cases where the presence or absence of ART could be ascertained (ASD n = 467; ADHD n = 64; TS n = 83), the rate of ART in cases of persons with ASD (4.5%) was 1.8 times the frequency expected in the GP, while ART was not present in cases of persons with ADHD and TS. These preliminary results remain tentative pending replication with larger, community-based samples.     

Motor flexibility problems as a marker for genetic susceptibility to attention-deficit/hyperactivity disorder.

BACKGROUND: Since many children with attention-deficit/hyperactivity disorder (ADHD) have fine visuomotor problems that are already evident at a young age, motor dysfunctioning is investigated in family-genetic perspective. We hypothesized that if fine motor problems may be a marker for genetic susceptibility to ADHD, nonaffected siblings of ADHD probands would experience motor problems similar to those of their ADHD siblings. METHODS: Twenty-five carefully phenotyped ADHD probands with a family history of ADHD, their nonaffected siblings (n = 25), and 48 normal control subjects (aged 6 to 17) completed a motor fluency task and a motor flexibility task. The motor fluency task involved completion of a familiar, automatized trajectory, whereas the motor flexibility task required continuous adjustment of movement to complete an unpredictable random trajectory. RESULTS: On the motor fluency task, the performance of the nonaffected children was significantly better than that of the ADHD probands; strikingly, on the motor flexibility task, they performed as well as their ADHD siblings. CONCLUSIONS: Nonaffected siblings experience complex motor problems similar to their ADHD siblings but only in nonautomatized movements that require controlled processing. The results suggest that higher-order controlled motor deficits in ADHD may be associated with genetic susceptibility for ADHD.     

Neurotrophin-3 gene,intelligence, and selective attention deficit in a Korean sample with attention-deficit/hyperactivity disorder

Objective

Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder with a strong genetic component. Neurotrophin-3 (NTF3), which participates in the differentiation and survival of dopaminergic and noradrenergic neurons, has been identified as a factor in the development of ADHD. We investigated the relationships between ADHD and NTF3 gene polymorphism.

Methods

We conducted a case–control analysis of 202 ADHD subjects and 159 controls, performed a transmission disequilibrium test (TDT) on 151 trios, and compared the intelligence quotient (IQ) and a continuous performance test (CPT) according to the genotype of two single-nucleotide polymorphisms (SNPs) (rs6332 and rs6489630) in the NTF3 gene.

Results

In the case–control and family-based analyses, NTF3 was not significantly associated with ADHD. However, in the ADHD probands, the subjects with AA genotype in the rs6332 SNP had significantly higher mean T-scores for commission errors on the CPT than did those with the AG genotypes (p = 0.045). The mean IQ of the ADHD probands who had the CC genotype of the rs6489630 SNP were higher compared with those who had the CT or TT genotype (p = 0.035). The mean T-score for response time on the CPT was higher in the subjects with TT genotype in the rs6489630 SNP compared to those with the CC or CT genotype, even after adjusting for the effect of IQ (p = 0.021).

Conclusions

These results provide preliminary evidence of an association between NTF3 and the intelligence and selective attention deficit in the Korean population.     

Deficits in visuo-spatial working memory,inhibition and oculomotor control in boys with ADHD and their non-affected brothers

Summary Few studies have assessed visuo-spatial working memory and inhibition in attention-deficit/hyperactivity disorder (ADHD) by recording saccades and consequently little additional knowledge has been gathered on oculomotor functioning in ADHD. Moreover, this is the first study to report the performance of non-affected siblings of children with ADHD, which may shed light on the familiality of deficits. A total of 14 boys with ADHD, 18 non-affected brothers, and 15 control boys aged 7–14 years, were administered a memory-guided saccade task with delays of three and seven seconds. Familial deficits were found in accuracy of visuo-spatial working memory, percentage of anticipatory saccades, and tendency to overshoot saccades relative to controls. These findings suggest memory-guided saccade deficits may relate to a familial predisposition for ADHD. Correspondence: Nanda N. J. Rommelse, Department of Clinical Neuropsychology, VU University Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands     

Delay Aversion in Attention Deficit/Hyperactivity Disorder: an empirical investigation of the broader phenotype

Background

Delay-related motivational processes are impaired in children with Attention Deficit/Hyperactivity Disorder (ADHD). Here we explore the impact of ADHD on the performance of three putative indices of Delay Aversion (DAv): (i) the choice for immediate over delayed reward; (ii) slower reaction times following delay; and (iii) increased delay-related frustration—to see whether these tap into a common DAv construct that differentiates ADHD cases from controls and shows evidence of familiality.

Method

Seventy seven male and female individuals (age range 6-17) with a research diagnosis combined type ADHD, 65 of their siblings unaffected by ADHD and 50 non-ADHD controls completed three delay tasks.

Results

As predicted the size of the correlation between tasks was small but a common latent component was apparent. Children with ADHD differed from controls on all tasks (d = .4-.7) and on an overall DAv index (d = .9): The battery as a whole demonstrated moderate sensitivity and specificity. In general, deficits were equally marked in childhood and adolescence and were independent of comorbid ODD. IQ moderated the effect on the MIDA. Scores on the DAv factor co-segregated within ADHD families.

Discussion

There is value in exploring the broader DAv phenotype in ADHD. The results illustrate the power of multivariate approaches to endophenotypes. By highlighting the significant, but limited, role of DAv in ADHD these results are consistent with recent accounts that emphasize neuropsychological heterogeneity.     

The loudness dependence of the auditory evoked potential (LDAEP) in schizophrenia,bipolar disorder,major depressive disorder,anxiety disorder,and healthy controls

Background

Serotonergic dysfunction in schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, and healthy controls was evaluated by measuring the activity of the loudness dependence of the auditory evoked potential (LDAEP).

Methods

The 357 subjects who were evaluated comprised 55 normal controls, 123 patients with major depressive disorder, 37 with bipolar disorder, 46 with schizophrenia, 37 with panic disorder (PD), 31 with generalized anxiety disorder (GAD), and 28 with post-traumatic stress disorder (PTSD).

Results

LDAEP was significantly stronger in healthy controls than in patients with either bipolar disorder (p = 0.025) or schizophrenia (p = 0.008), and significantly stronger in patients with major depressive disorder than in those with bipolar disorder (p = 0.01) or schizophrenia (p = 0.03). LDAEP did not differ significantly between patients with major depressive disorder and healthy control subjects (p = 0.667), or between healthy control subjects and patients with anxiety disorder, including PD (p = 0.469), GAD (p = 0.664), and PTSD (p = 0.167).

Conclusion

The findings of the present study reveal that patients with major psychiatric disorders exhibit different strengths of LDAEP according to their serotonin-related pathology. Studies controlled for psychotropic medication, menstruation cycle, and smoking are needed.     

Association between the dopamine transporter gene and the inattentive subtype of attention deficit hyperactivity disorder in Taiwan

Attention deficit hyperactivity disorder (ADHD) is a common heritable childhood psychiatric disorder. Since methylphenidate, one of the main drugs used to treat ADHD, targets the dopamine transporter, this study examined the linkage disequilibrium (LD) structure of the dopamine transporter gene (DAT1) and investigated whether the DAT1 gene was associated with ADHD. This Chinese family-based association sample consisted of 273 DSM-IV diagnosed ADHD probands and their family members (n = 906). We screened 15 polymorphisms across the DAT1 gene, including 14 single nucleotide polymorphism (SNP) markers and the variable number of tandem repeat (VNTR) polymorphism in 3′-untranslated region (3′UTR). Calculations of pairwise LD revealed three main haplotype blocks (HBs): HB1 (intron 2 through intron 6), HB2 (intron 8 through intron 11), and HB3 (3′UTR). Family-Based Association Tests showed that no allele was significantly more transmitted than expected to the ADHD children for these 15 markers. Haplotype-Based Association Tests showed that a haplotype rs27048 (C)/rs429699 (T) was significantly associated with the inattentive subtype (P = 0.008). In quantitative analyses, this haplotype also demonstrated significant association with the inattention severity (P = 0.012). Our finding of the haplotype rs27048 (C)/rs429699 (T) as a novel genetic marker in the inattentive ADHD subtype suggests that variation in the DAT1 gene may primarily affect the inattentive subtype of ADHD.     

Association study of RELN polymorphisms with schizophrenia in Han Chinese population

Schizophrenia (SZ) is a common and complex psychiatric disorder with a strong genetic component. Previous research suggests that mutations altering genes in neurodevelopmental pathways contribute to SZ. Reelin gene (RELN) maps to chromosome 7q22.1, the encoded protein plays a pivotal role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports had indicated that reduced RELN expression is associated with human mental illnesses such as SZ, mood disorders and autism. In this study, case-control association analyses were performed in the Han Chinese population to determine if the RELN gene is a susceptibility gene for SZ. Thirty-seven single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was found between rs12705169 and SZ (p = 0.001). Moreover, the haplotypes constructed from five SNPs showed significant differences between cases and controls (p = 0.041). When subjects were divided by gender, rs12705169 remained significant difference only in females (OR = 0.24, 95%CI = 0.14-0.40 for CC and OR = 0.40, 95%CI = 0.27-0.58 for AC), both in the allele and genotype (p = 0.0001 for both). This study describes a positive association between RELN and SZ in the Han Chinese population, and provides genetic evidence to support the gender difference of SZ.     

Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder

Objective

We conducted a genome-wide association study of blood pressure in an open-label study of the methylphenidate transdermal system (MTS) for the treatment of attention-deficit/hyperactivity disorder (ADHD).

Method

Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0. Multivariate association analyses were conducted using the software package PLINK. After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD.

Results

We observed no genome-wide statistically significant findings, but a SNP in a K⁺-dependent Na⁺/Ca²⁺ exchanger expressed in vascular smooth muscle (SLC24A3) was included in our top associations at p < 1E-04. Genetic enrichment analyses of genes with ≥ 1 SNP significant at p < 0.01, implicated several functional categories (FERM domain, p = 5.0E-07; immunoglobulin domain, p = 8.1E-06; the transmembrane region, p = 4.4E-05; channel activity, p = 2.0E-04; and type-III fibronectins, p = 2.7E-05) harboring genes previously associated with related cardiovascular phenotypes.

Conclusions

The hypothesis generating results from this study suggests that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD.     

Youths with ADHD with and without tic disorders: comorbid psychopathology, executive function and social adjustment

Attention deficit/hyperactivity disorder (ADHD) and tic disorders (TD) commonly co-occur. Clarifying the psychiatric comorbidities, executive functions and social adjustment difficulties in children and adolescents of ADHD with and without TD is informative to understand the developmental psychopathology and to identify their specific clinical needs. This matched case-control study compared three groups (n = 40 each) of youths aged between 8 and 16 years: ADHD with co-occurring TD (ADHD + TD), ADHD without TD (ADHD − TD) and typically developing community controls. Both ADHD groups had more co-occurring oppositional defiant disorder than the control group, and the presence of TD was associated with more anxiety disorders. TD did not impose additional executive function impairments or social adjustment difficulties on ADHD. Interestingly, for youths with ADHD, the presence of TD was associated with less interpersonal difficulties at school, compared to those without TD. The potential various directions of effects from co-occurring TD should be carefully evaluated and investigated for youths with ADHD.