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PubMed2000

No association of the dopamine DRD4 receptor (DRD4) gene polymorphism with attention deficit hyperactivity disorder (ADHD) in the Irish population.

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset syndromes affecting 3%-6% of school-age children worldwide. Although the biological basis of ADHD is unknown, a dopaminergic abnormality has long been suggested. The dopamine D4 receptor gene (DRD4) has been mapped to chromosome 11p15.5 and has been implicated in predisposition to ADHD. Several independent genetic association studies have demonstrated increased frequency of the DRD4 7-repeat allele in ADHD cases compared with controls or excess transmission of the 7-repeat allele from parents to affected offspring. However, there have also been few negative studies. In this study we investigated 78 ADHD parent proband trios and 21 parent proband pairs for the transmission of the DRD4 alleles in HHRR and case control design. We found no significant differences in the frequency of the DRD4 alleles transmitted or not transmitted to ADHD cases from their parents nor when comparing case allele frequencies to ethnically matched controls. Therefore, it is unlikely that the DRD4 7-repeat allele is associated with ADHD in the Irish population.

Adolescent↗

PubMed2004

Etiology of sex differences in the prevalence of ADHD: an examination of inattention and hyperactivity-impulsivity.

Several studies have examined the predictions of two models (i.e., the polygenic multiple threshold (PMT) model and the constitutional variability (CV) model) developed to explain sex differences in the prevalence of attention-deficit/hyperactivity disorder (ADHD), and the results of these studies are conflicting. Although there is substantial evidence that two distinct, moderately correlated symptom dimensions (inattention and hyperactivity-impulsivity) underlie ADHD symptoms, all of these studies have examined ADHD as a unidimensional construct. Therefore, we tested the PMT and CV models for the two ADHD symptom dimensions separately. Dizygotic twins or siblings of girls with ADHD had a higher number of ADHD symptoms than twins or siblings of boys with ADHD. This evidence for the PMT model and against the CV model was found for both inattention and hyperactivity-impulsivity, but became weaker for hyperactivity-impulsivity as symptom severity increased.

Attention Deficit Disorder with Hyperactivity↗

PubMed2004

Phenotype studies of the DRD4 gene polymorphisms in ADHD: association with oppositional defiant disorder and positive family history.

The objective of this study was to investigate association of DRD4 polymorphisms with ADHD subtypes for which there is evidence for increased heritability. The genetic variants tested were the 120 bp insertion/deletion, the -616, -521, -376, and the 48 bp DRD4 VNTR. The primary analyses were of association with oppositional defiant disorder (ODD), conduct disorder (CD), and diagnostic subtypes. Secondary analyses of clinical subtype were exploratory in nature and included analysis of association of DRD4 polymorphisms with family history of ADHD. We observed significant association between DRD4 7-repeat allele transmission and ADHD children with comorbid ODD (chi(2) = 6.74, df = 1, P = 0.01, OR = 2.45) The DRD4 7-repeat allele was also significantly associated with family history positive ADHD (chi(2) = 10.12, df = 1, P = 0.0021, OR = 3.57). We observed no significant distortion in the transmission of any of the tested DRD4 variants with inattentive or hyperactive-impulsive subtypes or symptom dimensions. In conclusion, our findings of increased DRD4 7-repeat allele transmission in ODD extend those reported by Holmes et al. To our knowledge, this is the first study to report association of the DRD4 7-repeat allele with ADHD children who have a positive family history of ADHD. Overall, the results from this study support the investigation of clinical subtypes in molecular genetic studies of ADHD.

Adult↗

PubMed2005

Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B.

It has been widely postulated that the categorical diagnosis of attention deficit hyperactivity disorder (ADHD) should be seen as the extreme end of a set of traits quantitatively distributed in the general population. A consequence of this is that the genes associated with DSM-IV ADHD should also influence these underlying traits in non-affected individuals. The aim of this study was to examine if specific candidate loci previously shown to be associated with DSM-IV ADHD, also act as quantitative trait loci (QTLs) for ADHD-symptoms in the general population. We have genotyped five candidate markers in a population-based sample of male dizygous twin-pairs (n = 329 pairs). We found little evidence to support a role for the previously-nominated alleles of a DRD4 VNTR, a 5HT1B SNP, or a microsatellite marker near to DRD5, in the distribution of ADHD-symptoms scores; however, we found some evidence to suggest that the DAT1 3'UTR VNTR and weak evidence that a microsatellite in SNAP-25 may have a role in continuous measures of ADHD-symptoms hyperactivity above and beyond their role in clinical ADHD.

Alleles↗

PubMed2005

Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention-deficit/hyperactivity disorder (ADHD): increased prevalence of the 2-repeat allele.

There is an increased prevalence of the 7-repeat (7R) allele of the dopamine receptor D4 (DRD4) gene in attention-deficit/hyperactivity disorder (ADHD). However, the population prevalence of the 7R allele varies considerably across ethnicity and is very low in Asians. To test whether this 7R allele/ADHD association still held in a Chinese clinical sample, 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate-responders were genotyped. None of them had a DRD4 7R allele. Instead, we observed a significantly increased prevalence of the 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically-matched controls (20%) (chi(2)(1d.f.) = 5.90, P = 0.015). This approximately 1.65-fold increase of the 2R allele in our probands is close to the observed increase of the 7R allele in European-ancestry ADHD children. Recent genetic studies have indicated that the 2R allele in Asians is likely derived from the 7R allele. Further, available biochemical data indicate that both the 2R and 7R protein have blunted responses to dopamine compared to the 4R protein. Based on these results, we propose that the observed increased prevalence of the 2R allele in our Han Chinese ADHD probands is still consistent with the 7R allele hypothesis of ADHD in European-ancestry children. Recent studies have suggested that any variant from the conserved ancestral 4R allele might potentially alter biochemistry/phenotype. We hypothesize that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD that holds across ethnicity. The present findings, however, obtained with a small ADHD sample size, should be replicated.

Adolescent↗

PubMed2006

ADHD and the dopamine transporter: are there reasons to pay attention?

The catecholamine dopamine (DA) plays an important role as a neurotransmitter in the brain in circuits linked to motor function, reward, and cognition. The presynaptic DA transporter (DAT) inactivates DA following release and provides a route for non-exocytotic DA release (efflux) triggered by amphetamines. The synaptic role of DATs first established through antagonist studies and more recently validated through mouse gene-knockout experiments, raises questions as to whether altered DAT structure or regulation support clinical disorders linked to compromised DA signaling, including drug abuse, schizophrenia, and attention deficit hyperactivity disorder (ADHD). As ADHD appears to have highly heritable components and the most commonly prescribed therapeutics for ADHD target DAT, studies ranging from brain imaging to genomic and genetic analyses have begun to probe the DAT gene and its protein for possible contributions to the disorder and/or its treatment. In this review, after a brief overview of ADHD prevalence and diagnostic criteria, we examine the rationale and experimental findings surrounding a role for human DAT in ADHD. Based on the available evidence from our lab and labs of workers in the field, we suggest that although a common variant within the human DAT (hDAT) gene (SLC6A3) is unlikely to play a major role in the ADHD, contributions of hDAT to risk maybe most evident in phenotypic subgroups. The in vitro and in vivo validation of functional variants, pursued for contributions to endophenotypes in a within family approach, may help elucidate DAT and DA contributions to ADHD and its treatment.

Adult↗

PubMed1996

Contribution of ADHD symptoms to substance problems and delinquency in conduct-disordered adolescents.

We examined adolescents with conduct disorder (CD) and substance problems to determine if those with attention deficit hyperactivity disorder (ADHD) symptomatology had more severe delinquency and substance involvement. ADHD symptomatology was assessed in two ways: (1) by self-reports using the Diagnostic Interview Schedule for Children (DISC) and (2) by use of DISC plus reports of others (parents, program staff, and program teacher). We divided boys into three ADHD groups based on DISC: those who met criteria, those who reported at least eight current symptoms, and those who reported fewer than eight symptoms. We also divided the same boys into two groups: those with reports of ADHD by two or more sources and those without this multisource ADHD. Examining these definitions of ADHD revealed that boys with either self- or multisource ADHD had more CD symptoms, earlier age of CD onset, more substance dependence diagnoses, and more comorbid depression and anxiety.

Adolescent↗

PubMed2006

Anatomical and functional brain imaging in adult attention-deficit/hyperactivity disorder (ADHD)--a neurological view.

In this review, we discuss current structural and functional imaging data on ADHD in a neurological and neuroanatomical framework. At present, the literature on adult ADHD is somewhat sparse, and so results from imaging have to therefore be considered mainly from the childhood or adolescence perspective. Most work has considered the impairment of executive functions (motor execution, inhibition, working memory), and as such a number of attention networks and their anatomical correlates are discussed in this review (e.g. the cerebello-(thalamo-)-striato-cortical network seems to play a pivotal role in ADHD pathology from childhood to adulthood). The core findings in ADHD imaging are alterations in the architecture and function of prefrontal cortex and cerebellum. The dorsal part of anterior cingulated cortex (dACC) is an important region for decision making, and executive control is impaired in adult ADHD. Finally, dysfunction of basal ganglia is a consistent finding in childhood and adulthood ADHD, reflecting dysregulation of fronto-striatal circuitry. The cerebellum, and its role in affect and cognition, is also persistently implicated in the pathology of ADHD.

Aged↗

PubMed2004

Attention-deficit/hyperactivity disorder (ADHD): parents' judgment about school, teachers' judgment about home.

OBJECTIVE: The aim of this study was to separate sources of observer and situational variance in reporting attention-deficit/hyperactivity disorder (ADHD) symptomatology. METHOD: In a sample of 30 children diagnosed with ADHD, ADHD symptomatology was assessed with the Diagnostic Interview Schedule for Children-Parent Version (DISC-P), with parents and teachers as informants. Both parents and teachers reported about the child's ADHD symptomatology at home as well as at school. RESULTS: Parents and teachers showed high within-observer cross-situational presence of ADHD symptoms. However, the between-observer agreement on the presence of ADHD symptoms within the same situation (home or school) was low. This pattern held equally true for attention/concentration and hyperactivity/impulsivity symptom scores. CONCLUSIONS: In evaluating ADHD symptomatology, it is important to obtain independent reports about the child's behaviour at school from the teacher and about the child's behaviour at home from the parents.

Adolescent↗

PubMed2004

Co-existing disorders in ADHD -- implications for diagnosis and intervention.

BACKGROUND: It is only recently that "comorbidity" in ADHD has come to the forefront as one of the most important aspects of the disorder. It is agreed that, often, these problems are at least as important as ADHD in contributing to the longer term outcome in the individual child. OBJECTIVE: To provide the reader with basic information about clinics and treatment of "comorbidity" in ADHD. METHOD: Review of the empirically based literature. RESULTS: ADHD exists in a surprisingly high frequency together with a broad range of child neuropsychiatric disorders. This is accompanied with many still unresolved treatment problems. CONCLUSION: It would not be appropriate to develop ADHD-services where clinicians would only have expertise in ADHD as such. Anyone working with children, adolescents and adults with ADHD would need to have training in general neuropsychiatry. Further research in this field is urgently needed.

Age Factors↗

PubMed2002

Attention deficit hyperactivity disorder, combined type (ADHD-CT): differences in blood pressure (BP) due to posture and the child report of anxiety.

AIM: ADHD-CT and anxiety has been associated with increased diastolic BP in controlled trials of single dosage studies of methylphenidate, although parent and child reports of anxiety have not been considered separately. Therefore, we tested the hypothesis that primary school-age children with ADHD-CT and anxiety have increased diastolic BP from a sitting to a standing position compared to children with ADHD-CT without anxiety, whether defined from a parent or child perspective. METHOD: Thirty-eight medication naive children with ADHD-CT were studied. Four groups were formed from parent and child reports of anxiety, using categorical and continuous measures of anxiety. The groups were compared using one-way ANOVA. Where omnibus F was significant, the post hoc SNK procedure (p < 0.05) was used to determine the source of this significance. RESULTS: Primary school-age children with ADHD-CT and anxiety, defined from the child's report alone, had significantly increased diastolic BP from a sitting to a standing position than children with ADHD-CT without anxiety. CONCLUSIONS: The recognition of anxiety and its management in primary school-age children with ADHD-CT is generally poorly understood. In this particular group of children, only the child's report of anxiety was associated with significantly increased diastolic BP from a sitting to a standing position. Therefore, careful and thorough assessment of the child's perspective is required. The characteristics of this anxiety and its association with postural BP require further careful longitudinal study. Biological implications are noted.

Analysis of Variance↗

PubMed2005

State regulation and response inhibition in children with ADHD and children with early- and continuously treated phenylketonuria: an event-related potential comparison.

BACKGROUND: The presentation rate of stimuli plays an important role in explaining the performance inefficiency in children with ADHD. In general, children with ADHD have been found to perform more poorly in conditions of relatively slow event rates as compared with fast and moderate event rates. The state regulation hypothesis states that these children have problems in correcting their energetic state necessary to counteract a performance decrement, which requires extra effort allocation. In this study, we investigated state regulation in children with ADHD and used children with early- and continuously treated phenylketonuria (PKU) as a clinical contrast group. METHOD: We measured the parietal P3 during a Go/No-Go task that incorporated a condition with a fast and a slow presentation rate. RESULTS: We were able to show that children with ADHD, relative to controls, responded more slowly and more variably in the slow condition only, which was accompanied by a smaller P3, suggesting less effort allocation. In contrast, the children with PKU did not show a state regulation deficit. The PKU group showed prolonged stimulus evaluation processing, as indexed by P3 latency, compared to controls and children with ADHD. In addition, they made more errors of commission than the controls and the ADHD group. CONCLUSIONS: Our electrophysiological data support the state regulation hypothesis of ADHD. Only the children with PKU had more problems in inhibiting pre-potent responding than controls, which is in accord with the prefrontal dysfunction hypothesis of PKU.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Online story comprehension among children with ADHD: which core deficits are involved?

Children with ADHD have difficulty understanding causal connections and goal plans within stories. This study examined mediators of group differences in story narrations between children ages 7-9 with and without ADHD, including as potential mediators both the core deficits of ADHD (i.e., inattention, disinhibition, planning/working memory) as well measures of phonological processing and verbal skills. Forty-nine children with ADHD and 67 non-referred children narrated a wordless book and completed tasks assessing the core deficits of ADHD, phonological processing, and verbal skills. Results revealed that, although no shorter than those of non-referred children, the narratives of children with ADHD contained fewer elements relating to the story's causal structure and goal plan. Deficits in sustained attention accounted for the most variance in these differences. Results have implications for understanding and ameliorating the academic problems experienced by children with ADHD.

Achievement↗

PubMed2005

Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD.

BACKGROUND: Preclinical and genetic studies have implicated the 5HT1B receptor gene (HTR1B) in attention-deficit/hyperactivity disorder (ADHD). Association with a single nucleotide polymorphism (SNP; G861C) has been observed, but more extensive linkage disequilibrium analyses have not been reported. METHODS: To examine haplotype structure, we genotyped 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. We identified a haplotype block encompassing HTR1B and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD probands. In light of previous studies suggesting distinct genetic influences on ADHD subtypes, we also examined association with the inattentive and combined subtypes. RESULTS: We observed nonsignificant overtransmission of the G861 allele to ADHD offspring (one-tailed p = .07). Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype (global p < .01). Additionally, three SNPs in this block were nominally (p < .05) associated with the inattentive subtype, although these did not remain significant after correction for multiple testing. As reported in previous studies, we found paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases. CONCLUSIONS: These analyses suggest that variation in the HTR1B gene may primarily affect the inattentive subtype of ADHD.

Adolescent↗

PubMed2006

Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype.

BACKGROUND: In utero exposure to smoking and alcohol are common risk factors that have been associated with attention-deficit/hyperactivity disorder (ADHD) in human beings and animal models. Furthermore, molecular studies have focused on the association between ADHD and DNA polymorphisms in dopamine pathway-related genes. We examined the joint effects of genetic and prenatal substance exposures on DSM-IV and population-defined subtypes of ADHD. METHODS: Logistic regression was used to assess the relationship between ADHD subtypes, DAT1 and DRD4 polymorphisms, and prenatal substance exposures in a birth-record sample of male and female twin pairs, aged 7-19 years. RESULTS: Interactions between prenatal exposure to smoking and variations in the DAT1 and DRD4 loci were observed in children with either the DSM-IV or population-defined ADHD combined subtypes. The odds of a diagnosis of DSM-IV combined subtype was 2.9 times greater in twins who had inherited the DAT1 440 allele and who were exposed, than in unexposed twins without the risk allele. The OR was 2.6 in the population-defined subtype. Odds ratios for the DRD4 seven-repeat allele were 3.0 (2.8) in the population-defined (DSM-IV) combined ADHD subtypes. The OR for exposed children with both alleles was 9.0 (95% confidence interval=2.0-41.5) for the population-defined combined subtypes. CONCLUSIONS: Results indicate that smoking during pregnancy is associated with specific subtypes of ADHD in genetically susceptible children.

Adolescent↗

PubMed2005

Regional cerebral blood flow in children with ADHD: changes with age.

The aim of this study was to investigate the changes in regional cerebral blood flow (rCBF) with age in patients with attention deficit hyperactivity disorder (ADHD). Twenty-nine drug-naive ADHD subjects (24 boys, 5 girls; age 7-13; mean+/-SD=age 9.2+/-2.1) and 12 subjects with epilepsy (all diagnosed as having complex partial seizure, 6 boys, 6 girls; age 7-14; mean+/-SD=8.5+/-2.1) were included in the study. All cases of ADHD were diagnosed according to DSM-IV criteria. Cerebral blood flow was evaluated with Tc-99m-hexamethylpropyleneamine oxime (Tc99m HMPAO) brain single photon emission tomography (SPECT) during standard resting condition in all of the cases. Asymmetry indices for each region of interest were calculated. Absolute rCBF values were normalized as the absolute rCBF values divided by the whole brain absolute value. The prefrontal lobe asymmetry indices were significantly negatively correlated with age in ADHD cases (r=-0.408, P=0.025), which indicated the increased prefrontal rCBF lateralization from the right to the left side with age. When ADHD cases older than 7 years of age were compared with those with epilepsy, the ADHD cases had lower right prefrontal and frontal rCBF and higher left parietal rCBF. The epilepsy group showed no significant correlations between age and asymmetry indices and showed a different developmental trajectory for prefrontal asymmetry and right prefrontal rCBF values. The results indicated that the left hemisphere dominance in the prefrontal cortex significantly increases with age in ADHD cases.

Adolescent↗

PubMed2005

Symptoms related to ADHD observed in patients with pervasive developmental disorder.

To elucidate attention-deficit/hyperactivity disorder (ADHD)-related factors observed in high-function pervasive developmental disorder (PDD) and their impact on daily life, we classified high-function PDD patients according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for ADHD with the exception of the exclusion criteria (coexistence with PDD), and studied the relationship between ADHD-related aspects and daily behavior problems using the Child Behavior Checklist (CBCL). The subjects were divided into two groups: Group 1, eight patients less than 6 years of age; and Group II, eight patients 6 years of age and older. Six patients in Group II met the criteria for ADHD. Five of them were classified as having the predominantly inattentive type of ADHD, and the remaining patient exhibited the combined type. However, no patient in Group I met the criteria for ADHD, suggesting the low sensitivity of the DSM-IV criteria for assessing the inattentiveness of preschoolers. The analyses of the correlation between corresponding items in the DSM-IV criteria and CBCL scores suggested that ADHD-related symptoms in high-function PDD patients have an impact on their daily lives.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Rolandic spikes increase impulsivity in ADHD - a neuropsychological pilot study.

The present study was designed to examine the association of Rolandic spikes with the neuropsychological profile of children with ADHD. A total of 48 children (mean age 9.4 +/- 1.6 years, range 6.7-14.9 years; 16 ADHD children with Rolandic spikes, 16 ADHD children without epileptiform discharges and 16 healthy controls) matched for age, gender, and IQ were examined with a neuropsychological assessment battery focussing on attentional processing, cognitive efficiency, response inhibition, visuospatial and auditory-verbal short-term memory and language function (CPT-AX, Stroop, digit span, Complex Figure of Rey, Heidelberg Language Development Test). ADHD children with Rolandic spikes performed worse than ADHD children without epileptiform discharges and healthy controls in a variety of CPT and Stroop test measures. In particular, they made significantly more commission errors, reflecting impaired inhibition of an ongoing response. In addition, they had pronounced difficulties in the color word condition of the Stroop test and exhibited lower interference scores, indicating poorer interference control. Results of this pilot study suggest that in some ADHD children Rolandic spikes or an associated dysfunction aggravate the course of ADHD and predispose to increased impulsivity, evidenced in deficient inhibition of an ongoing response, and decreased interference control.

Adolescent↗