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PubMed2002

Mutation screening of the dopamine D2 receptor gene in attention-deficit hyperactivity disorder subtypes: preliminary report of a research strategy.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable syndrome with onset in childhood that is associated with clinical response to drugs, which increase the release of monoamines, especially dopamine. A variety of studies have reported on genetic associations of ADHD with polymorphisms for various component genes of the dopamine pathway. The promise of preliminary associations found with several genes is mitigated by the significant controversy that exists over what are the appropriate clinical characteristics of ADHD associated with its familial transmission. In the current report, we describe a strategy for mutation screening in common, complex disorders and its application to the systematic screening for coding region variation in the dopamine D2 receptor (DRD2) gene. We used groups of individuals who met diagnostic criteria for DSM-IV-defined ADHD subtypes, as well as recently defined latent class criteria for pure familial forms of ADHD. No coding region sequence variations were identified in the DRD2 gene that met our requirements for prevalence to be considered a candidate variant contributing to susceptibility for ADHD.

Adolescent↗

PubMed2005

Differences between attention-deficit disorder with and without hyperactivity: a 1H-magnetic resonance spectroscopy study.

Using proton magnetic resonance spectroscopy ((1)H-MRS) to investigate possible neurometabolic differences between the predominantly inattentive subtype (ADHD-I), the combined subtype (ADHD-C) and normal controls. Proton spectra were acquired bilaterally on the lenticular nucleus in 20 schoolboys having ADHD and 10 matched controls. The boys with ADHD were divided into ADHD-C subtype (n=10) and ADHD-I subtype (n=10) according to DSM-IV criteria. The peaks of N-acetylaspartate (NAA), Choline moieties (Cho), myo-inositol (mI), creatine (Cr) and alpha-Glx were measured and their ratios to Cr were calculated. One-way ANOVA and post-hoc Bonferroni tests were used to detect the difference of the peak-area ratios of NAA, Cho, mI, and alpha-Glx to Cr among the three groups. There was a significant overall group difference in the NAA/Cr ratio both in the right and left lenticular nucleus (right: P=0.002; left: P=0.003). Only the ADHD-C subtype group showed a significant difference with controls (right: P=0.001; left: P=0.003) the right lenticular nucleus, the NAA/Cr ratio in the ADHD-C group was significantly lower than that in the ADHD-I group (P=0.012). In the left lenticular nucleus, the NAA/Cr ratio in the ADHD-C group showed a significant trend compared to the ADHD-I group (P=0.06). This study demonstrated the existence of measurable difference between children with ADHD-C and ADHD-I using (1)H-MRS.

Adolescent↗

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

Sex differences in adolescent ADHD: findings from concurrent EEG and EDA.

OBJECTIVE: Attention Deficit Hyperactivity Disorder (ADHD) occurs more frequently in male children and adolescents than in females, with a ratio of approximately 3 to 1. We determined whether psychophysiological differences are associated with the expression of ADHD in males and females, using simultaneously recorded electroencephalography (EEG) and electrodermal activity (EDA). METHODS: Quantitative EEG and EDA measures were acquired simultaneously and continuously (2min) during an eyes closed resting condition for 70 ADHD adolescents (48 males, 22 females) and their age- and sex-matched controls. RESULTS: Males and females with ADHD were differentiated by both EEG theta activity and EDA. ADHD males showed increased theta (widespread), whereas ADHD females showed a localised frontal enhancement of theta with reduced rate of EDA decrement. These sex differences were unrelated to ADHD subtype. CONCLUSIONS: These findings suggest that different psychophysiological processes may underlie ADHD in each sex. The profile of theta enhancement in ADHD males is consistent with a developmental deviation model of ADHD, whereas ADHD in females may be better understood within an arousal model, which emphasizes both central and autonomic function. SIGNIFICANCE: These findings highlight the potential for concurrent EDA measures to inform EEG studies of ADHD, particularly in regard to sex differences.

Adolescent↗

PubMed2006

Fine motor skills in South African children with symptoms of ADHD: influence of subtype, gender, age, and hand dominance.

BACKGROUND: Motor problems, often characterised as clumsiness or poor motor coordination, have been associated with ADHD in addition to the main symptom groups of inattention, impulsiveness, and overactivity. The problems addressed in this study were: (1) Are motor problems associated with ADHD symptoms, also in African cultures? (2) Are there differences in motor skills among the subtypes with ADHD symptoms? (3) Are there gender differences? (4) Is there an effect of age? (5) Are there differences in performance between the dominant and non-dominant hand? METHOD: A total of 528 children (264 classified as having symptoms of ADHD and 264 matched comparisons) of both genders and from seven different South African ethnic groups participated in the study. They were assessed with three simple, easy to administer instruments which measure various functions of motor speed and eye-hand coordination: The Grooved Pegboard, the Maze Coordination Task, and the Finger Tapping Test. The results were analysed as a function of subtype, gender, age, and hand dominance. RESULTS: The findings indicate that children with symptoms of ADHD performed significantly poorer on the Grooved Pegboard and Motor Coordination Task, but not on the Finger Tapping Test than their comparisons without ADHD symptoms. The impairment was most severe for the subtype with symptoms of ADHD-C (combined) and less severe for the subtypes with symptoms of ADHD-PI (predominantly inattentive) and ADHD-HI (predominantly hyperactive/impulsive). With few exceptions, both genders were equally affected while there were only slight differences in performance between the dominant and non-dominant hand. The deficiencies in motor control were mainly confined to the younger age group (6-9 yr). CONCLUSION: An association between the symptoms of ADHD and motor problems was demonstrated in terms of accuracy and speed in fairly complex tasks, but not in simple motor tests of speed. This deficiency is found mainly in the children with ADHD-C symptoms, but also to a lesser degree in the children with symptoms of ADHD-PI and ADHD-HI.

Journal Article↗

PubMed2004

Evidence for an error monitoring deficit in attention deficit hyperactivity disorder.

We studied error monitoring in ADHD and control children in a task requiring inhibition of a motor response. The extent of slowing following successful (stopped) and failed (nonstopped) inhibition was compared across groups. We also measured the time required to inhibit a response (stop signal reaction time, SSRT). Compared to controls, ADHD participants slowed less following nonstopped responses. Slowing did not vary with comorbid reading, oppositional, conduct or anxiety disorder, sex or ADHD subtype. Slowing after nonstopped responses was marginally, although significantly correlated with total ADHD symptoms and with age. ADHD participants had significantly longer SSRT than controls, but SSRT was not significantly correlated with slowing. The apparent deficit in error monitoring in ADHD and its independence from the inhibition deficit observed in ADHD has implications for executive control models of ADHD, performance problems associated with the disorder and for component theories of executive control.

Adolescent↗

PubMed1998

Bipolar and antisocial disorders among relatives of ADHD children: parsing familial subtypes of illness.

Attention deficit hyperactivity disorder (ADHD) is a familial disorder that is highly comorbid with conduct disorder and sometimes co-occurs with bipolar disorder. This pattern of comorbidity is also seen among relatives of ADHD probands. A growing literature suggests that ADHD with antisocial comorbidity may be nosologically distinct from other forms of ADHD. A similar pattern has been observed for ADHD and bipolar disorder. Given these results, along with the observed comorbidity between conduct and bipolar disorders, we used data from our study of 140 ADHD and 120 control families to determine if conduct and bipolar disorders in ADHD boys should be considered alternative manifestations of the same familial disorder. The probands and their relatives were examined with DSM-III-R structured diagnostic interviews and were assessed for cognitive, achievement, social, school, and family functioning. Our results provide fairly consistent support for the hypothesis that antisocial- and bipolar-ADHD subtypes are different manifestations of the same familial condition. As predicted by this hypothesis, there was a significant three-way association between variables assessing the family history of each disorder. Moreover, when families were stratified into bipolar, antisocial, and other types, few differences emerged between the bipolar and antisocial families.

Adolescent↗

PubMedDate not supplied

[Psychopathology associated to attention deficit hyperactivity disorder in school age children].

INTRODUCTION: Attention Deficit Hyperactivity Disorder (ADHD) represents a frequent and highly comorbid disorder in children and adolescents. Comorbidity differs according to ADHD subtype and gender and has been reported to have a direct effect on the severity of ADHD. METHODS: A descriptive, cross-sectional study was designed to determine the patterns of ADHD comorbidity in 102 children, aged 6 to 12 years, who attend the outpatient services of a child psychiatric hospital in Mexico City. The evaluation was performed using the Child Behavior Checklist (CBCL). RESULTS: The sample had about five comorbid disorders. The hyperactive-impulsive subtype had more severe externalizing symptoms, while the combined subtype had a higher severity of anxious depressive symptoms, delinquent behavior and internalized symptoms. Somatic complaints were more frequent in boys. A linear regression analysis showed that the severity of attention problems was influenced by the severity of aggressive behavior. CONCLUSIONS: School age children who came to psychiatric attention services with ADHD are highly comorbid. The comorbidity increases the severity of attention problems, particularly in patients with the hyperactive-impulsive or combined subtypes.

Attention Deficit Disorder with Hyperactivity↗

PubMed2001

Comorbidity in adults with attention-deficit/hyperactivity disorder.

This paper describes the clinical manifestations of attention-deficit/hyperactivity disorder (ADHD) in adulthood, with particular emphasis placed on issues relating to comorbidity. Prospective and retrospective studies are reviewed to evaluate the degree to which adults with ADHD exhibit clinical features that mirror their childhood counterparts with analogous comorbid psychiatric (e.g., antisocial, mood, and anxiety) and/or cognitive (i.e., learning) disorders. We also address the question of whether comorbid disorders in adults represent independent diagnostic entities and whether the presence of psychiatric comorbidity varies as a function of ADHD subtype (i.e., inattentive, hyperactive-impulsive, combined, and residual). As is the case for ADHD in childhood, comorbidity is not uncommon among adults with ADHD. However, the reported prevalence of comorbid conditions among adults with ADHD varies considerably depending upon whether the research used a prospective or retrospective design.

Attention Deficit Disorder with Hyperactivity↗

PubMed2002

ADHD and conduct disorder: an MRI study in a community sample.

MRI studies of children with Attention-Deficit Hyperactivity Disorder (ADHD) have consistently attributed core deficits of inattention and impulsivity to frontal-striatal-cerebellar abnormalities; however, no study has investigated the neuroanatomical characteristics of children with ADHD and Conduct Disorder (CD). This study examined a community sample of 12 children with combined subtype ADHD (aged 8-12, 7 with CD) and 19 healthy controls matched for age, gender, handedness and poverty. Volume measurements, including left/right asymmetries, were quantified from MRI of the total brain, caudate and cerebellar vermis. No significant differences in total brain volume, caudate volume, asymmetry of the hemispheres or asymmetry of the caudate were found between the groups. Measurements of the left and total posterior superior and inferior lobes of the vermis, however, indicated smaller volumes for both pure ADHD and co-morbid children compared to the controls. Analysis of variance demonstrated no significant volumetric differences between the pure ADHD and co-morbid types. Prolonged exposure to methylphenidate was associated with caudate volumes. These results suggest ADHD and ADHD co-morbid with CD have similar deviant cerebellar morphology and replicate previous studies with an epidemiologically derived sample.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies.

It is well established that attention deficit hyperactivity disorder (ADHD) is a familial and highly heritable disorder. Consequently, much effort is being directed towards searching for specific susceptibility genes. There is a growing trend, across the field of complex disease genetics, towards undertaking secondary analyses based on refined phenotypic definitions and in testing whether specific susceptibility genes modify the phenotypic presentation of the disorder in question. It is crucial that good, empirically derived arguments are made before undertaking multiple analyses on different phenotype refinements. In this review article, we consider the evidence from genetic epidemiological studies as well as key clinical studies that provide guidance on examining the ADHD phenotype for the purpose of molecular genetic studies. Specifically, findings on categorical versus dimensional conceptualisations of ADHD, reporter effects, comorbidity, ADHD subtypes and persistence are reviewed. Current evidence suggests that for the purpose of identifying susceptibility genes for ADHD, parent and teachers should be used as informants and that focusing on the clinical diagnosis of ADHD is useful. There is also good empirical support in favour of examining antisocial behaviour in ADHD. Genetic studies of dimensional ADHD are useful for other complementary purposes.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

Structural brain imaging of attention-deficit/hyperactivity disorder.

Many investigators have hypothesized that attention-deficit/hyperactivity disorder (ADHD) involves structural and functional brain abnormalities in frontal-striatal circuitry. Although our review suggests that there is substantial support for this hypothesis, a growing literature demonstrates widespread abnormalities affecting other cortical regions and the cerebellum. Because there is only one report studying adults with ADHD, this summary is based on children. A key limitation of the literature is that most of the studies until recently have been underpowered, using samples of fewer than 20 subjects per group. Nevertheless, these studies are largely consistent with the most comprehensive and definitive study (Castellanos et al 2002). Moreover, studies differ in the degree to which they address the influence of medications, comorbidities, or gender, and most have not addressed potentially important sources of heterogeneity such as family history of ADHD, subtype, or perinatal complications. Despite these limitations, a relatively consistent picture has emerged. The most replicated alterations in ADHD in childhood include significantly smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum. These results suggest that the brain is altered in a more widespread manner than has been previously hypothesized. Developmental studies are needed to address the evolution of this brain disorder into adulthood.

Adult↗

PubMed2005

Family adversity in DSM-IV ADHD combined and inattentive subtypes and associated disruptive behavior problems.

OBJECTIVE: This study evaluated the relationship between a family adversity index and DSM-IV attention-deficit/hyperactivity disorder (ADHD) subtypes and associated behavior problems. The relationship of family adversity to symptoms and subtypes of ADHD was examined. METHOD: Parents and 206 children aged 7-13 completed diagnostic interviews and rating scales about socioeconomic status, parental lifetime psychiatric disorders, marital conflict, and stressful life events. RESULTS: Children with ADHD combined type experienced more risk factors than community controls (p = .002) or children with ADHD predominantly inattentive type (p = .02). The families of children with ADHD combined type described more risk factors associated with family adversity than the families of children with ADHD inattentive type and the control group. Parent-rated symptoms of child inattention/disorganization were related uniquely to the adversity index score independently of conduct disorder symptoms. Children's perceptions of marital conflict were independently related to inattention and hyperactivity behaviors as rated by parents and teachers after control of all other risk factors. Oppositional defiant symptoms were independently related to marital conflict and maternal psychopathology, whereas conduct disorder symptoms were uniquely related to low socioeconomic status and maternal psychopathology. CONCLUSIONS: Family adversity is related to ADHD combined type in children and may be related specifically to ADHD symptoms in addition to conduct disorder symptoms.

Adolescent↗

PubMedDate not supplied

Adult attention-deficit/hyperactivity disorder: neuropsychological correlates and clinical presentation.

We compared the neuropsychological test performance of adult ADHD patients to the neurocognitive profiles of control subjects recruited from the general population. We administered a neuropsychological test battery consisting of measures considered sensitive to either orbitofrontal or dorsolateral-prefrontal (DLPF) dysfunction. Orbitofrontal hypoarousal is associated with behavioral disinhibition and a relative indifference to punishment. The DLPF region may function as a central executive system. Indeed, DLPF dysfunction may underlie many of the cardinal symptoms associated with ADHD. We tested the following hypotheses: (1) adult subjects meeting DSM-IV criteria for ADHD, predominantly hyperactive-impulsive type, would display neuropsychological deficits on tasks sensitive to orbitofrontal dysfunction; (2) adult subjects meeting DSM-IV criteria for ADHD, predominantly inattentive type, would perform poorly on measures sensitive to DLPF dysfunction; and (3) adult subjects meeting DSM-IV criteria for ADHD, combined type, would exhibit performance deficits on orbitofrontal measures and on DLPF tasks. Results partially confirmed our hypotheses. Subtyping ADHD patients revealed important group differences. Distinct neurocognitive and clinical profiles were observed.

Adult↗

PubMed2003

Family dynamics and preadolescent girls with ADHD: the relationship between expressed emotion, ADHD symptomatology, and comorbid disruptive behavior.

BACKGROUND: Despite the strong biological underpinnings of attention-deficit/hyperactivity disorder (ADHD), family factors remain salient influences on the course of the disorder. However, relatively little is known about how family-level variables relate to ADHD in girls and whether these variables are linked primarily to core ADHD symptomatology or to comorbid aggressive conditions. METHODS: We investigated the relationship between parental expressed emotion (EE), measured via the five-minute speech sample (FMSS), and ADHD as well as comorbid disruptive behavior disorders, in a diverse sample of 131 girls aged 6-12 years. RESULTS: High parental EE was associated with both ADHD and aggression, whether these constructs were measured categorically or continuously. The EE component of criticism, as opposed to emotional overinvolvement (EOI), showed the stronger associations with both constructs. ADHD subtypes (Inattentive vs. Combined) were equivalent with respect to prediction from high EE status. Whereas linkages with EE were stronger for ADHD than for aggression and withstood control of comorbid aggression, the converse was not true--i.e., the link between EE and aggression did not hold with control of ADHD. Multiple regression analyses revealed that the associations were independent of parenting stress and maternal depression; exploratory analyses revealed interactions between EE and (a) maternal depression and (b) Child Verbal IQ with respect to predictions of disruptive behavior. CONCLUSIONS: These findings add to a growing body of literature on ADHD in girls and highlight a pivotal link between family dynamics and the spectrum of ADHD-related behaviors. They also indicate that inattentive symptoms may be equally challenging to parents as hyperactive/impulsive symptoms.

Attention Deficit Disorder with Hyperactivity↗

PubMed1998

Latent class and factor analysis of DSM-IV ADHD: a twin study of female adolescents.

OBJECTIVE: In an attempt to validate the current DSM-IV criteria for attention-deficit/hyperactivity disorder (ADHD) in females and to determine whether symptoms are continuously distributed or categorically discrete, the authors performed factor and latent class analysis on ADHD symptom data from a large general population of adolescent female twins (1,629 pairs). METHOD: A structured diagnostic assessment of DSM-IV ADHD was completed with at least one parent of 1,629 pairs by telephone. ADHD symptoms from 1,549 pairs were subjected to latent class and factor analysis. RESULTS: Latent class and factor analyses were consistent with the presence of separate continuous domains of inattention (ATT), hyperactivity-impulsivity (H-I), and combined ATT with H-I problems. Severe latent classes corresponding to the predominantly inattentive, predominantly hyperactive-impulsive, and combined types were identified with lifetime prevalence estimates of 4.0%, 2.2%, and 3.7%, respectively. Membership in the severe ATT class predicted academic problems, family problems, and referral to health care providers. Membership in the H-I and combined classes also predicted impaired social relationships. CONCLUSIONS: These results suggest that DSM-IV ADHD subtypes can be thought of as existing on separate continua of inattention, hyperactivity-impulsivity, and combined type problems. Membership in any of there severe ADHD latent classes did not preclude academic excellence, but it was associated with different types of impairment and health care-seeking behavior. These data have implications in the areas of diagnosis, classification, treatment, and research.

Adolescent↗

PubMed2005

Mother-son interactions in families of boys with Attention-Deficit/Hyperactivity Disorder with and without oppositional behavior.

Parenting responsiveness and over-reactivity were assessed among 25 mothers of 7-9-year-old sons with Attention-Deficit/Hyperactivity Disorder (ADHD) and oppositional behavior (Oppositional Defiant, OD), 24 mothers of sons with ADHD only, and 38 mothers of nonproblem sons. Responsiveness was observed during mother-son play and clean-up interactions and over-reactivity was assessed using self-reports of parenting in discipline situations. Mothers of sons with ADHD/OD were less responsive and more over-reactive than mothers of nonproblem sons, and mothers of sons with ADHD only did not differ from the other groups. Mothers of sons with ADHD/OD reported more hostility than mothers of nonproblem sons, and controlling for maternal hostility eliminated the significant group differences in responsiveness during clean-up and in over-reactivity. Controlling for the child's ADHD subtype did not alter the pattern of results. The implications for addressing responsiveness and over-reactivity as components of parent-mediated behavioral treatments for ADHD are considered.

Adult↗

PubMed2001

A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To determine whether docosahexaenoic acid (DHA) supplementation for 4 months decreases the symptoms of attention-deficit/hyperactivity disorder (ADHD). STUDY DESIGN: Sixty-three 6- to-12-year-old children with ADHD, all receiving effective maintenance therapy with stimulant medication, were assigned randomly, in a double-blind fashion, to receive DHA supplementation (345 mg/d) or placebo for 4 months. Outcome variables included plasma phospholipid fatty acid patterns, scores on laboratory measures of inattention and impulsivity (Test of Variables of Attention, Children's Color Trails test) while not taking stimulant medication, and scores on parental behavioral rating scales (Child Behavior Checklist, Conners' Rating Scale). Differences between groups after 4 months of DHA supplementation or placebo administration were determined by analysis of variance, controlling for age, baseline value of each outcome variable, ethnicity, and ADHD subtype. RESULTS: Plasma phospholipid DHA content of the DHA-supplemented group was 2.6-fold higher at the end of the study than that of the placebo group (4.85 +/- 1.35 vs 1.86 +/- 0.87 mol % of total fatty acids; P <.001). Despite this, there was no statistically significant improvement in any objective or subjective measure of ADHD symptoms. CONCLUSION: A 4-month period of DHA supplementation (345 mg/d) does not decrease symptoms of ADHD.

Analysis of Variance↗