Association of the DAT1 polymorphism with attention deficit hyperactivity disorder (ADHD): a family-based approach.

The dopamine transporter gene (DAT1) is of particular interest in the genetic study of attention deficit hyperactivity disorder (ADHD), because psychostimulants interact directly with the dopamine transporter protein. Association between ADHD and the 10-repeat allele of a 40 base pair (bp) variable number of tandem repeats (VNTR) polymorphism of DAT1 was first reported in 1995 [Cook et al. (1995); Am J Hum Genet 56:993-998]. Subsequently, several investigators have also confirmed this association, although others reported conflicting results. We analyzed the DAT1 polymorphism in a sample of 33 Korean probands with a Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV) diagnosis of ADHD and found evidence of increased transmission of the 10-repeat allele using transmission disequilibrium test (TDT) (P = 0.001; OR = 7.88, CI = 2.20-28.29). These data support the role of DAT1 in ADHD susceptibility among Asian populations.     

Personality assessment of children with attention deficit hyperactivity disorder

The present research was designed to assess several potentially important factors in the personality structure of a sample of children with attention deficit hyperactive disorder (ADHD) as compared to normal control children. Three questionnaires were administered to a group of 28 ADHD boys and to a control group of 83 boys: (1) The Locus of Control Scale for Children; (2) The Revised Children's Manifest Anxiety Scale; and (3) The Persistence Scale for Children. Results showed that the ADHD children had significantly higher external locus of control, were significantly less persistent, and reported an elevated level of “concentration/social worry” (an anxiety subscale). Such findings can help to clarify both the personality structure and the coping styles of the ADHD child.     

Inhibition of return in children with attention deficit hyperactivity disorder

Earlier studies have suggested an impairment in the attention and eye movement control of children with ADHD. An important phenomenon in the control of attentional shifts and eye movements is the inhibition of return (IOR), which states that our brain works in a way that prevents our attention from returning to a spatial location that has been attended to, either overtly or covertly. This current study addresses whether the IOR in oculomotor planning is compromised in children with ADHD. Eleven ADHD and 12 age- and gender-matched control subjects participated in a behavioral task, in which they made saccades to a peripheral target after a valid, invalid or neutral cue. The latency difference between cued and uncued saccades over a range of cue-target onset asynchrony as well as the positive component of this latency profile (i.e., IOR) was compared between groups. The results show that ADHD children demonstrate a biphasic latency profile that is grossly similar to that observed in control subjects, although the magnitude of IOR appears to be slightly smaller in ADHD subjects. These preliminary results suggest that the inhibitory attention mechanism subserving IOR is at least not fully compromised in ADHD children. Electronic Publication     

Mean platelet volume in children with attention deficit hyperactivity disorder

The mean platelet volume (MPV), the accurate measure of platelet size, is considered a marker and determinant of platelet function. MPV can be a potentially useful prognostic biomarker in patients with cardiovascular disease. After reviewing literature, we hypothesized that attention deficit hyperactivity disorder (ADHD) in childhood may be a risk factor for coronary heart disease (CHD) in adulthood. The aim of this study was investigation of MPV and platelet count (PLT) in children with ADHD and healthy subjects. The MPV and the PLT were measured in 70 children with ADHD (aged 6–16 years), and compared with 41 healthy controls. The MPV was found to be significantly increased in ADHD group compared to control group (p = .006). There was no significant difference in the PLT between groups (p > .05). To our knowledge, this was the first study of investigating the levels of MPV and PLT in children with ADHD. Although significance and cause of increased MPV level in ADHD remain unclear in present study, further studies are warranted to investigate relationships among MPV, ADHD in childhood and CHD in adulthood.     

注意缺陷多动障碍儿童的工作记忆损害特征

目的:探讨注意缺陷多动障碍(ADHD)儿童工作记忆功能特征。方法:本研究为横断面研究。根据美国精神疾病诊断和统计手册第4版(DSM-IV),对符合ADHD诊断标准的未经治疗的100名门诊患儿及年龄、性别相匹配的100名正常儿童分别采用韦氏儿童智力测验量表中国修订本(C-WISC)及其中的顺背数字(反映言语存贮、加工)、倒背数字(反映言语存贮、加工、中央执行)、Corsi木块和空间n-Back任务(反映视空间存贮和中央执行)进行言语及空间工作记忆测试。结果:ADHD组儿童在顺背数字最高位数及总得分、倒背数字最高位数及总得分、Corsi木块最多木块数及总得分均低于对照组儿童,空间2-Back任务反应时短于对照组儿童(均P0.05)。结论:ADHD儿童存在工作记忆功能缺陷,此缺陷涉及言语环路、视空间存贮系统及中央执行。     

Executive function profile of children with attention deficit hyperactivity disorder

We explored the neuropsychological profile for executive functions of children with attention deficit hyperactivity disorder (ADHD) to assess whether problems associated with the two most cited relevant processes-inhibition and attentional problems-were the core of any executive function difficulty. A battery of executive function tests was administered to 31 children with a clinical diagnosis of ADHD and to 33 normal control participants, all aged between 7 and 12. The executive function battery encompassed a number of tasks, selected because each had multiple measures: a sustained attention reaction time task, a related vigilance task, an adaptation of the Hayling Sentence Completion Test, an adaptation of the Brixton Spatial Rule Attainment Test, a Letter Fluency task, a number Stroop task, and an “n-back” working memory task. The overall pattern of the results fit well with those obtained in previous studies as far as abnormalities of the ADHD group in the domain of inhibitory processes, attentional functions, and executive functions. The children with ADHD, although performing well on baseline tasks, performed more poorly than the controls on all the experimental tasks with one borderline exception: Letter Fluency, where the children with ADHD showed a very different pattern than most adult frontal lobe subgroups. However, there was no specific impairment on measures of inhibitory processes. In addition, strategy generation and use were severely affected in the ADHD group. Particular findings fitted well with disorders of a high-level effort system and of a monitoring system.     

Serotonin genes and attention deficit/hyperactivity disorder in a Brazilian sample: preferential transmission of the HTR2A 452His allele to affected boys.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Low serotonin activity has been associated in both animal and human studies with measures of impulsivity, aggression, and disinhibited behaviors, which make genes from the serotonin system reasonable candidates for ADHD susceptibility. In the present study, we investigated a polymorphism in the promoter region of the serotonin transporter (SLC6A4) and two polymorphisms (-1438 A > G and His452Tyr) in the serotonin 5-HTR2A receptor gene using family based association analyses in a sample of 243 Brazilian ADHD children and adolescents and their parents. No linkage disequilibrium between the two HTR2A polymorphisms was detected in this sample (P = 0.76). Considering several evidences from animal models for sexual dimorphism in serotonin genes expression, analyses were performed separately for the whole sample and for male probands. No evidences for biased transmissions of both HTR2A -1438 A > G and SLC6A4 polymorphisms to ADHD youths were observed. Preferential transmission of the HTR2A His452 allele was observed only in families with affected boys (P = 0.04). Our results suggest that findings from ADHD association studies for serotonin genes might be understood in the context of a gender effect, which may help to explain conflicting results in these association studies.     

Sleep disorders in Taiwanese children with attention deficit/hyperactivity disorder

To assess obstructive sleep apnea syndrome (OSAS) and periodic limb movement disorder (PLMD) in children with attention deficit/hyperactivity disorder (ADHD) compared with a control group. The ADHD was diagnosed based on Diagnostic and Statistical Manual, version IV (DSM-IV) criteria on successively seen elementary school children aged 6-12 years referred to a psychiatric clinic for suspected ADHD. A standardized interview (Kiddie-SADS-E), parents and teacher questionnaires, neuropsychological testing, and nocturnal polysomnography were completed for each child. Eighty-eight children (77 boys) with ADHD and 27 controls were involved in the study. Fifty children with ADHD (56.8%) had an apnea-hypopnea index (AHI) >1 event h(-1) and 17 (19.3%) had an AHI >5 event h(-1). Nine children (10.2%) had a periodic limb movement index (PLMI) >5 events h(-1). There is one child with AHI >1 and none with a PLMI > 5 in the control group. In the test of variables of attention (TOVA), the response time was significantly worse in ADHD with sleep disorders than those without them. The child behavior checklist (CBCL) showed a significant difference between groups in the hyperactivity subscale. The diagnostic criteria for ADHD based on DSM-IV do not differentiate between children with or without sleep disorders. Evaluation of sleep disorders should be considered before starting drug treatment for ADHD.     

Methylenetetrahydrofolate reductase gene polymorphisms in children with attention deficit hyperactivity disorder

Objective: The purpose of this study was to evaluate the relationship between 5,10- methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Attention Deficit Hyperactivity Disorder (ADHD) in a sample of Turkish children.Study Design: MTHFR gene polymorphisms were assessed in 40 patients with ADHD and 30 healty controls. Two mutations in the MTHFR gene were investigated using polymerase chain reactions and restriction fragment length polymorphisms.Results: Although there were no statistically significant differences in genotype distributions of the C677T alleles between the ADHD and the control groups (p=0,678) but the genotypic pattern of the distributions of the A1298C alleles was different between the ADHD patients and the controls (p=0,033).Conclusions: Preliminary data imply a possible relationship between A1298C MTHFR polymorphisms and the ADHD.     

Evidence-based assessment of attention deficit hyperactivity disorder in children and adolescents.

This article examines evidence-based assessment practices for attention deficit hyperactivity disorder (ADHD). The nature, symptoms, associated features, and comorbidity of ADHD are briefly described, followed by a selective review of the literature on the reliability and validity of ADHD assessment methods. It is concluded that symptom rating scales based on the Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM-IV]; American Psychiatric Association, 1994), empirically and rationally derived ADHD rating scales, structured interviews, global impairment measures, and behavioral observations are evidence-based ADHD assessment methods. The most efficient assessment method is obtaining information through parent and teacher rating scales; both parent and teacher ratings are needed for clinical purposes. Brief, non-DSM based rating scales are highly correlated with DSM scales but are much more efficient and just as effective at diagnosing ADHD. No incremental validity or utility is conferred by structured interviews when parent and teacher ratings are utilized. Observational procedures are empirically valid but not practical for clinical use. However, individualized assessments of specific target behaviors approximate observations and have both validity and treatment utility. Measures of impairment that report functioning in key domains (peer, family, school) as well as globally have more treatment utility than nonspecific global measures of impairment. DSM diagnosis per se has not been demonstrated to have treatment utility, so the diagnostic phase of assessment should be completed with minimal time and expense so that resources can be focused on other aspects of assessment, particularly treatment planning. We argue that the main focus of assessment should be on target behavior selection, contextual factors, functional analyses, treatment planning, and outcome monitoring.     

Contextual abnormalities of saccadic inhibition in children with attention deficit hyperactivity disorder

Abnormalities of executive function are observed consistently in children with attention-deficit hyperactivity disorder (ADHD), and it is hypothesised that these arise because of disruption to a behavioural inhibition system. Executive and inhibitory functions were compared between unmedicated and medicated children with ADHD (combined type), age-matched healthy children and healthy adults. Executive functions were measured using a test of spatial working memory shown previously to be sensitive to ADHD and to stimulant medication. Inhibitory functions were measured using an ocular motor paradigm that required individuals to use task context to control the release of fixation. Context was set according to the probability that a target would appear at either of the two locations. In one block, targets appeared on 80% of trials. In the other block, targets appeared on 20% of trials. The ability to control the release of fixation was inferred from the fixation offset effect (FOE), or the difference in saccade latency when the current fixation is offset 200 ms prior to the onset of the saccade target (gap condition), compared with when there is no offset (overlap condition). Although the healthy children made more errors on the spatial working memory task than the healthy adults, there was no difference between the two groups in their ability to control fixation using context. Both showed a larger FOE when target probability was low. As expected, the unmedicated ADHD group made more errors on the spatial working memory test than the healthy children, although spatial working memory performance was normal in the medicated ADHD group. However, both the unmedicated and medicated ADHD groups were unable to modulate the FOE according to context, and this was due to their inability to voluntarily inhibit saccades when there was a low target probability. These data suggest that the context-based modulation of fixation release is not controlled by the same systems that control executive function. Furthermore, deficits in executive function and inhibitory control appear independent in children with ADHD.     

注意缺陷多动障碍儿童的眼动抑制缺陷对照研究

目的:探讨注意缺陷多动障碍(Attention Deficit Hyperactivity Disorder,ADHD)儿童在抑制性眼动任务中的反应特征。方法:采用注视、主动眼动及反向眼动任务对21例ADHD儿童和21例正常对照儿童进行评估。结果:(1)注视任务中,ADHD组侵入性眼跳数目高于对照组[无分心条件:(12.67±12.28)vs.(6.38±6.95),P=0.040;分心条件:(16.91±10.00)vs.(11.29±5.99),P=0.030];(2)主动眼动任务中,两组儿童眼跳参数差异无统计学意义;(3)反向眼动任务中,ADHD组眼跳方向错误率高于对照组[间隔条件:(68.14±17.85)%vs.(54.10±20.22)%,P=0.020;重叠条件:(62.49±17.54)%vs.(49.27±17.21)%,P=0.020]。结论:注意缺陷多动障碍儿童眼动抑制能力存在缺陷,推测可能是由于注意缺陷多动障碍儿童具有异常的额叶-纹状体结构和/或功能所致。     

Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: preferential transmission of the MAO-A 941G allele to affected children.

Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Monoamine oxidases A and B (MAO-A and MAO-B) degrade biogenic amines such as dopamine and serotonin and thereby control the levels of these neurotransmitters in the central nervous system. We examined four polymorphisms in the MAO-A gene (30 bp promoter VNTR, CA microsatellite in intron 2, 941G/T SNP in exon 8, and A/G SNP in intron 12) as well as two markers in the MAO-B gene (CA microsatellite in intron 2 and T/C SNP in intron 13) for association with ADHD in an Irish sample of 179 nuclear families. TDT analysis of the examined MAO-A markers revealed a significant association of the more active MAO-A 941G allele with the disorder (chi2 = 5.1, P = 0.03, OR = 1.7). In addition, haplotype analysis revealed a significantly increased transmission of a haplotype consisting of the shorter allele of the promoter VNTR (allele 1), the 6-repeat allele of the CA microsatellite and the G-allele of the 941G/T SNP (famhap global statistic 34.54, P = 0.01) to ADHD cases. No significant distortion in the number of transmitted alleles was observed between the two examined MAO-B polymorphisms and ADHD. These findings suggest the importance of the 941G/T MAO-A polymorphism in the development of ADHD at least in the Irish population.     

注意缺陷多动障碍儿童的脑功能磁共振成像研究

【摘要】目的对正常儿童和注意缺陷多动障碍（ADHD））L童进行对比研究,观察2者的脑功能结构是否有生理性差异,从而加深对注意缺陷多动障碍病理机制的理解与认识,为诊断和治疗提供可靠的依据。方法利用脑功能磁共振成像（fiR[）技术,对2组儿童进行数据采集（一组为正常儿童,一组为注意缺陷多动障碍患者）,每组各5名;并对采集的数据分别用独立成分分析和统计参数映射技术进行处理分析,以研究这2种方法在处理数据过程中的优劣和差异。结果2种方法虽分别从数据和模型化2个不同方面对数据进行处理,各有优缺点,但都显示出ADHD患者与正常组被试的大脑激活区域的明显差异。ADHD患者的小脑扁桃体激活区增强,前额叶系统功能激活区减弱。结论通过不同方法对比fMRI结果各组之间的差异,进一步验证了ADHD患者的反应抑制缺陷。     

A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3'-UTR of dopamine transporter gene and attention deficit hyperactivity disorder.

The association between the 10-repeat allele of the dopamine transporter gene (DAT) and attention deficit hyperactivity disorder (ADHD) is uncertain. This study aimed to conduct a meta-analysis of the association between the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (UTR) of the DAT1 gene and ADHD. We pooled up 18 published transmission disequilibrium test (TDT) studies between the 40-base pair VNTR polymorphism in the3'-UTR of the DAT1 gene and ADHD. It included a total of 1,373 informative meioses, 7 haplotype-based haplotype relative risk (HHRR) studies, and 6 case-control-based association studies. There were statistically significant evidences for heterogeneity of the odds ratio in TDT and HHRR studies (P < 0.10), but not in case-control studies. The results of random effects model showed small but significant association between ADHD and the DAT1 gene in TDT studies (OR = 1.17, 95% CI = 1.05-1.30, chi-square = 8.11, df = 1, P = 0.004), but not in HHRR and case-control studies. The 10-repeat allele of a VNTR polymorphism in the 3'-UTR the DAT1 gene has a small but significant role in the genetic susceptibility of ADHD. These meta-analysis findings support the involvement of the dopamine system genes in ADHD liability variation. However, more work is required to further identify the functional allelic variants/mutations that are responsible for this association.     

Collicular dysfunction in attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterised by (inter alia) an increase in distractibility. The current front-line pharmacotherapies for the treatment of ADHD, namely the psychostimulants methylphenidate and amphetamines, have clear abuse potential, hence there is a strong need to develop new drug treatments for this disorder. Central to this process is the identification of the pathophysiological changes which underlie ADHD. Given the heterogeneity of the disorder, multiple loci are probably involved, providing multiple potential therapeutic targets. Here, we hypothesise (Hypothesis 1) that one such locus is the superior colliculus (SC), a sensory structure intimately linked with distractibility and the production of eye and head movements. It is proposed that in ADHD, the colliculus is hyper-responsive, leading to the core symptom of increased distractibility. Hypothesis 1 is supported by: 1. ADHD patients show increased distractibility in tasks which are sensitive to collicular function; 2. ADHD patients have a general problem inhibiting saccades, the generation of which involves the SC; 3. Saccadic deficits in ADHD include defects in the production of saccadic types (anti-saccades and express saccades) which are particularly associated with the colliculus; 4. Covert shifts in attention (which also have been argued to involve the SC) are also impaired in ADHD; 5. Reading disorders are frequently co-morbid with ADHD; dyslexia (which is associated with eye movement problems) is linked to a specific visual perceptual deficit in the M pathway, a major recipient of which is the colliculus. Whether or not the SC is indeed hyper-responsive in ADHD as Hypothesis 1 suggests, the SC may well represent an important therapeutic target for drugs. In fact current psychostimulant therapies, which reduce distractibility, may already work at that level (Hypothesis 2), a contention which is supported by: 1. The colliculus and structures immediately afferent to it contain the neurochemical machinery necessary to respond to these drugs; 2. d-Amphetamine depresses visually evoked activity in the rat colliculus in a dose-dependent manner. Fortunately, again, even if psychostimulants do not achieve their therapeutic effects on distractibility in ADHD by acting on the SC, then the development of drugs which dampen stimulus-related activity in the colliculus could still represent an important novel path for drug development to take. Pharmacological manipulations of this structure are able to decrease distractibility. As a consequence, sensory responsiveness in the SC may represent a new model system for use in the development of non-addictive pharmacotherapies for ADHD.     

Effects of methylphenidate on aggressive urban children with attention deficit hyperactivity disorder

Determined the efficacy of methylphenidate (MPH) in a clinical population of aggressive, urban children diagnosed with attention deficit hyperactivity disorder (ADHD). In previous studies of prepubertal children with ADHD, MPH has been shown to be effective when compared with placebo. Eighteen inner-city children (ages 6 to 12 years), diagnosed with ADHD and attending a summer treatment program for youth with disruptive behavior disorders, participated in a double-blind placebo trial with assessment data obtained from staff in the program and parents at home. Based on staff ratings of the children's behavior in the program and an academic classroom, the children displayed significant improvements in ADHD symptoms and aggressive behavior with low- and high-dose MPH conditions. At home, parents and guardians reported few significant differences between placebo and MPH on behavior ratings. In both settings, MPH was well tolerated with few side effects found during active drug conditions.     

Hypothalamic-pituitary-adrenal reactivity in boys with attention deficit hyperactivity disorder

The hypothesis 'whether subjects with attention-deficit/ hyperactivity disorder (ADHD), who showed under-reactivity of the hypothalamic-pituitary-adrenal (HPA) axis to stress, would make more commission errors in attention tasks', was examined. Forty-three boys, with ADHD, who visited the psychiatric outpatient clinic, at Kangbuk Samsung Hospital, were the subjects of this study. Both pre- and post-test morning saliva samples were collected from the patients at the Korean Educational Development Institute-Wechsler Intelligence Scale for Children (KEDI-WISC), and Tests of Variables of Attention (T.O.V.A.) performed. The Standard scores of the T.O.V.A were compared between the patients with decreases, or increases, in the salivary cortisol levels after the test. Decreases, or increases in the salivary cortisol levels after the test were shown in 28 and 15 patients, respectively. The patients with decreased cortisol levels after the test tended to make more commission errors in compared with those with increased cortisol levels. The patients with the decreased cortisol levels after test had more omission errors in the first quarter of the test, and more commission errors in the second half of the test compared to those with the increased cotisol levels. Subjects who show decreased salivary cortisol levels after stress make more commission errors in attention tests. This suggests that the blunted HPA axis response to stress is related to the impulsivity in patients with ADHD.