title: Development of cognitive control and executive functions from 4 to 13 years: Evidence from manipulations of memory, inhibition, and task switching Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder Covert orienting and focusing of attention in children with attention deficit hyperactivity disorder Maternal smoking habits and cognitive development of children at age 4 years in a population-based birth cohort. Assessing the heritability of attentional networks Functional effects of the DAT1 polymorphism on EEG measures in ADHD. Cellular and subcellular localization of the dopamine transporter in rat cortex. A “line item” approach to the identification of genes involved in polygenic behavioral disorders: The Adrenergic α2A (ADRA2A) gene Absence of the 7‐repeat variant of the DRD4 VNTR is associated with drifting sustained attention in children with ADHD but not in controls Dissecting the attention deficit hyperactivity disorder (ADHD) phenotype: Sustained attention, response variability and spatial attentional asymmetries in relation to dopamine transporter (DAT1) genotype Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD. Covert visual spatial attention in boys with attention deficit hyperactivity disorder: Lateral effects, methylphenidate response and results for parents A Pilot Twin Study of Psychological Measures of Attention Deficit Hyperactivity Disorder SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate
abstract: Predictions concerning development , interrelations , and possible independence of working memory , inhibition , and cognitive flexibility were tested in 325 participants ( roughly 30 per age from 4 to 13 years and young adults ; 50 % female ) . All were tested on the same computerized battery , design ed to manipulate memory and inhibition independently and together , in steady state ( single-task blocks ) and during task-switching , and to be appropriate over the lifespan and for neuroimaging ( fMRI ) . This is one of the first studies , in children or adults , to explore : ( a ) how memory requirements interact with spatial compatibility and ( b ) spatial incompatibility effects both with stimulus-specific rules ( Simon task ) and with higher-level , conceptual rules . Even the youngest children could hold information in mind , inhibit a dominant response , and combine those as long as the inhibition required was steady-state and the rules remained constant . Cognitive flexibility ( switching between rules ) , even with memory dem and s minimized , showed a longer developmental progression , with 13-year-olds still not at adult levels . Effects elicited only in Mixed blocks with adults were found in young children even in single-task blocks ; while young children could exercise inhibition in steady state it exacted a cost not seen in adults , who ( unlike young children ) seemed to re-set their default response when inhibition of the same tendency was required throughout a block . The costs associated with manipulations of inhibition  were greater in young children while the costs associated with increasing memory dem and s were greater in adults . Effects seen only in RT in adults were seen primarily in accuracy in young children . Adults slowed down on difficult trials to preserve accuracy ; but the youngest children were impulsive ; their RT remained more constant but at an accuracy cost on difficult trials . Contrary to our predictions of independence between memory and inhibition , when matched for difficulty RT correlations between these were as high as 0.8 , although accuracy correlations were less than half that . Spatial incompatibility effects and global and local switch costs were evident in children and adults , differing only in size . Other effects ( e.g. , asymmetric switch costs and the interaction of switching rules and switching response-sites ) differed fundamentally over age Attention-deficit/hyperactivity disorder ( ADHD ) is the most common behavioral disorder in childhood with substantial heritability . Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD . Here , we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 ( TPH2 ) , the rate-limiting enzyme of serotonin ( 5-HT ) synthesis in the brain , in children and adolescents with ADHD . We analyzed three single nucleotide polymorphisms ( SNPs ) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children .  Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test . Preferential transmissions were detected for the two SNPs in TPH2 's regulatory region ( rs4570625 , P=0.049 ; rs11178997 , P=0.034 ) , but not for the third SNP in intron 2 ( rs4565946 , P=0.3517 ) . Haplotype analysis revealed a strong trend of association between the regulatory region SNPs ( rs4570625 , rs11178997 ) and ADHD ( P=0.064 ) . Our results link potentially functional TPH2 variations to the pathophysiology of ADHD , and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes Performance on the covert visuo-spatial attentional functions of orienting and focusing by a group of ADHD children ( n = 20 ) was compared to that of age and sex-matched control children . In Experiment 1 , responses were given to cued targets at valid and invalid locations . In Experiment 2 , responses were given to targets presented in small , medium-sized or large visual field locations . For both experiments , the hypotheses that reaction times of ADHD children would be greater than those of control children and that performance would be asymmetrical , were supported . For Experiment 1 , ADHD children showed bilaterally greater ' benefits ' from having directed attention to the cued location and greater ' costs ' in having to relocate the attentional focus than controls . In Experiment 2 , the hypothesis that the function of focusing attention by ADHD children may show breakdown in the usual pattern of an increase in reaction time with focus area was partly supported by the finding of similar reaction times to targets presented in medium-sized and large regions of the left visual hemifield . These results have been interpreted as reflecting a stronger anchorage of attention by ADHD children upon a cued location and an inability to shift covert attention easily to an alternative location . The breakdown of the focusing function suggests adoption of similar time response sets across focus area size by the more compromised right hemisphere BACKGROUND Active  maternal smoking  during pregnancy has been associated with a higher risk of  behavioural disorders in children , but a few cohort studies measuring smoking data prospect ively have studied its specific effects on the cognitive abilities of pre-schoolers . METHOD A birth cohort was set up in Menorca Isl and in 1997 within the Asthma Multicenter Infants Cohort Study . A total of 420 ( 87 % of those eligible ) children had complete data for final analyses at age 4 years .  Interviewer-administered question naires were completed by mothers during the third trimester of pregnancy and then every year up to age 4 years of their child . A st and ardized version of the McCarthy Scales of Children 's Abilities ( MCSA ) was used to evaluate the child 's motor and cognitive capabilities . Multivariable regressions were used with MCSA 's assessed outcomes adjusting for : home location , maternal alcohol consumption , mother 's social class and level of education during pregnancy , parity , marital status , father 's education level , child 's gender , birth weight and height , breastfeeding duration , passive smoking , school season , age during test administration and evaluator ( psychologist ) . RESULTS A high global consistency in maternal smoking habits was found ( total agreement = 88.7 % ) . Maternal social class and education level were inversely associated with maternal smoking behaviour . Maternal smoking during pregnancy ( in cig./day ) was associated with a decrease ( in points ) of children 's global cognitive score [ beta = -0.60 , ( 95 % CI : -1.10 ; -0.09 ) ] ; as well as global cognitive sub- areas like verbal score [ beta = -0.59 , ( 95 % CI : -1.11 ; -0.07 ) ] ; quantitative score [ beta = -0.57 , ( 95 % CI : -1.08 ; -0.06 ) ] ; executive function score [ beta = -0.71 , ( 95 % CI : -1.23 ; -0.20 ) ] ; and working memory score [ beta = -0.46 , ( 95 % CI : -0.92 ; -0.01 ) ] . CONCLUSION Our findings suggest an association with maternal smoking during pregnancy and lowered cognitive development in children at age 4 years Background Current efforts to study the genetics of higher functions have been lacking appropriate phenotypes to describe cognition . One of the problems is that many cognitive concepts for which there is a single word ( e.g. attention ) have been shown to be related to several anatomical networks . Recently we have developed an  Attention Network Test ( ANT ) that provides a separate measure for each of three anatomically defined attention networks . In this small scale study , we ran 26 pairs of MZ and DZ twins in an effort to determine if any of these networks show sufficient evidence of heritability to warrant further exploration of their genetic basis . Results The efficiency of the executive attention network , that mediates stimulus and response conflict , shows sufficient heritability to warrant further study . Alerting and overall reaction time show some evidence for heritability and in our study the orienting network shows no evidence of heritability . Conclusions These results suggest that genetic variation contributes to normal individual differences in higher order executive attention involving dopamine rich frontal areas including the anterior cingulate . At least the executive portion of the ANT may serve as a valid endophenotype for larger twin studies and subsequent molecular genetic analysis in normal subject population OBJECTIVE This paper examines whether dopamine transporter gene ( DAT1 ) allele status mediates medication-related change in cognitive and neurophysiological measures among children with attention-deficiency/hyperactivity disorder ( ADHD ) . METHOD A single 10-mg dose of methylpheni date was given in a double-blind , placebo-controlled fashion to children with ADHD who were seen for cognitive testing and EEG recording . Buccal sample s were obtained and genotyped for the DAT1 polymorphism . RESULTS DAT1 allele status was associated with performance on a sustained attention task and medication-related EEG changes . Compared with those with one or more copies of the DAT1 9-repeat allele ( 9R ) , children with two copies of the 10-repeat allele ( 10R ) exhibited poorer performance on the vigilance task . In addition , children with 10R exhibited medication-related EEG changes of increased central and parietal beta power , decreased right frontal theta power , and lower theta/beta ratios ; 9R carriers showed the opposite pattern . CONCLUSIONS The data suggest that the DAT1 polymorphism mediates medication-related changes in cortical activity among children with ADHD Publisher Summary Ultrastructural subcellular studies indicate that most of the dopamine transporter ( DAT ) protein in striatal dopamine axons is distributed at the periphery of synapses and at nonsynaptic membrane sites . The extensive distribution of the DAT protein is likely to greatly restrict the extracellular diffusion of dopamine in this brain region . Several neurochemical observations suggest that extracellular dopamine in the prelimbic division , or prefrontal cortex ( PFC ) , undergoes less regulation by DAT-mediated uptake , compared with the striatum . Relative to total tissue content , extracellular dopamine levels are 20 times higher in the PFC than in the striatum . The electron microscopic results from six rats with the best morphology and most robust staining with the rat antibody were quantified in the experiment demonstrated in this chapter . One to two tissue sections per region per animal were examined , and the surface of the tissue was sample d at r and om until at least 40 DAT-immunoreactive processes were photographed . Processes were then numbered on the micrographs from upper left to lower right , and a r and om number generator was used to select 30 processes per region per animal . The processes were then traced using an image analysis system , which calculated their maximum diameter along the short axis . By electron microscopic examination of the dorsolateral striatum , peroxidase immunoreactivity for DAT was abundantly expressed in axon varicosities , some of which made punctate symmetric synapses on spines or distal dendrites The usual approach for using single base pair polymorphisms ( SNPs ) for the investigation of the genetics of behavioral disorders is to examine a single diagnostic syndrome or personality trait based on variables relating to a cluster of behavioral symptoms . However , since some of these variables may address behaviors that are associated with one allele while others are associated with the other allele , the overall association may be non‐significant and significant sub‐syndromal associations may be missed . Thus , we have reversed the process in a technique we term a “ line item ” approach . As a test of the technique we have examined the association between genotypes of a C‐ > G‐1291 Msp I promotor SNP of the ADRA2A gene and 390 individual symptoms from a structured review of DSM‐IV criteria for twelve different groups of symptoms . We examined 334 individuals consisting of controls and subjects with Tourette syndrome ( TS ) . Based on the mean scores for each genotype , those symptoms that were individually significant at α ≤ 0.05 fell into three major groups by mode of inheritance : allele 1 codominant ( 11 > 12 > 22 ) , allele 2 codominant ( 22 > 12 > 11 ) , and negative heterosis ( 12 < 11 , 22 ) . Within each mode of inheritance group , the number of symptoms that were significant for the twelve symptom clusters was compared by chi‐square analysis . This showed that symptoms were drawn from the diagnostic groups in a significantly non‐r and om fashion . Thus , the allele 1 codominant symptoms came from the anxiety , affective , schizoid , and somatization diagnostic groups ( internalizing symptoms ) ( χ2 = 80.0 , d.f . = 11 , P ≤ 0.0000001 ) , while the allele 2 codominant symptoms came from the ADHD and oppositional defiant/conduct disorder diagnostic groups ( externalizing symptoms ) ( χ2 = 81.0 , d.f . = 11 , P ≤ 0.0000001 ) . The questions that fell in the negative heterosis type of inheritance were not significantly associated with specific diagnostic groups ( P = 0.87 ) . These results showed that the ADRA2A gene was associated with symptoms of autonomic , sympathetic dysfunction from different diagnostic groups . The advantages of the “ line item ” approach include ( a ) the identification of the symptoms associated with each allele , ( b ) the identification of symptom clusters independent of DSM diagnoses , ( c ) the elucidation of heterosis and other mode of inheritance effects , ( d ) the distinction between an association with a primary disorder versus a comorbid disorder , ( e ) the identification of associations with sub‐syndromal symptom clusters that do meet full DSM‐IV criteria , and ( f ) the identification of symptom clusters across data bases . © 2003 Wiley‐Liss , Many genetic studies have demonstrated an association between the 7‐repeat ( 7r ) allele of a 48‐base pair variable number of t and em repeats ( VNTR ) in exon 3 of the DRD4 gene and the phenotype of attention deficit hyperactivity disorder ( ADHD ) . Previous studies have shown inconsistent associations between the 7r allele and neurocognitive performance in children with ADHD . We investigated the performance of 128 children with and without ADHD on the Fixed and R and om versions of the Sustained Attention to Response Task ( SART ) . We employed time‐series analyses of reaction‐time data to allow a fine‐grained analysis of reaction time variability , a c and i date endophenotype for ADHD . Children were grouped into either the 7r‐present group ( possessing at least one copy of the 7r allele ) or the 7r‐absent group . The ADHD group made significantly more commission errors and was significantly more variable in RT in terms of fast moment‐to‐moment variability than the control group , but no effect of genotype was found on these measures . Children with ADHD without the 7r allele made significantly more omission errors , were significantly more variable in the slow frequency domain and showed less sensitivity to the signal ( d ' ) than those children with ADHD the 7r and control children with or without the 7r . These results highlight the utility of time‐series analyses of reaction time data for delineating the neuropsychological deficits associated with ADHD and the DRD4 VNTR . Absence of the 7‐repeat allele in children with ADHD is associated with a neurocognitive profile of drifting sustained attention that gives rise to variable and inconsistent performance . © 2008 Wiley‐Liss , ADHD is a childhood-onset behavioural disorder with a heterogeneous profile of neuropsychological impairment . Neuropsychological heterogeneity may , in part , reflect underlying genetic differences . Here we examined sustained attention , response variability and spatial attentional asymmetries in a sample of children and adolescents with ADHD ( n=22 ) in relation to dopamine transporter genotype ( DAT1 ) and also controls ( n=20 ) . Participants performed the sustained attention to response task ( SART ) ( testing sustained attention and response variability ) and the greyscales task ( a perceptual measure of attentional bias ) . The latter has previously been shown to yield a robust leftward attentional asymmetry in healthy subjects . The 10-repeat allele of the DAT1 gene has been associated with ADHD in a number of studies and appears to have biological significance . The ADHD group was sub-divided into those individuals with two copies of the " high-risk " 10-repeat allele ( high-risk DAT1 ) versus those with one or no copies of this allele ( low-risk DAT1 ) . The high-risk DAT1 ADHD group displayed greater response variability on the SART than either the low-risk DAT1 group or healthy controls , whereas the latter two groups did not differ . Further , the high-risk DAT1 group showed an attenuated spatial asymmetry , relative to the low-risk DAT1 ADHD group , who showed the typical leftward attentional asymmetry . Our results suggest that the 10-repeat DAT1 allele may mediate neuropsychological impairment in ADHD . The application of molecular genetics may help to define neuropsychological impaired subgroups of ADHD Attention-deficit hyperactivity disorder ( ADHD ) is a heritable disorder , prevalent from childhood through adulthood . Although the noradrenergic ( NA ) system is thought to mediate a portion of the pathophysiology of ADHD , genes in this pathway have not been investigated as frequently as those in the dopaminergic system . Previous association studies of one c and i date gene in the NA system , ADRA2A , showed inconsistent results with regard to an MspI polymorphism . In the current study , two nearby single-nucleotide polymorphisms , which define HhaI and DraI restriction fragment length polymorphisms , were also genotyped and were in significant linkage disequilibrium with the MspI RFLP . Transmission disequilibrium tests ( TDTs ) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype ( P=0.03 ) , and the quantitative TDT showed association of this polymorphism with the inattentive ( P=0.003 ) and hyperactive-impulsive ( P=0.015 ) symptom dimensions . The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive ( P=0.001 ) and hyperactive-impulsive ( P=0.004 ) symptom dimensions . This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism We report three related studies of covert visual spatial orienting in child attention deficit hyperactivity disorder ( ADHD ) . In Study 1 , we examined covert visual spatial orienting in ADHD and comparison boys , Study 2 comprised a dose-response study of methylpheni date for the ADHD group , and Study 3 was an investigation of biological and adoptive parents . In contrast with comparison subjects ( n = 17 ) . ADHD boys aged 6 - 12 ( n = 27 ) showed both slower reaction times overall and within-condition ( lateral ) asymmetries in reaction times . Specifically , boys with ADHD  reacted more slowly to uncued targets in the left visual field than in the right visual field . Responses to stimuli in the two visual fields were differentially affected by methylpheni date for the ADHD group . Medication equalized visual field responses to the uncued targets , result ing in a significant cue x dose x visual field interaction . Further , medication altered the relative cue responsivity in the two visual fields , result ing in a significant dose x visual field interaction for the Validity Effect . Biological parents of ADHD boys ( n = 16 ) also showed slower reaction times to uncued left visual field targets than to right visual field targets ; in addition they showed slower response to invalidity cued targets in the right visual field . These literal effects were not observed in adoptive parents of ADHD boys ( n = 12 ) or biological parents of comparison boys ( n = 14 ) . Possible abnormal hemispheric asymmetry of attention functions in boys with ADHD and their biological parents is discussed There has been much interest in the genetics of attention deficit hyperactivity disorder and molecular genetic studies are now underway . The success of genetic studies will depend on how well the phenotype is defined . Twin studies using parent and teacher rated question naires or interviews all appear to yield highly heritable measures . Nevertheless , there is evidence to suggest that parent measures are subject to rater bias . Consequently there has been much interest in obtaining more objective measures of related traits such as attention span and impulsiveness using , computerised neuropsychological tasks . However there have been few twin studies examining the genetic contribution to these neuropsychological measures . The present study aims to investigate whether performance on the  Matching Familiar Figures Test ( MFFT ) and Continuous Performance Task ( CPT )  is genetically influenced in childhood . 20 monozygotic ( MZ ) and 20 dizygotic ( DZ ) twin pairs were r and omly selected from the Greater Manchester Twin Register . Preliminary data suggest that MZ twins perform more similarly than DZ twins on the MFFT , but not the CPT . Future work needs to examine whether other neuropsychological measures commonly used in research on ADHD are genetically influenced using larger twin sample Tryptophan hydroxylase ( TPH ) , being the rate-limiting enzyme in the bio synthesis of serotonin plays a major role as c and i date gene in several psychiatric disorders . Recently , a second TPH isoform ( TPH2 ) was identified in mice , which was exclusively present in the brain . In a previous post-mortem study of our own group , we could demonstrate that TPH2 is also expressed in the human brain , but not in peripheral tissues . This is the first report of an association study between polymorphisms in the TPH2 gene and major depression ( MD ) . We performed single-nucleotide polymorphism ( SNP ) , haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene .  Significant association was detected between one SNP ( P=0.0012 , global P=0.0051 ) and MD . Haplotype analysis produced additional support for association ( P<0.0001 , global P=0.0001 ) . Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system . These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders The symptoms of attention deficit hyperactivity disorder ( ADHD ) can be treated with methylpheni date ( MPH ) , a potent blocker of dopamine transporter ( DAT ) . The homozygosity of the 10-repeat allele at the DAT gene ( DAT1 ) seems to be associated with a poor response to MPH in children with ADHD . In the present study , we investigated the association between DAT density using I-123-N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)tropane [123I]IPT single photon emission computed tomography ( SPECT ) ] and the homozygosity for 10-repeat allele at DAT1 and response to MPH in Korean children with ADHD . Eleven drug-naive children with ADHD were included in the study and treated with MPH for about 8 weeks . After the genotyping and SPECT were performed , we compared DAT density between ADHD children with and without the homozygosity for 10-repeat allele at DAT1 and investigated the correlation between the homozygosity for 10-repeat allele and response to MPH .  ADHD children with 10/10 genotype ( n=7 ) had a significantly greater increase of the DAT density in basal ganglia than the children without 10/10 genotype ( n=4 ) . We found that while only 28.6 % ( 2/7 ) of the subject with 10/10 genotype showed good response to  MPH  treatment , 100 % ( 4/4 ) of the subjects without 10/10 genotype showed good response to  MPH treatment . Our findings support an association between homozygosity for 10-repeat allele at DAT1 and the DAT density assessed in vivo and correlation between the homozygosity for 10-repeat allele and poor response to MPH
target: Association of high reaction time variability with the 7-repeat allele absence appears to be the most consistent result and seems to be specific to ADHD .
  Speed of processing , set-shifting and cognitive impulsiveness were less frequently investigated but seem to be altered in the 7-repeat allele carriers .
  High reaction time variability seems to be the most replicated cognitive marker associated with the 10-repeat homozygosity .
background: BACKGROUND We review ed systematic ally the results of genetic studies investigating associations between putative susceptibility genes for attention-deficit hyperactivity disorder ( ADHD ) and neuropsychological traits relevant for this disorder .