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?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.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).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. Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent, heterogeneous, and debilitating neurodevelopmental disorder with an early onset. The disorder consists of a persistent pattern of inattentiveness, impulsiveness, and/or hyperactivity that is inconsistent with the child's developmental level . ADHD isAlthough referral practices and assessment procedures are neither well developed nor standardized in developing countries , ADHD isDSM-IV  identifiBesides the symptoms of inattention, hyperactivity, and impulsiveness, the ADHD child's motor ability is frequently significantly lower than would be expected of his age and level of intellectual functioning . The widDevelopment Coordination Disorder (DCD) is a disorder with marked impairment in the development of motor coordination which cannot be attributed to a general medical condition or mental retardation . AlthougThe aspects of motor performance to be assessed in the present study were manual dexterity, complex coordination, and motor planning (by the Grooved Pegboard and the Maze Coordination Task), and manual dexterity (by the Finger Tapping Task).The problems addressed were: Are motor problems associated with ADHD, also in African cultures? Are there differences in motor skills among the ADHD subtypes? Are there gender differences? Is there an effect of age? Are there differences in performance between the dominant and non-dominant hand?Children in the Limpopo Province of South Africa, consisting of 7 ethnic groups  were recruited from a school-based population. The 528 children (378 boys and 150 girls) were recruited following screening for ADHD of the general population of primary school children representative of all socio-economic levels. Written permission was obtained from the Department of Education, Limpopo Province, as well of the principals of the selected schools.The Disruptive Behavior Disorders (DBD) rating scale ,32 was sADHD symptoms (95th percentile or above) and comparison group (85th percentile or below) were based on the results from the prevalence study [and inattentive items less than 17 were regarded as comparisons. Scores higher than 18 on the Hyperactive/Impulsive items were classified as having symptoms of ADHD-HI and higher than 21 on the Inattention items were classified as having ADHD-PI symptoms. If the criteria were met on both types of items they were classified as having symptoms of ADHD-C.Children were divided into a group with symptoms of ADHD and a comparison group without ADHD symptoms Table , based oce study  in whichThe final sample consisted of children from seven ethnic groups inhabiting the Limpopo Province Table . ChildreAssessment of, and research, on ADHD in developing countries like South Africa could be improved with standardized tests reliably differentiating between children with and without ADHD symptoms. The tests selected in the present study measure various aspects of fine motor functions, mainly assess basic non-verbal skills. They are simple, inexpensive, easy to transport to and use in remote rural areas without the conveniences of Western settings.The three tests which measure different aspects of fine manual motor skills were the Grooved Pegboard Test   consists of a metal board (10 × 10 cm) that contains a 5 × 5 set of holes each with a groove oriented randomly in different directions. Twenty-five round metal pegs with a ridge running lengthwise have to be rotated into the correct position for insertion into the holes. The child is instructed to insert the pegs as fast as possible, completing one row before starting on the next. The test is performed once with each hand, always starting with the dominant hand. Time to completion (in s) is the final score for each hand.The The following instruction is given in the child's own language:"You are now going to put each of these pegs into the holes of this board (show). You can only use one hand. Pick up one peg at a time. Notice that the pegs are not round, neither are the holes in the board. In order to insert it you will have to rotate the peg so that it fits exactly . When I tell you to start, you shall start over here (point to the upper left hole if the child is using its right hand and to the upper right hole if the child is using its left hand), fill this upper row, continue on the next, and so on until all the pegs are inserted. Try to be quick. Use only your (dominant/non-dominant) hand."Maze Coordination Task  is a simple maze without blind alleys. The maze is placed at ~60 degree angle with the table. The child is required to go through the maze with an electric stylus, trying not to touch the sides. The stylus is connected to an electronic clock and a counter, which record the number of contacts the stylus is making with the sides (counter) and the cumulative time these contacts last (timer). The aim is to move the stylus through the maze, without touching the sides. There is no speed requirement. The test is performed twice with each hand. The total sum of touches and cumulative time of contact of two trials with the same-side hand are the final scores.The The following instruction is given in the child's own language:"In this test, take this stylus and move it through the maze all the way to here (point). Try to avoid touching the sides (show). Do this with about this speed. (Show by moving stylus through about 1/4 of the maze). You do not have to rush, if you move too quickly you will make more errors. Try to be accurate. Start with your (dominant) hand. Do not rest your hand or arm against anything".Finger Tapping Test apparatus  is a micro-switch operated by a key consisting of a metal arm and a round disk (20 mm in diameter). The key is placed at the short end of a 223 mm × 151 mm × 38 mm (h) plastic box where the operating hand is to be rested. The length of the metal arm from the micro-switch to the centre of the disc is 60 mm. The switch needs ~65 g dead weight to close. An electronic counter records the number of micro-switch closings (taps). The child has to press the switch ~15 mm to activate the counter. It is important that the hand is rested in a constant position in contact with the surface of the plastic box to ensure that only the index finger is moving. A stopwatch is used to time each 10-s trial. The child may rest at any time between trials, but is told to take a break at least after every third trial. For each hand, the test is terminated after ten trials, or when five consecutive trials do not vary by more than five taps. The means of the five trials with the highest number of taps are computed for each hand and used as the final scores.The The following instruction is given in the child's own language:"Can you, please, show me how fast you can press this button with your (dominant) index finger? . Rest your arm in a comfortable position and try for yourself. You have to press the button all the way down and release it, or the counter will not work properly. Keep your wrist and arm still and remember to press as fast as you can. I will tell you when to start and when to stop."The children were always tested by a tester fluent in the child's own language. Most assessments of motor functions of the South African children were done at their schools during school hours. The exceptions were the children whose school was within a radius of 2 km from the University and the children referred for assessment, which were tested at the University Clinic.To assess hand dominance, the children were asked to hit a nail with a small hammer, throw a ball, and to write their name. Experimental tests were presented in the following order: Grooved Pegboard, Maze Coordination Task, and Finger Tapping Test. For the Afrikaans group, the IQ was established with the Senior South African Individual Scale (SSAIS) . As therRaw scores were converted to standard scores (z-scores) for each ethnic group, to eliminate the effects of possible differences between testers and the translation of instructions. Group differences on demographic variables were analysed using analysis of variance (ANOVA) using the Statistica 6.1 programme . The resIn general, children with high scores on the Disruptive Behavior Disorders (DBD) rating scales, who were classified as having ADHD symptoms, performed more poorly on the Grooved Pegboard and Motor Coordination Task than the comparison group without ADHD symptoms. Further, girls performed worse than boys. There were no differences in performance on the Finger Tapping Test.Figures The statistical results are shown in Table Post-hoc testing (with Bonferroni correction) of the Grooved Pegboard and the Maze Coordination Task showed that in both tests, the children with symptoms of the ADHD-C subtype had the poorest performance. The differences, when compared with the non-ADHD group, were statistically significant for both genders. Both girls and boys with symptoms of the ADHD-PI subtype performed significantly poorer than the comparison group only in the Maze Coordination Task with the dominant hand. This was the case for both genders. When girls with ADHD-HI symptoms used their dominant hand, they performed significantly worse than the boys on the Grooved Pegboard as well as the Maze Coordination Task.Figures The effects of ADHD subtype symptoms, gender and age for all three tests are shown in Table post-hoc tests on the Grooved Pegboard and the Maze Coordination Task showed that again, that the groups with symptoms of the ADHD-C subtype had the poorest performance. This was however, only in the case in the younger group. No significant effect was found in the difference between the older children with symptoms of ADHD-C and their non-ADHD comparisons. Independent of hand used, the younger children with symptoms of ADHD-HI differed significantly from the comparisons in the Grooved Pegboard, but not in the Maze Coordination Task. Similarly, independent of hand used, the younger children with ADHD-PI symptoms differed significantly from the comparisons on the Maze Coordination Task, but only with the non-dominant hand on the Grooved Pegboard. The older group (10 – 13) did not differ significantly, from the non-ADHD comparisons in any of the tasks.Bonferroni corrected The primary aim of the present study was to investigate if there is an association between symptoms of ADHD and motor skills, in African cultures also, as has already been implicated in Western studies ,24,40,41The performance of all groups with symptoms of the three ADHD subtypes was significantly poorer on the Grooved Pegboard and the Maze Coordination Task than that of the non-ADHD comparisons. Maybe because the Finger Tapping Test is a simple measure of motor speed and does not involve complex coordination and goal-directed movements, there was no significant difference in performance between the children with ADHD symptomatology and the non-ADHD comparison group on this test. This result replicates that of a European study . DeficitThe results of the present study show that the groups with ADHD symptoms were less impaired on the speeded task (Grooved Pegboard) than on the more complex Maze Coordination Task which requires more control, stability, and motor planning. The poor performance on the Maze Coordination Task indicated that children with ADHD symptoms appear to have problems with eye-hand coordination, and control of the task by means of prestructured motor plans  as this All three subgroups showing symptoms of the ADHD had motor performance problems when compared to children without ADHD symptoms. The group with ADHD-C symptoms performed significantly poorer on both the Grooved Pegboard and the Maze Coordination Task, while there were no significant differences for the Finger Tapping Test. It is interesting to notice that the group with ADHD-PI symptoms only differed significantly from the comparison group on the Maze Coordination Task, but not on the Grooved Pegboard. An explanation may be that the Maze Coordination Task is slightly more complex than the Grooved Pegboard, which measures accuracy, and motor speed, but not the same degree of complex eye-hand coordination and motor planning as is required by the Maze Coordination Task.Only the girls with ADHD-HI symptoms differed significantly from the comparison group in both the Grooved Pegboard and Maze Coordination Task. This was however only the case with the dominant hand. In general, the findings were in line with other studies which found the most pronounced impairment in the children with symptoms of ADHD-C and ADHD-PI subtypes ,41,50-52Sex differences have only been infrequently assessed in the literature. Gaub and Carlson in their meta-analysis  found noAge was the most pronounced of the statistical effects. For all measures, except one, significant differences were only found in the younger group with symptoms of ADHD, when compared with the non-ADHD comparison group. The exceptions were the children with ADHD-C symptoms on the Grooved Pegboard. Independent of hand used, their performance was significantly poorer than that of the comparison group without ADHD symptoms. Some studies show that, although some children seem to outgrow their motor problems, they often persist into adulthood . The resWhen the children with symptoms of ADHD showed significantly poorer performance with one hand only, it was the dominant hand. This was the case for both the boys and girls with ADHD-PI symptoms in the Maze Coordination Task and for only the girls with ADHD-HI symptoms on the Grooved Pegboard. This supports the findings of Kalff and co-workers  that chiThis study shows that African children from different ethic groups with ADHD symptoms have poorer motor control, accuracy and speed when the tasks are fairly complex like in the Grooved Pegboard and Maze coordination Task. There was no observable difference when the task consists of a simple motor movement, like in the Finger Tapping Test. This deficiency in motor functioning is found in all ADHD subtypes, with the group with symptoms of ADHD-C most severely affected.The study did generally not reveal striking gender differences; the exception was the significantly poorer performance of the ADHD-HI girls with the dominant hand on both the Grooved Pegboard and the Maze Coordination Task. The boys did not differ significantly from their non-ADHD comparisons when using the dominant hand. This result is difficult to explain, as it was only found in one ADHD subtype, but it cannot be attributed to chance, as it was observed in both the Grooved Pegboard and the Maze Coordination Task.The results also showed that problems with motor control were less noticeable in the older groups, probably due to the effect of maturation, which made the tasks too easy for this particular age group.Usually there were no differences between performances with the dominant and non-dominant hand when the children with ADHD symptoms were compared with the non-ADHD comparison group, the exception being the girls with ADHD-HI symptoms who performed significantly poorer with their dominant hand on two of the tasks than the non-ADHD girls. The younger boys on the other hand did have problems only on the Maze Coordination Task with their non-dominant hand.The present study shows that problems with motor control in children with ADHD symptoms are not associated with culture or ethnicity, were present in all three ADHD subtypes, that both genders are affected, are less pronounced in older children, and that the problems exist in both hands. These are significant findings as children with motor problems are at risk for learning problems and poorer psychological adjustment ,58. BecaADHD – Attention-Deficit/hyperactivity DisorderADHD-C – ADHD (Combined subtype)ADHD-HI – ADHD (Hyperactive/impulsive subtype)ADHD-PI – ADHD (Predominantly Inattentive subtype)DBD – Disruptive Behavior Disorders rating scaleThe author(s) declare that they have no competing interests.AM participated in the development of the study design, supervised the data collection, prepared the data, performed the statistical analysis, and wrote the manuscript.TS participated in the development of the study design, worked on the manuscript and approved the final draft.


Cognition in children with anxiety disorders (ANX) and comorbid Attention Deficit Disorder (ADHD) has received little attention, potentially impacting clinical and academic interventions in this highly disabled group. This study examined several cognitive features relative to children with either pure condition and to normal controls.One hundred and eight children ages 8–12 and parents were diagnosed by semi-structured parent interview and teacher report as having: ANX , ADHD (n = 21), or ANX + ADHD (n = 35). All completed measures of academic ability, emotional perception, and working memory. Clinical subjects were compared to 35 normal controls from local schools.Groups did not differ significantly on age, gender, or estimated IQ. On analyses of variance, groups differed on academic functioning , perception of emotion , and working memory . ANX + ADHD and children with ADHD did poorly relative to controls on all differentiating measures except auditory perception of anger, where ANX + ADHD showed less sensitivity than children with ANX or with ADHD.Though requiring replication, findings suggest that ANX + ADHD relates to greater cognitive and academic vulnerability than ANX, but may relate to reduced perception of anger. Anxiety Disorders (ANX) and Attention Deficit Hyperactivity Disorder (ADHD) both constitute major mental health problems of childhood, with affected children facing impairment at home, at school, and with peers . Rates oTo develop effective treatments and academic interventions for these children, an understanding of the cognitive processes that underlie ANX + ADHD is crucial. Effective treatments for anxiety, for example, place high demands on certain language-based cognitive processes . CognitiStudies of information processing are challenging to conduct for both theoretical and methodological reasons (reviewed in ). Small With these considerations in mind, we undertook an initial cognitive study and demonstrated that children with ANX + ADHD are cognitively distinct from either pure condition . We examThe present study sought to build on this work by further elucidating the cognitive characteristics of these children, in comparison to children with ANX only, children with ADHD only, and normal controls. Executive dysfunction, particularly impairments in inhibitory control and working memory, have been demonstrated repeatedly in ADHD (reviewed in ). Given Cognition in anxious children has been characterized as biased by selective perception and selective memory for threatening stimuli or emotions (reviewed in ). Anxietimplicit rather than explicit attention to threat [The cognitive vulnerability to anxiety is thought to relate to an automatic tendency for anxious individuals to selectively encode emotionally threatening information (reviewed in ). This eo threat , suggestIn children with clinical anxiety disorders, Vasey and others  demonstrWorking memory is an aspect of executive function. It has been described as a limited capacity system for the temporary storage and processing of information . It is tIn children with ANX, deficits may occur due to the interference of worry with normal processing of information . EysenckIn ADHD, working memory impairments have been linked theoretically  to the dStudies using complex tasks that place a high demand on working memory have shown greater impairment for children with internalizing disorders and ADHD than for those with ADHD alone -12. TannBased on the above, we hypothesized (1) that children with ANX would show heightened perception of negative emotions relative to the other children studied, a bias that might not be evident in the comorbid group ; (2) thaWe were also interested in overall academic ability, and hypothesized difficulty in all clinical groups relative to normal controls, but perhaps more so in the comorbid group.Children were recruited from two outpatient clinics  in two university-based clinical research centers serving a large urban and suburban population. Investigators met regularly to ensure standardized procedures at the two clinics. A consecutive sample of children ages 8 to 12 years meeting study criteria were recruited. All racial and socioeconomic groups were represented, but with some over-representation of Caucasian versus non-Caucasian families and more affluent versus less affluent families, relative to the local census population.Control subjects were recruited from local schools in the same geographic area, based on principals' nomination of students with no evidence of emotional or behavioral problems. Each student was also asked to nominate a friend . Controls were only included if they were within one standard deviation of the population mean for total scores on standardized measures of anxiety and ADHD symptoms (see below). While two potential controls were excluded for this reason, neither showed evidence of clinical disorder on interview.All children were in an unmedicated state at the time of the study. Children receiving psychoactive medication  discontinued it for a period of seven medication half-lives prior to study participation, to ensure adequate washout. Children who had received a course of cognitive behavioral therapy (8 sessions or more) for their anxieties were excluded, as this form of therapy may alter cognitive processes. There were no differences among clinical groups for the number of mental health services received in the previous 4 years, nor for the proportion of children receiving ongoing mental health follow-up in the previous year .Prior to participation, potential subjects and their parents completed the Anxiety Disorders Interview Schedule , a wellAll ADHD subtypes were included, and all childhood anxiety disorders were included apart from post-traumatic stress disorder and obsessive compulsive disorder (as the latter are likely to be cognitively distinct). Childhood anxiety disorders are highly comorbid: 40% of anxious children have more than one disorder , so mixeBecause this was a clinical sample, other comorbid conditions  were expected. Although these could potentially confound interpretation of data, they are so frequent in this population that excluding subjects with them would likely have rendered the study non-feasible. There is no evidence that comorbid Oppositional Defiant Disorder alters the cognitive features of ANX or ADHD. The other three comorbidities listed were assessed for each participating child. LD was defined as a standardized score on the Wide Range Achievement Test  that waWe excluded children who had a full-scale IQ < 80, lacked fluency in English, or were suffering from psychosis or serious visual, auditory, or speech deficits.The project was approved by our hospital Research Ethics Board, and children and parents provided informed assent and consent respectively. Research was carried out in compliance with the Helsinki Declaration. Administration of measures was done by a research technician blind to child diagnosis, and counterbalanced to control for any order effects. Children completed the Wide Range Achievement Test-Revised : The DANCHIPASAT : The CHBackward digit span : StandaFinger windows backwards: The Finger Windows subtest from the Wide Range Assessment of Memory and Learning (WRAML)  was admiThe Statistical Package for the Social Sciences – PC version (SPSSPC) was used for all analyses. Groups were compared on demographic characteristics and cognitive characteristics using analyses of variance (ANOVA). Chi-square was used for categorical measures. To test our hypotheses about specific group differences, post-hoc tests were done for all variables that showed significant group differences on ANOVA, with Bonferroni correction for multiple comparisons.To further corroborate relationships between ADHD, ANX, and various cognitive measures, bivariate correlations between these measures and maternal Conners' ADHD Symptom Index and child MASC scores, respectively, were examined in secondary analyses. Further post hoc analyses were done to include estimated IQ (based on Vocabulary and Block Design scores) and each of the three comorbidities likely to affect cognition  measured as continuous variables. These variables were entered as covariates, one at a time, in analyses of covariance (ANCOVAs) to determine if between-group differences remained, as described by Nigg et al. . Thus, wSample characteristics by group are described in Table Data was screened for outliers and conformity with the statistical assumptions of analysis of variance. Also, the effect of specific anxiety diagnosis was examined by comparing children with a primary diagnosis of GAD (about 50% of both ANX and ANX + ADHD groups) with those with other primary anxiety diagnoses on all measures of interest. No significant differences were found, so all anxiety diagnoses were examined together in subsequent analyses.To test our main hypotheses regarding emotional perception in ANX and working memory in ANX + ADHD, groups were compared on measures relevant to these domains. Table For all significant ANOVAs, post-hoc analyses were done to test our hypotheses regarding specific group differences  were evident for: Chipasat 2.0, Chipasat 2.8, Digit Span Backwards , WRAT Spelling, and WRAT Arithmetic subtests. All correlations were in the expected direction (ie. worsening test performance with increasing Mother Conners' symptoms). Correlations were also examined between the child-report MASC (our continuous measure of anxiety) and the cognitive measures of interest. A significant correlation (p < .05) was evident for DANVA: angry adult voice, detected more by children with higher MASC scores.When covarying for estimated IQ, all previously significant comparisons remained significant. When covarying for depressive symptoms and for conduct disorder symptoms, all previously significant comparisons remained significant. To assess the effect of learning problems, we ran group comparisons covarying for the discrepancy between estimated IQ and specific WRAT scores for each subject, consistent with our operational definition of LD above. Using this approach, all previously significant working memory and emotional perception comparisons remained significant (obviously not applicable to WRAT comparisons). Interestingly, covarying for the actual WRAT scores (without relating them to IQ) showed that reading ability on WRAT eliminated all group differences apart from that for the DANVA: auditory anger.Although we did not hypothesize any gender differences, we re-ran all group comparisons covarying for gender. All significant group differences remained, and a significant effect for gender was found only on one measure, the Chipasat, where females tended to score lower than males at the slower speed .Although effect sizes were modest, group differences between anxious children, anxious children comorbid for ADHD, and normal controls were found on several cognitive measures. The lack of group differences in demographic characteristics  suggests that these factors are unlikely to account for these findings. The degree of anxiety reported for the two ANX groups was also very similar, as was the degree of severity of ADHD symptoms in the two ADHD groups, suggesting that cognitive differences are unlikely to be due to symptom severity in one or the other group. Clinical groups were also comparable in prior mental health service utilization, suggesting that length of illness is unlikely to account for cognitive differences.We hypothesized that 'pure' anxious children would show enhanced perception of negative emotions. Consistent with this hypothesis, 'pure' anxious children were found to have an enhanced perception of auditory anger relative to comorbid children, with normal control scores intermediate between these two groups. This finding partially replicates our previous work showing reduced perception of negative emotion in ANX + ADHD . Our conIn relation to working memory, we hypothesized the greatest impairment in ANX + ADHD. Instead, we found that both ADHD groups were impaired relative to normal controls and ANX. This difference was more robust for verbal than nonverbal working memory, and occurred whether or not the task was timed. Maternal (continuous) report of ADHD symptoms also correlated with verbal working memory. These findings are consistent with previous reports suggesting that lack of vigilance or distraction by external stimuli can interfere with working memory in ADHD . We did Academic differences were greatest between children with ADHD and normal controls, though some academic impairment was evident in ANX as well. ANX + ADHD did not appear to have worse academic performance than children with 'pure' ADHD, highlighting the need for school supports for all children meeting ADHD criteria.We examined other reasons for the group differences (apart from diagnosis per se) by covarying for IQ, gender, academic deficits relative to IQ, comorbid depressive symptoms, and comorbid conduct symptoms. All group differences remained significant, and only one measure (Chipasat at slower speed) showed a significant gender effect . Controlling for academic ability, however, eliminated all but one group difference: the difference in auditory perception of anger. Thus, emotional perception may be relatively independent of academic ability, but working memory appears to show some association. This association disappears, however, when academic ability is measured relative to IQ. This finding suggests that group differences in working memory cannot be accounted for entirely by differential academic deficits.Although needing replication, these findings have potentially interesting implications for understanding the comorbidity between ANX and ADHD. Vance and Luk  hypothesFurther studies that include larger, more diverse samples are needed to replicate and extend these findings. The collection of the sample from two university-based clinics may also have resulted in some sample bias. This bias may limit generalizability to other populations . Vasey and colleagues  have alsThe nature of the cognitive deficits in ANX + ADHD may be relevant to these children's ability to benefit from cognitive behavioral therapy for anxiety, particularly since these deficits are less likely to be ameliorated by stimulant treatment than in 'pure' ADHD children. Thus, even a medicated child with comorbid ANX + ADHD may find the verbal reasoning required in cognitive behavioral therapy confusing, due to limited verbal working memory. ADHD may also make the child appear disruptive or difficult to manage if CBT is offered in a group format (increasingly favored to contain costs). CBT may require modification and/or administration in an individual format in order for these children to benefit.Given the above deficits, children with ANX + ADHD are also likely to be disadvantaged academically. They may require different teaching strategies geared to their unique cognitive profile. If they encounter school failure, this may exacerbate anxiety leading to further problems. Enhancing teachers' and clinicians' awareness of the particular vulnerabilities of these children may improve their therapeutic and academic outcomes.Findings suggest that ANX + ADHD relates to greater cognitive and academic vulnerability than ANX, especially with respect to working memory, but may relate to reduced perception of anger. Awareness of this vulnerability may allow tailoring of psychological and academic intervention to better meet the needs of affected children. Further studies of larger, more diverse samples are indicated to replicate these findings and further elucidate the cognitive and neurological substrates of ANX + ADHD.The author(s) declare that they have no competing interests.KM was the principal investigator of this study, principal author of this paper, and leads one of the participating outpatient clinics. RT was a co-investigator of this study, and developed the initial study design jointly with KM. AY contributed valuable ideas to the final design and procedures of the study, and leads the second participating outpatient clinic. All authors read and approved the final manuscript.


It is now estimated that attention deficit-hyperactivity disorder (ADHD) afflicts at least 4% of adults in the United States and is associated with high levels of morbidity and functional impairment. One key area of dysfunction associated with ADHD is impaired motor vehicle operation. Our goal was to examine the association between ADHD and specific driving outcomes in a sample of adults using a driving simulator.Subjects were 20 adults with full DSM-IV ADHD and 21 controls without ADHD of equal gender distribution. However, the mean age of subjects with ADHD was somewhat older. All analyses were adjusted for age and gender. All subjects participated in a driving simulation that lasted for one hour and consisted of a short training period, a high stimulus segment and a low stimulus segment with two distinct monotonous periods.In the second monotonous period within the low stimulus environment, ADHD subjects were significantly more likely than controls to collide with an obstacle suddenly appearing from the periphery, adjusting for age and gender.Adults with ADHD were more likely than controls to collide with an obstacle during a driving simulation suggesting that deficits in directed attention may underlie driving impairments in this population. It is now estimated that Attention Deficit Hyperactivity Disorder (ADHD) persists in a substantial number of cases  and afflAn emerging literature shows that drivers with ADHD are more likely than drivers without ADHD to commit traffic violations and have adverse driving outcomes. A follow-up of adolescents and young adults with and without ADHD found those with ADHD were more likely to be involved in traffic accidents, to be at fault in automobile accidents and to have received more traffic citations than controls . AnotherFurthermore, documentation through surveys and RMV questionnaires has shown that individuals with ADHD have worse driving histories than subjects with other psychiatric disorders  and dispIn recent years driving simulator paradigms have been developed to help quantify key components of driving behaviors among individuals with ADHD ,15. ThesTo address the limitations of the extant literature, our group has developed and validated a novel driving simulator paradigm for the study of impaired driving behavior in individuals with ADHD . ConvergThis new paradigm was designed to assess the core components of the clinical picture of ADHD that could account for driving impairments in individuals with ADHD. Therefore proxies of impulsivity, hyperactivity and inattention were incorporated into the development of the driving paradigm. To assess inattention, the driving simulation included a monotonous driving period punctuated with a sudden peripheral stimulus (a dog running into the road). Such a setting was designed to mimic a non-stimulating section of highway situation whereby individuals with ADHD become bored and become less attentive. To assess impulsivity, the simulator included a slow moving lead vehicle and assessed whether the drivers could tolerate not passing the vehicle through the frequency of lane departures indexing passing attempts. Hyperactivity was assessed through the logging of driving speed throughout the simulation as well as rate of stopping before a traffic light or stop sign.The main purpose of this study was to evaluate the driving impairments in individuals with ADHD using this new well-developed and ecologically valid paradigm. We hypothesized that ADHD drivers will show specific driving impairments associated with the proxies indexing the core features of ADHD: inattention, hyperactivity and impulsivity.Subjects were 20 adults with DSM-IV ADHD and 21 controls without ADHD of equal gender distribution. However, the mean age of subjects with ADHD was somewhat older. All analyses were adjusted for age and gender similar age and sex. All ADHD subjects met full DSM-IV criteria and had symptom onset in childhood and persistent symptomatology into adulthood. ADHD subjects with and without prior histories of treatment for the condition were included. Controls were included if they failed to meet criteria for ADHD and endorsed fewer than 3 ADHD symptoms at any level of severity. Participants were required to be English speakers. Excluded were subjects with an IQ less than 80. Subjects were recruited through clinical referrals to an adult ADHD program at a major medical center and through advertisement in local media. The local institutional review board approved this study and all subjects provided written informed consent for participation.Diagnostic assessment relied on the Structured Clinical Interview for DSM-IV  supplemeTo have been given a full diagnosis of adult ADHD, the subject must have (1) met full DSM-IV criteria (at least 6 of 9 symptoms) for inattentive or hyperactive/impulsive subtypes, with the onset of multiple symptoms by age 7 years; (2) described a chronic course of ADHD symptoms from childhood to adulthood; and (3) endorsed a moderate or severe level of impairment attributed to the ADHD symptoms.To elicit ADHD symptomatology, we used the ADHD module from the Kiddie SADS-E, wording questions to inquire if symptoms in childhood were currently present, and then asking whether the symptoms were present currently to a clinically meaningful degree. By using this method, we assured that the syndrome observed in adulthood had some continuity with the syndrome reported in childhood.The driving simulator used an instrumented full cab 2001 Volkswagen Beetle with a front projection screen that provided the driver with a near 40-degree view of virtual roadway. The original equipment manufacture (OEM) accelerator, brake, and steering wheel recorded inputs from the driver. Driving simulation software used STISEM Drive and STISIM Open Module to compute graphical updates, based upon a validated driving simulation . The driThe training segment provides subjects with an approximately 10 minute driving period to become acclimated to the simulated driving environment . The proAs mentioned earlier, the first and last portions of the low-stimulus testing period included "monotonous" segments where the driver travels for two miles along a two-lane highway with a posted speed limit of 55 MPH without oncoming traffic. The low-stimulus segments of monotonous driving were punctuated with a sudden peripheral stimulus in the form of a dog, which appears 60 feet off the right side of the roadway and 350 feet ahead. The dog moved toward the road at 18 feet per second. To avoid impacting driver's subsequent performance by a collision, no major action was required to avoid collision in the first presentation of the dogs. During the second presentation of the stimulus, however, the timing of the dogs was such that major evasive action was required to avert a collision.When entering the car, drivers were instructed on procedures for adjusting the seat, the visual presentation of the rearview mirror and using the OEM speedometer. Participants were told that they would receive a base compensation of $40 for their participation. Finally, to encourage subjects to obey traffic laws, while balancing the need to drive at an appropriate speed, a two part financial incentive structure was presented ,21. PartDriver performance was categorized across a number of parameters: velocity, lane position, reaction time and a binary measure of collision with the sudden peripheral stimulus. Velocity was measured as the maximum velocity reached by the driver, relative to the posted speed limit. This aspect of driving behavior was measured as a proxy of hyperactivity. Lane position was measured as the variability of the driver's position within lane. Reaction time was measured as the time from the start of any sudden movement of the steering wheel or depression of the brake pedal and rate of stopping before a traffic light or stop sign was also designed to be a proxy of hyperactivity.Demographic variables were analyzed using two-sample t-tests and Pearson's chi-squared test for continuous and binary outcomes, respectively. Driving outcomes were assessed with a series of linear and logistic regression models for continuous and binary outcomes, respectively, with the driving outcome as the dependent variable and ADHD status and any confounding factors as the independent variables. As an exploratory analysis, we repeated these regressions, modeling the driving outcomes as a function of ADHD status, gender, and the ADHD-by-gender interaction. The interaction tests if the association between ADHD and the driving outcome differs by gender. If the interaction term is significant, we estimated the ADHD effect within stratum of gender. This interaction analysis was repeated using ADHD status, age (18-2 versus 27–51) and the ADHD-by-age interaction as independent variables. Alpha was set at 0.01 to avoid type I errors and all tests were two-tailed.2(1) < 0.0, p = 0.88). However, the mean age of ADHD subjects was somewhat older than controls  = -2.0, p = 0.06).The gender distribution did not differ between ADHD and control subjects  ,23. MoreThe "object", which in the case of our simulator was a dog running across the road could have been a pedestrian, a child running after a ball or a bicyclist. Such results indicate the risk associated with impaired directed attention in drivers with ADHD can have serious consequences.In contrast, results of the portions of the simulator designed to tease out impulsivity and hyperactivity did not result in abnormal findings when compared with Controls. The steering variability, rate of stopping and rate of passing under adverse conditions were all at similar levels to controls across the driving simulation. These results are consistent with the literature that purports that inattention is the dominant component of the clinical picture of adults with ADHD -26.Our results should be considered in light of several methodological limitations. Since the majority of our subjects were Caucasians, our results may not generalize to other ethnic groups. Since our subjects were referred, our results may not generalize to community samples. Additionally, since our sample was relatively small, we may not have had sufficient power to detect small-sized effects on some outcomes. Also, our limited sample size precluded the examination of interactions between ADHD and age or psychiatric comorbidity on driving outcomes. Future research with larger samples should address these issues.Despite the considerations, our results showed that ADHD subjects were selectively more likely than controls to collide with an obstacle, suddenly appearing from the periphery while driving in low stimulus environment. These results suggest that deficits in directed attention may underlie driving impairments in adults with ADHD and that such impairments in attention can result in serious accidents. Additional research is needed to evaluate whether intervention strategies can help correct ADHD-associated driving impairments and help prevent adverse occurrences. Considering the high prevalence of ADHD, such research would be of great clinical and public heath benefit.Dr. Joseph Biederman receives/d research support from the following sources: Shire, Eli Lilly, Pfizer, McNeil, Abbott, Bristol-Myers-Squibb, New River Pharmaceuticals, Cephalon, Janssen, Neurosearch, Stanley Medical Institute, Novartis, Lilly Foundation, Prechter Foundation, Astra-Zeneca, Forest Laboratories, Glaxo-SmithKline, NIMH, NICHD and NIDA. Dr. Joseph Biederman is a speaker for the following speaker's bureaus: Shire, Lilly, McNeil, and Cephalon, UCB Pharma, Inc, Novartis. Dr. Joseph Biederman is on the advisory board for the following pharmaceutical companies: Eli Lilly, Shire, McNeil, Janssen, Novartis, and CephalonDr. Craig Surman has received research support from McNeil Pharmaceuticals, is on the speaker's bureau for Novartis Pharmaceuticals, and served in an advisory capacity to Shire Pharmaceuticals and Takeda Pharmaceuticals.Dr. Thomas Spencer receives research support from the following sources: Shire Laboratories, Inc and Eli Lilly & Company, Glaxo-Smith Kline, Pfizer Pharmaceutical, McNeil Pharmaceutical, Novartis Pharmaceutical, and NIMH. Dr. Thomas Spencer is a speaker for the following speaker's bureaus: Glaxo-Smith Kline, Eli Lilly & Company, Novartis Pharmaceutical, Wyeth Ayerst, Shire Laboratories Inc, McNeil Pharmaceutical. Dr. Thomas Spencer is on the advisory board for the following pharmaceutical companies: Shire Laboratories, Inc and Eli Lilly & Company, Glaxo-Smith Kline, Pfizer Pharmaceutical, McNeil Pharmaceutical, and Novartis PharmaceuticalDr. Stephen V. Faraone receives research support from the following sources: Eli Lilly & Company, McNeil Consumer & Specialty Pharmaceuticals, Shire Pharmaceutical, the National Institute of Mental Health, the National Institute of Child Health and Development and the National Institute of Neurological Diseases and Stroke. Dr. Stephen V. Faraone is a speaker for the following speaker's bureaus: Eli Lilly & Company, McNeil Consumer & Specialty Pharmaceuticals, Novartis, Cephalon, Inc. and Shire Pharmaceuticals. Dr. Stephen V. Faraone has had an advisory or consulting relationship with the following pharmaceutical companies: McNeil Consumer & Specialty Pharmaceuticals, Shire Laboratories, Cephalon, Inc. and Eli Lilly & CompanyJB: Had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. I am also responsible for editing the final draft.RF: Involved in the writing of the manuscript including reading the literature and integrating the literature with the findings and writing the discussion.MCM: Provided the statistical analysis as well as integrating the information from the laboratory at M.I.T with the data at the laboratory at Massachusetts general Hospital.BR: Worked closely with all authors on the design and analysis of the driving data.JFC: Worked closely with all authors on the design and analysis of the driving data.CBS: Involved in the writing of the manuscript including reading the literature and integrating the literature with the findings and writing the discussion.MA: involved with recruitment of subjects, setting up the design of the study and editing the initial draft of the manuscript.MD: involved with recruitment of subjects, setting up the design of the study and editing the initial draft of the manuscript.SS: Generated the literature search, edited the paper for details and included all the references.TJS: Involved in the writing of the manuscript including reading the literature and integrating the literature with the findings and writing the discussion.SVF: Involved in the writing of the manuscript including reading the literature and integrating the literature with the findings and writing the discussion.


PLoS Medicine article, Christine Phillips writes: “ADHD [attention deficit hyperactivity disorder] joins dyslexia and glue ear as disorders that are considered significant primarily because of their effects on educational performance” [In her recentrmance” . A “disormance” . In neurIn 1948, “neuropsychiatry” was divided into “neurology,” dealing with diseases, and “psychiatry,” dealing with emotions and behaviors . If therAt the September 29, 1970, hearing on Federal Involvement in the Use of Behavior Modification Drugs on Grammar School Children, Ronald Lipman of the United States Food and Drug Administration (FDA), argued: “hyperkinesis is a medical syndrome. It should be properly diagnosed by a medical doctor” .In 1986, Nasrallah et al.  reportedAt the 1998 National Institutes of Health (NIH) Consensus Development Conference on ADHD, Carey  stated: However Swanson and Castellanos , having The Consensus Conference Panel concluded: “We do not have a valid test for ADHD... there are no data to indicate that ADHD is a brain malfunction” . .In 2002, the Advertisement Commission of Holland  determinIn 2003, Ireland prohibited GlaxoSmithKline from claiming that the antidepressant Paxil “works by bringing serotonin levels back to normal.” Wayne Goodman of the FDA acknowledged that claims that selective serotonin reuptake inhibitors correct a serotonin imbalance go “too far,” but had the temerity to suggest that “this is reasonable shorthand for expressing a chemically or brain-based problem” (quoted in ).At an FDA hearing on March 23, 2006, I testified: “Saying any psychiatric diagnosis ‘is a brain-based problem and that the medications are normalizing function’ is an anti-scientific, pro-drug lie” . Yet thiJournal articles , press rThe FDA is the agency most responsible for conveying the facts needed by the public to make risk versus benefit and informed consent decisions. Instead—by protecting industry, not the public—the FDA is a purveyor of the psychiatric “disease” and “chemical imbalance” lie. This must change.


Early onset (EO) alcohol dependence (AD) has been found to represent a subtype of alcoholism with a distinct profile and prognosis compared to late onset (LO) alcohol dependence. Externalizing disorders, especially attention deficit hyperactivity disorder (ADHD) that may continue as attention deficit hyperactivity disorder, residual type  in adulthood, may increase susceptibility to early-onset AD.To examine the relationship between ADHD and ADD, RT symptoms and age at onset of AD in a sample of Indian male patients. 70 male subjects with AD presenting to the De-Addiction Services of the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, were studied. The study had a retrospective design.Patients were examined for evidence of past ADHD in childhood and current ADD, RT using structured instruments. Chi-square tests and odds ratios were used to express the relative risk of association of ADHD with early- and late-onset AD.P < 0.05) ADD, RT was also over-represented in EO probands.Significantly more EO alcoholics  had a history of ADHD in childhood compared to LO alcoholics (7/28, 25%, The results of this study are consistent with previous research that shows a high incidence of ADHD in early-onset alcoholics. This may have important management implications. Early onset (EO) of alcohol dependence (AD) represents a discrete form of alcoholism2 which i52ADHD is one of the most studied disruptive behavior disorders in childhood. It usually first manifests by the age of 7 and is more common in boys (M: F = 2-3:1). Outcome studies of children with ADHD have showed that the disorder can persist into adolescence in 50-80% of cases.16 Althouet al.[et al.[et al.[Various studies have examined the co-occurrence of ADHD and substance use disorder in adolescents and adults. ADHD has been robustly associated with nicotine use disorder in mid-adolescence, as well 18et al. reportedet al.21–23 A fet al. of childet al. The assol.[et al. Impulsivl.[et al. Milin etl.[et al. reportedl.[et al.3070 male subjects aged 16-60 years, admitted for alcohol related problems to the De-addiction Centre at the National Institute of Mental Health and Neurosciences, India, who met ICD-10 Diagnostic Criteria For Research for AlcoThe patients who satisfied the criteria for AD were assessed and divided into Early Onset  and Late Onset (LO - developed dependence after 25 years) groups. To minimize the potential overlap between these groups, subjects who had developed dependence after the age of 30 yrs were purposively selected. The severity of AD was rated using the Short Alcohol Dependence Data (SADD) questionnaire.th percentile of childhood hyperactivity. The PRS has been used by earlier researchers[34Two or more first degree relatives who lived in close contiguity to the subject - preferably the subjects’ mother and/or older siblings - who by reason of the extended or joint family systems commonly found in India, were likely to be most informative - were then interviewed to collect information on family history of AD, childhood symptoms of ADHD and current ADD, RT. If the mother or older sibling was not available, information was collected from at least three first-degree relatives. Family history of AD was collected using the Family Interview for Genetic Studies FIGS  and retrsearchers3435 to rarchers34 based on70 subjects with AD were recruited. Of these, 37 had an EO of dependence and 33 had a LO. Of these, the records of seven subjects in the EO group and five in the LO group had to be discarded as there was insufficient data on both childhood ADHD and adult ADD, RT symptoms.t = 12.36, P<0.001). The two groups did not differ significantly on other demographic or clinical variables such as education, income, religion, marital status, residential status, and severity of alcoholism scores on the SADD.The EO subjects had a significantly lower age at onset of AD than the LO subjects  and there was similar over-representation of ADD, RT in EO probands .The odds ratio of a subject with ADHD and/or ADD, RT developing EO alcoholism was 5.8. This was in contrast to the odds ratio of 0.17 obtained for subjects with ADHD and/or ADD, RT developing LO alcoholism .A significantly higher number of the EO subjects had a history of ADHD and/or ADD, RT compared to the LO subjects. The results of this study are consistent with previous research that show a high incidence of childhood ADHD and ADD, RT in substance abusers.2237–4022The odds ratio of subjects with ADHD and/or ADD, RT developing EO dependence was nearly 6:1 compared to those without comorbid ADHD. This supports the evidence that the presence of externalizing symptoms, especially ADHD, is an important risk factor for AD at an early age, and is in line with previous studies in this patient population.17 This aThe prevalence of ADHD in our sample was higher than in previous studies. However, most previous studies2122 have2170.8% of all subjects (17 of 24) in our study who had evidence of ADHD in childhood also had ADD, RT as adults. This data lends support to the finding that ADHD symptoms persist from childhood into adulthood in over 50% of cases.164016et al.[Several studies have shed light on the mechanisms underlying the association between disruptive behavior disorders and ADHD. Kuperman et al. found thet al. Various et al.26 impulset al. and seroet al.11 while The findings of this study must be interpreted in the context of several methodological limitations. Firstly, the retrospective assessment of ADHD relies heavily on the observation of informants, which may be coloured by recall and confounding biases, especially when delineating ADD, RT from alcohol-related behaviors. Secondly, the study sample was selected from a tertiary care center, and may have included severely ill patients, accounting for the high rates of comorbid ADHD. Other comorbidities, especially externalizing disorders, were not assessed, and the clinical profile of the two subgroups, apart from severity of dependence, was not compared, making it difficult to draw conclusions about the impact of comorbid ADHD. Thirdly, we do not have information on all those subjects who were screened and excluded from the study, or their socio-demographic or clinical variables. These people were excluded from the study at screening itself because neither parent was available to provide information. Finally, the study was cross-sectional in origin, so that course and outcome could not be commented upon.Nevertheless, these results strongly suggest a need for greater evaluation of ADHD in populations of adults with AD, especially those with an EO of AD, and more intensive management of this high-risk group in view of their poorer prognosis. Since treatment of ADHD in adolescents, including stimulants, is known to reduce substance use, including alcohol use,43 assess


The paper presents the Motor Function Neurological Assessment (MFNU), as a tool for identifying typical motor function problems in children with Attention Deficit Hyperactivity Disorder (ADHD). The study investigated motor functions in boys diagnosed with Hyperkinetic Disorder . HKD corresponds to the ADHD-combined (ADHD-C) diagnosis in the DSM-IV. The paper addresses the ability of the instrument to discriminate between non-medicated boys with HKD and a control group consisting of normal non-referred boys without any clinical significant ADHD symptoms.25 drug-naïve boys, aged 8–12 years and recently diagnosed as HKD F90.0, were compared with 27 controls, all boys in the same age range, on 17 MFNU subtests, and with a 'Total score' parameter.On the individual subtests 80–96% (median 88%) of the ADHD group showed 'moderate' to 'severe' problems, compared to 0–44% (median 14.8%) within the control group. The percentage of 'severe problems' ranged from 44–84%, (median 64%) in the ADHD group, and 0–44% (median 0%) in the control group. The highly significant differences found between the groups on all subtests, and on the Total score scores, indicated that the MFNU had a high discriminative power when children with ADHD and normal controls were compared. The Total score parameter seemed to be a meaningful discriminator of a common underlying factor of the 17 subtests used in the study.The study confirms our clinical findings that the MFNU measures a consistent pattern of motor function problems in children with HKD, and that these problems are rarely represented in individuals without ADHD. Further research is needed to investigate to what extent the MFNU taps motor problems that are truly specific to ADHD, in contrast to motor problems common to children with DCD or other clinical problems. The Motor Function Neurological Assessment (abbreviated MFNU in the Norwegian edition of 'Motorisk Funksjonsnevrologisk Undersøkelse') has been developed over a 25 year period based on clinical observations and assessments of children referred for evaluation of possible Attention Deficit Hyperactivity Disorder (ADHD). The individual subtests were for a large part based on a wide representation of established tests of motor functions in children . The selWhen parents and teachers were asked to describe the individual children problems besides ADHD symptoms, they rarely mentioned problems with motor skills. On the contrary, motor skills were very often rated as major assets. Our experience is in accordance with Fliers et al. . They foA close examination of the specific motor tasks involved in the MFNU subtests indicated that the children had problems with motor inhibition. The children with ADHD also displayed increased muscle tone in the gross movement muscles (e.g. m. Iliopsoas and m. Latissimus dorsi) restricting movements of shoulders, arms and thorax. In most cases we found little or no training effect even after prolonged training periods focusing on the special tasks involved in the subtests. We also observed marked improvements in performance on the MFNU 1 1/2 hour after administration of central stimulants . When the physiological effect of the stimulant subsided, the motor problems returned undiminished. We observed this pattern even in individuals who had been medicated with MPH for many years . An examThe definition of ADHD used in Norway, and in our work, is based on the International Classification of Diseases ICD-10) diagnosis hyperkinetic disorders . HKD usually arises in the first 5 years of life. Six or more symptoms of inattention, three or more symptoms of hyperactivity and one or more symptoms of impulsiveness are necessary for the diagnosis  diagnosi. The AmeIn its definition of HKD the ICD-10 states that: "Impairment of cognitive functions is common, and specific delays in motor and language development are disproportionately frequent." . There iPitcher et al.  have demAn overlap of 30–50% has been reported between ADHD and the DCD diagnosis ,26,27. DRasmussen and Gillberg  found thStray  and StraMotor inhibition problems typically reported in the ADHD literature are mainly associated with higher order executive functions like motor planning, timing and evaluation . Our cliAltered brain activity is found in the right inferior frontal cortex, left sensorimotor cortex, and bilateral cerebellum and the vermis as well as in the right anterior cingulated cortex, left sensorimotor cortex, and bilateral brainstem in children with ADHD during resting-state . BerquinProblems with motor inhibition are observed with the MFNU both at the fine and gross motor level through varying motor tasks performed by the child, and in examinations of passive movements. A typical characteristic is increased muscular tone when flexion-extension movements are repeated several times in succession, resulting in a restricted movement range and in jerkiness of the movement. Such a restriction can be illustrated by the subtest 'Thumb movement'  is partly connected to the reticular formation in the brainstem . Stray  and StraThrough the development period of the MFNU  motor inOur research questions were:To what extent do children with ADHD-C/HKD show motor problems, as measured by the MFNU, and how well does the test discriminate between children with ADHD and normal controls? We hypothesized that children with ADHD-C/HKD would display consistently high problem scores, and show significantly more motor problems on all the subtests of the MFNU, used in this study, compared to children without ADHD.Fifty-two boys, all Caucasian Norwegians, participated in the study. Informed consent was given by the parents. Twenty-five drug naïve boys, aged 8–12 , out-patients of the Child Psychiatry Department of the Regional Hospital in Kristiansand participated to this study. They were recently diagnosed as HKD F90.0 .Twenty-seven boys, all Caucasian Norwegians, aged 8–11 years (Mean age 9.5 SD 1.1) without ADHD were recruited from two local schools, one for young and one for older children, to the control group. The schools were located in a suburban area with a predominantly Caucasian, low middle class population with no known history of socio-cultural problems. Written permission was obtained from the Local Education Authority of the municipality. A letter with information about the project, and Barkley's DSM-IV rating scale of ADHD  was distWISC-R testing was not carried out in the control group due to resource constraints. Time restrictions and the special recruitment procedures applied, involving only freshly diagnosed children, prohibited a close matching of age between the groups. This resulted in a slightly older ADHD group, difference between mean age = 0.7 years, p < .05. Matching of socio-economic background was not performed for the same reasons.The MFNU was developed by the first author during the 1990-ies in close collaboration with well-educated and specialized personnel trained within the fields of ADHD, learning and behavioral problems. Some of the subtests were originally developed, and some are modified versions of subtests of the Danish 'Funksjonsnevrologisk Undersøgelse (FNU)' . The subIn MFNU a qualitatively based scoring system is used. The test is performed in a very "dynamic" and interactional way with no limits concerning time and number of attempts in order to focus the attention of the child ,9.Most of the subtests of the MFNU  within the total set of subtests  making tThe MFNU is described in detail in a user manual and an accompanying DVD . Table 1MFNU is scored on a sheet applying a ranked 3-category format 0-1-2). The subtests are scored according to the criteria in Table . The subNormally when evaluating test-retest changes in performance with the MFNU a 7-category scoring system is used . This syPreliminary inter-rater reliability analyses have shown high to very high degree of agreement among raters on all subtests (Cohen's Kappa ranging from 0.67 to 1.00) [The present study involved two assessments with MFNU for all children 'Assessment 1' (A1) and 'Repeated assessment' (A2), with at an interval of at least 1 day . The repeated assessment (A2) was performed in order to investigate possible training effects due to repeated testing. To prevent possible negative test results due to distraction or to emotional reactions to an unfamiliar situation, the ADHD group was given a preliminary session introducing the test situation and the different subtests to the parents and child. The assessment of the ADHD group took place at the hospital with the parents being present.The control group was assessed at school. Practical restraints prohibited a preliminary consultation and participation of the parents during the assessment. Practical considerations and limited resources made it necessary to test the ADHD- and control group in different environments, thus prohibiting a blinded design. The subjects were assessed individually by a physiotherapist (the first author of this article) and videotaped by the physician (the fourth author). The videotapes were rated at a later point in time by a physiotherapist with no prior experience with the children. This physiotherapist had long experience both with administering the MFNU and with video rating MFNU sessions. To evaluate differences in performance between the two sessions, two parallel monitors were used. One scoring sheet was used for both assessments.The statistic analyses were carried out using SPSS software 15.0. Descriptive statistics were used on data from each subtest in the ADHD and control group in order to view the percent distribution of the scoring categories (0-1-2) and on the variable 'Total score' which is the sum of the scores on 17 subtests. 'Total score' ranged from 0 – 34. The non-parametric Mann-Whitney U-test was used to compare the ranked scores of the ADHD and control group on each of the 17 subtest. Since the data were not assumed to be normally distributed, the Mann-Whitney test was used to compare the ADHD- and control group on the 'Total score'. Pearsons Chi square test was used, due to the small group sizes, when examining possible effects of age on motor performance. A Cronbach alpha analysis was performed to establish the internal consistency of the total set of subtests. The Wilcoxon Signed Rank Test for related samples was used to compare changes in performance on repeated measurements.The study was approved by The Norwegian Data Inspectorate, The Regional Committee for Medical Research Ethics, the research committee and the director of medicine at the Department of Child Psychiatry, Sørlandet Hospital, Kristiansand, Norway, and the school authorities at the municipality of Songdalen, Norway, where the control group was recruited.The ADHD group showed a high percentage of 'severe problems' (score 2) in most of the subtests, most pronounced in the 'Passive abduction of hip' subtests 13–14) with a 'severe' score in 80–84% of the cases. When the 'moderate problems' and 'severe' scores (score 1 and 2) were combined, the ADHD group presented problems within a range of 80%  to 96% . The control group typically presented few, if any severe problems , while the rest of the subtests showed p < .001. The differences were most pronounced in the youngest children (8–10 years). However, significant differences were also obtained between the older children with ADHD and the control group on all the subtests except for 'Catch ball' (see Table When split into two age groups (12 subjects were < 11 and 13 were > = 11 years) the older ADHD group performed significantly better than the younger group on two subtests, 'Reciprocal coordination' and 'Walking' (p < .05 using Pearsons Chi square test).Table Figure Mann-Whitney U-tests showed that the ADHD group (Median = 28) had significantly more motor problems  than the control group (Median = 1) both on A1: U = 26.6, p < .0001, and on A2: ADHD group (Median = 29), control group (Median = 1): U = 8.5, p < .0001. Cohen's δ of the 'Total score' between the groups on A1 was 1.67.Wilcoxon signed ranks tests were performed on each subtest score and 'Total score' of the A1 and the A2. No significant improvement was obtained on individual subtests or for the 'Total score' within the ADHD group. For the control group a minor, but significant improvement was found for the 'Total score' (p < .05). Motor problems in the control group were most frequent on the subtests '07 Catch ball' and on '03–04 Diadochokinesis', and least frequent on the 'Passive movement' (13–16) and on the 'Extension' subtests (10–12). In the control group, the two subjects with the highest 'Total score' score (14 and 20), both referred for physiotherapy after the study, showed little or no problems on the passive movement subtests and only moderate problems on the extension subtests. In the ADHD group the strongest differences from the control group were found on the 'Passive movement' and 'Extension' subtests.Our hypothesis that there is a discriminative power of the MFNU between boys aged 8–12 years with ADHD (HKD F90.0) and controls without ADHD was strongly supported by the test data across all subtests. Most of the ADHD-subjects achieved a marked to severe 'Total score'. While there were subjects in the control group who showed problems on some of the subtests, the problems appeared on fewer subtests and with less severity than in children in the ADHD group. There were no significant improvements in performance from A1 to A2 within the ADHD group. The high incidence of motor problems within the ADHD group, on all subtests of the MFNU, and the lack of training effect from repeated exposures to the subtests was consistent with our previous clinical observations.The passive movement subtests (13–16) discriminated strongly between the groups. These results seem to confirm our clinical observations that high muscle tone and neuromuscular inhibition problems seen in ADHD are not associated with inattention or impulsivity. Problems involved in the passive movement- and extension tests are not part of the criteria for DCD. These subtests were specifically designed for the MFNU, and are not included in standard motor assessment batteries. On the item 'Passive movement of the right foot' 100% of the controls showed no restriction against the passive movement, whereas 92% of ADHD group had a score of 1 or 2 on this item.repeated movements are emphasized in many subtests in order to reveal increasing inhibition problems when the movements are performed repeatedly. These aspects of motor inhibition problems are usually not assessed in traditional standardised tests, increasing the likelihood of overlooking significant problems.We found that motor problems are present in a higher percentage in the ADHD group . LLS receive 9%, TS 3% and SI 3% royalties.LLS has been the main contributor both in conception, design, acquisition, analysis and interpretation of data. She also is the main contributor in the drafting of the manuscript.TS has been involved in the analysis and interpretation of data, and in the drafting and revision of the manuscript.SI has been a contributor in the conception, design and revision of the manuscript.AR has been a contributor to the conception, design and acquisition of data.BE has contributed to the conception, design, interpretation of data and in revising the drafts of the manuscripts. He has given final approval of the version to be published.FET has been involved in the data analysis and in final revision and approval of the manuscript.Thumb movement ADHD no medication. This movie shows the MFNU subtest 'Thumb movement' performed by a child diagnosed with ADHD-C/HKD. The child had not received MPH the current day or the day before. The move is from the DVD accompanying the MFNU manual [U manual .Click here for fileThumb movement ADHD with MPH. This movie shows the MFNU subtest 'Thumb movement' performed by a child diagnosed with ADHD-C/HKD. The movie was made 1 1/2 after medication with 10. mg MPH on the same day as the previous movie. The move is from the DVD accompanying the MFNU manual [U manual .Click here for file01_Dynamic balance – 2 legs. This movie shows the MFNU subtest 01 'Dynamic balance – 2 legs' performed by a child without ADHD or motor problems. The move is from the DVD accompanying the MFNU manual [U manual .Click here for file02_Dynamic balance – 1 leg. This movie shows the MFNU subtest 02 'Dynamic balance – 1 leg' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file03 and 04_Diadochokinesis – right and left. This movie shows the MFNU subtests 03 and 04 'Diadochokinesis – right' and 'Diadochokinesis – left' performed by a child without ADHD or motor problems. The move is from the DVD accompanying the MFNU manual [U manual .Click here for file05_Reciprocal coordination. This movie shows the MFNU subtest 05 'Reciprocal coordination' performed by a child without ADHD or motor problems. The move is from the DVD accompanying the MFNU manual [U manual .Click here for file06_Thumb movement. This movie shows the MFNU subtest 06 'Thumb movement' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file07_Throw ball. This movie shows the MFNU subtest 07 'Throw ball' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file08_Catch ball. This movie shows the MFNU subtest 08 'Catch ball' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file09_Walking. This movie shows the MFNU subtest 09 'Walking' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [Click here for file10_Lifting arm. This movie shows the MFNU subtest 10 'Lifting arm' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file11_Lifting leg. This movie shows the MFNU subtest 11 'Lifting leg' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file12_Flying. This movie shows the MFNU subtest 12 'Flying' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file13 and 14_Passive abduction – right and left hip. This movie shows the MFNU subtests 13 and 14 'Passive abduction – right hip' and Passive abduction – left hip' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file15 and 16_ Passive movement – right foot and left foot. This movie shows the MFNU subtests 15 and 16 'Passive movement – right foot and left foot' performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file17_Synkinesis. This movie shows the MFNU subtest 17 'Synkinesis'performed by a child without ADHD or motor problems. The movie is from the DVD accompanying the MFNU manual [U manual .Click here for file


Secale cereale L.) belongs to tribe Triticeae and is an important temperate cereal. It is one of the parents of man-made species Triticale and has been used as a source of agronomically important genes for wheat improvement. The short arm of rye chromosome 1 (1RS), in particular is rich in useful genes, and as it may increase yield, protein content and resistance to biotic and abiotic stress, it has been introgressed into wheat as the 1BL.1RS translocation. A better knowledge of the rye genome could facilitate rye improvement and increase the efficiency of utilizing rye genes in wheat breeding.Rye  useful sequences with a cumulative length of 2,032,538 bp and an average read length of 732 bp. These sequences represent 0.5% of 1RS arm. The GC content of the sequenced fraction of 1RS is 45.9%, and at least 84% of the 1RS arm consists of repetitive DNA. We identified transposable element junctions in BESs and developed insertion site based polymorphism markers (ISBP). Out of the 64 primer pairs tested, 17 (26.6%) were specific for 1RS. We also identified BESs carrying microsatellites suitable for development of 1RS-specific SSR markers.This work demonstrates the utility of chromosome arm-specific BAC libraries for targeted analysis of large Triticeae genomes and provides new sequence data from the rye genome and molecular markers for the short arm of rye chromosome 1. Secale cereale L.) is a temperate cereal belonging to the tribe Triticeae, which is grown mainly in Europe and Northern America. Its uses include grain, hay, pasture, cover crop, green fodder, and green manure. More than 50% of the annual rye harvest is used for bread making, resulting in rich, dark bread that holds its freshness for about a week. Despite its relatively low acreage compared to other cereals, rye is of great importance due to its broad tolerance to biotic and abiotic stress, a feature generally lacking in other temperate cereals. Thus, rye remains an important grain crop species for cool temperate zones.Rye  has been introgressed into several hundreds of wheat cultivars . In fact quality . Thus, iDespite the economic importance of rye, little is known about its genetic make up at the DNA sequence level. To our knowledge, there is no ongoing sequencing project in rye, and there are no plans to target gene-rich fractions of its genome. Rye is underrepresented in the sequence databases compared to wheat and barley for which 1,104,002 and 529,839 sequences respectively, are deposited in GenBank. There are only 9,807 rye sequences (about 5 Mbp) available, of which about 90% are expressed sequence tags (ESTs). Updated list of rye genes, markers and linkage data was created by Schlegel and Korzun  and SccImp1RShA_0079_J11F [GenBank:FI104773], contained each one complete and one partial unit of this repeat with identity ranging from 85 to 95%. These sequences were used for multiple alignment  and consensus sequence calculation  against the complete BES data set revealed eight complete or partial units. Assuming that our data set represents 0.5% of 1RS, one can estimate that there is more than 1,000 COP1 units in chromosome 1RS. BLAST search against NCBI nr database  revealed additional units in BAC clones from T. turgidum subsp.durum [GenBank:EF081027], T. turgidum subsp. dicoccoides [GenBank:EF067844] and H. vulgare [GenBank:DQ871219] with similarities ranging from 70 to 90%. In each sequence, 3 – 5 tandemly organized units were identified.Searching BES with masked repeats against themselves and genome survey sequences (GSSs) from Aegilops tauschii [Repeat composition of rye BESs was compared to 10.8 Mbp sequence of random BESs obtained from wheat chromosome 3B  and 2.9 tauschii . The fre-30) against 960,574 plant PUTs downloaded from PlantGDB [-10) was identified for 17 of them. Eleven of them have a putative function  were identified in the data set using SciRoKo 3.3 software . In total, 216 SSRs were identified with an average length of 19.85 bp. The most abundant motifs were trinucleotides, which were found 92-times Table . On averSixty-four ISBP primer pairs were tested for 1RS specificity. Twelve of them (ora001 – ora012) provided an amplification product in rye and in the wheat-rye 1RS addition line but did not show any amplification with wheat DNA and thus were considered 1RS specific Figure . An addiAfa repeat proved that the repeat is localized on the D genome chromosomes. No signal was detected after FISH with the COP1 repeat on barley metaphase chromosomes  accounting for 0.5% DNA of the arm. This study provides the largest amount of genomic sequence data for rye and allows the first systematic analysis of the DNA sequence composition of the rye genome. Because the BAC clones selected for end sequencing were chosen randomly and originated from BAC libraries constructed with two different restriction enzymes, the BESs produced here are expected to be randomly distributed along the whole chromosome arm. Assuming that there is no or little difference in sequence composition among different rye chromosomes, one can consider this sequence as representative of the whole rye genome. The GC content of 1RS 45.9%) is comparable to 44.5% and 44% GC content in wheat  and ric% is compThe observed content of repetitive sequences 84.2%) is lower than expected and is similar to that found in the wheat B genome (85.9%) by Paux et al. . As indi4.2% is lAegilops speltoides have the same mating system, both being outcrossers. Moreover, the B genome is largest of the three homeoelogous wheat genomes and similar in size to the rye genome. On the other hand, the similarity in repeat composition between both genomes may simply reflect similar trends in the mode of their expansion via the LTR-retrotransposon activation.A comparison of the frequency of various types of repeats in genomes of rye and wheat B and D genomes suggested a greater similarity between the rye and wheat B genome than between the rye and wheat D genome. This close relationship of rye and wheat B genome was also supported at the sequence level. It is interesting to note that rye and the putative B genome progenitor A. thaliana genome is 33,000 (TAIR8 release) [Until now, the lack of sequence data did not permit estimation of the number of genes in rye. By analyzing 2 Mbp sequence from chromosome arm 1RS, we estimate 2,000 genes being present on 1RS and thus 36,000 genes in the rye genome. This first estimate for rye is consistent with the predicted gene numbers in other plants. Most recent estimate for gene number in release) , the currelease)  estimateIn addition to the analysis of the rye genome composition, we used BAC end sequences for marker development. There is still a low density of markers available for rye genome and additional markers are urgently needed. Development of a genetic linkage map of rye with 183 markers was reported by Korzun et al. . BednareThis work presents a method for targeted development of molecular markers from specific parts of the rye genome using the 1RS chromosome arm as a case study. Until now, there are only a few markers available for this critical part of the rye genome. This hampers marker assisted breeding not only in rye, but also in wheat where the markers from 1RS would permit selection of lines with introgressions of desired parts of 1RS without the harmful genes. We have developed twelve new ISBPs markers for 1RS and designed almost 200 additional primer pairs for potential ISBP markers that remain to be tested. If needed, generation of additional BAC end sequences from 1RS is possible. In addition to the development of new ISBP markers, BES containing microsatellites were used to develop new 1RS-specific SSR markers. Out of the 63 tested microsatellites that were tested, 21 were specific for 1RS . Thus, iOne of the potential problems in targeted marker development from the 1RS-specific BAC library is the contamination with clones from wheat DNA. This could explain the specificity of amplification for several ISBP markers with wheat DNA. As the 1RS arm was flow-sorted from a wheat-rye ditelosomic addition line, contamination by fragments of wheat chromosomes cannot be avoided. However, the contamination of the 1RS BAC library was estimated to be only 14%  and thusOryza sativa) and wild (Zizania latifolia) rice.The discovery of five ISBP markers, which were specific only for 1RS maintained in the wheat-rye ditelosomic addition line and were not found in diploid rye, was unexpected. Although the same cultivars  were used for the development of the 1RS wheat-rye addition line as well as for marker testing, these insertion sites were absent from rye and wheat. This suggests that some mobile elements were activated only after the addition of 1RS telocentric to wheat, most probably as a consequence of interspecific hybridization. Among the five activated elements three are retrotransposons  and two are DNA transposons (MITE and Mutator). Liu and Wendel  and ShanThis work provides the first insights into the composition of the rye genome and its chromosome arm 1RS, in particular. We demonstrate that the use of chromosome arm-specific BAC libraries facilitates the analysis of complex plant genomes by targeting particular genomic regions as well as by developing molecular markers for these regions. New molecular markers from 1RS should help in saturating the genetic map of 1RS, and aid marker assisted breeding and gene cloning.1RS: short arm of rye chromosome 1; BAC: bacterial artifical chromosome; BES: BAC end sequence; ISBP: Insertion Site Based Polymorphism; PUT: PlantGDB-assembled Unique TranscriptsJB, EP and RK participated in DNA sequence analysis. JB and MH mapped newly isolated ISBP markers. DK performed the FISH experiments. PS sorted chromosomes using flow cytometry. JŠ and HŠ made an intellectual contribution to the concept of the experiment. CT sequenced BAC ends. JB drafted the manuscript. TL and CF revised manuscript critically for important intellectual content, JD conceived and supervised the project and prepared the final version of the manuscript. All authors read and approved the final manuscript.List of 1RS-specific ISBP markersClick here for file


SLC6A3) has been considered a good candidate for ADHD. Most association studies with ADHD have investigated the 40-base-pair variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1. Only few studies have reported association between promoter polymorphisms of the gene and ADHD.Attention deficit hyperactivity disorder (ADHD) is a complex neurobehavioral disorder. The dopamine transporter gene (DAT1/To investigate the association between the polymorphisms -67A/T (rs2975226) and -839C/T (rs2652511) in promoter region of DAT1 in ADHD, two samples of ADHD patients from the UK (n = 197) and Taiwan (n = 212) were genotyped, and analysed using within-family transmission disequilibrium test (TDT).P = 0.001). There was also evidence of preferential transmission of the T allele of -67A/T polymorphism in combined samples from the UK and Taiwan (P = 0.003). No association was detected between the -839C/T polymorphism and ADHD in either of the two populations.A significant association was found between the T allele of promoter polymorphism -67A/T and ADHD in the Taiwanese population (The finding suggests that genetic variation in the promoter region of DAT1 may be a risk factor in the development of ADHD. Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder that affects 3–10% of children and 2–4% of adults .The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission by mediating the active reuptake of synaptic dopamine. Several lines of evidence implicate altered function of DAT in the aetiology of ADHD. In particular, the DAT is a major target for various pharmacologically active stimulants, including methylphenidate, which is one of the most commonly prescribed treatments for ADHD.Functional variants in the DAT1 gene have been widely studied in aetiological studies of ADHD. Most association studies between DAT1 and ADHD have concentrated on a variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the gene. Cook et al.  first reDAT1 gene, and recent evidence suggests the presence of independent risk variants at the 5' end of the gene. Rubie et al. [2 = 5.58, P = 0.018). Genro et al. [P = 0.03). Another study examined the association between the DAT1 promoters -67A/T polymorphism and ADHD in a case/control study, finding a significant association with the T allele [Linkage disequilibrium does not extend across the entire e et al.  found foe et al. ,28,29. Io et al.  also invIn this study we aimed to provide further clarification of reported associations by genotyping two polymorphisms in the DAT1 promoter region for association with ADHD in two independent family-based clinical samples from the UK and from Taiwan.For the UK sample DNA was collected using buccal swabs from 197 ADHD combined subtype probands, from both parents in 133 families, and from only the mother in 64 families. One hundred and seventeen of the ADHD probands had at least one sibling who was also genotyped. Cases were referred for assessment if they were thought by experienced clinicians to have a diagnosis of the combined subtype of ADHD under DSM-IV criteria, with no significant Axis I co-morbidity apart from oppositional defiant disorder (ODD) and conduct disorder (CD) and IQ greater than 70. The age range was 5–15 years at the time of assessment . Parents were interviewed with a modified version of the Child and Adolescent Psychiatric Assessment (CAPA) . InformaThe Taiwanese sample consisted of 212 children with ADHD diagnosed between the ages of 5–15 years . Both parents were available for 114 families, only the mother for 59 families and only the father for 39 families. ADHD cases were ascertained from the Child Psychiatric Clinics in the Chang Gung Memorial Hospital in Taipei area, Taiwan. A diagnosis of ADHD was made according to DSM-IV criteria following completion of a standard maternal interview , and comThe -67A/T (rs2975226) and -839C/T (rs2652511) polymorphisms were genotyped using PCR and enzyme digestion. For the -67A/T SNP the genomic DNA was amplified using forward primers 5'CCAGCCATCTGCGTCC-3' (spanning nucleotide position -151 to -135) and reverse primers 5'-GATGCCGAGAGCGACG-3' (spanning nucleotide position +98 to +113). For the -839C/T SNP the PCR was performed using forward primers 5'GCTCACGGGAGCATCGAG-3' (spanning nucleotide position -973 to -956) and reverse primers 5'-GCACTCGCCTAAGAAAACCA-3' (spanning nucleotide position -689 to -708). After amplification of genomic DNA the PCR product were digested with restriction enzyme Tth111I (for -67A/T SNP) and MspI (for -839C/T SNP) (New England Biolabs). The detail protocols were described in previous study .. Linkage disequilibrium (LD) was estimated by calculating D' and r2 statistics. The Bonferroni correction was applied for multiple comparisons and P < 0.0125 was considered to show a statistically significant difference.Family genotype data were analysed using the transmission disequilibrium test (TDT) implemented in UNPHASED program (TDTPHASE) , . Linka2 = 0.91 in UK samples; D' = 0.70, r2 = 0.59 in Taiwanese samples).Population frequencies for the two markers were estimated from parental genotypes. For the UK and the Taiwanese sample the A-allele frequency of the -67A/T polymorphism is 61% and 68%, respectively, and the C-allele frequency of the -839C/T polymorphism is 52% and 53%, respectively. Allele frequencies of both markers did not show any significant deviation from those expected according to Hardy -Weinberg equilibrium in either population. Significant LD was observed between the two markers . Even after correcting P- values using the Bonferroni method for multiple comparisons a significant association was still found between the -67T allele and ADHD cases in Taiwanese population. No significant association was seen in the UK sample for this marker using either standard TDT analysis, or the extended TDT analysis including siblings, although the T-allele was over-transmitted (OR = 1.16). A combined analysis including both population samples found significant association of the T-allele . No difference in the transmission of any alleles of the -839C/T polymorphism to ADHD was found in either of the two populations , while haplotype -67A/-839T was significantly under-transmitted to Taiwanese ADHD probands and combined samples   in an Iranian sample. We did not observe any association with the -839C/T polymorphism and ADHD in either of our samples, and were thus unable to replicate the findings by Brookes et al [In this study, we set out to investigate previously reported findings of association between the two promoter polymorphisms of the DAT1gene in two independent samples of ADHD probands from UK and Taiwan. We found a significant over-transmission of the -67T allele to ADHD combined subtype cases in Taiwanese population and the two combined samples from UK and Taiwan. Our study replicates a finding conducted by Ohadi et al. , who foues et al  and Genres et al . In thisIn conclusion, in this study we used family-based ADHD data in the UK and Taiwanese population to test for an association between two SNP variants in the promoter region of DAT1 and susceptibility to the disorder. Our findings support the notion that genetic variation in the promoter region of DAT1 might be a risk factor in the development of ADHD, particularly in the Taiwanese sample studied. Whilst further studies are needed to confirm these findings, our data suggest that association studies of DAT1 in ADHD should not be limited to variation at the 3' end of the gene, which has been the traditional focus for aetiological studies.The authors declare that they have no competing interests.XX selected the SNPs, performed genotyping, genetic analysis and drafted the manuscript. JM supervised sample preparation and revised the manuscript. BS assisted in the genotyping for the study. CKC, YSH and YYW provided the Taiwanese DNA samples and clinical data. PA supervised the study and revised the paper. All authors contributed to the final critical revision of the manuscript.The pre-publication history for this paper can be accessed here: