In this naturalistic clinical study, we explored the applicability and clinical effectiveness of Cogmed WMT, pharmacotherapy, and their combination for clinically referred children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Ninety youth with ADHD (ages 6–16 years) and their parents were offered the possibility to choose one of the three interventions. The motives for choosing various interventions were quite different. Medication was chosen because this treatment was expected to be most effective, but also because the Cogmed WMT program was regarded as too taxing. The choice for Cogmed WMT was mainly negatively motivated: participants tended to be strongly against the use of medication, found it a too rigorous step, or feared side effects and addiction problems. The choice for the combination treatment was strongly positively motivated: parents and youth indicated that they wanted to receive the best possible intervention and part of them also had high expectations of Cogmed WMT. In terms of clinical effectiveness, pharmacotherapy with stimulant medication and the combination treatment produced larger reductions in ADHD symptomatology than Cogmed WMT. Further, results indicated that Cogmed WMT selectively enhanced working memory performance. Finally, after conducting Cogmed WMT, youths and parents were more ‘open’ to accept pharmacotherapy as intervention, probably because the training increased greater insight in and awareness of the problematic features of ADHD. Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by symptoms of extreme inattention, hyperactivity, and impulsivity that interfere significantly with daily functioning and development , 2. AbouThere is no curative intervention for ADHD, although good care and treatment may help to normalize the behavior of these youngsters and to improve their eventual prognosis. Pharmacotherapy with psychostimulant medication such as methylphenidate and amphetamine is considered to be the first-line treatment , 10. PlaIn spite of these favorable outcomes, a considerable proportion of the parents dismiss psychostimulant medication as an intervention for their youngster with ADHD , and theIn search for a good alternative treatment for children and adolescents with ADHD, parents could opt for behavior therapy. This intervention has also been shown to yield favorable results, although some meta-analyses have indicated that the effects of this psychosocial intervention are smaller than those produced by pharmacotherapy with methylphenidate, the most commonly prescribed psychostimulant drug . WorkingWith this in mind, Klingberg et al.  developeFurthermore, while research on the efficacy of Cogmed WMT is important in order to learn more about performance of this intervention under ideal, well-controlled circumstances, studies are also needed on effectiveness, thus its performance under real-life conditions. The present investigation was conducted to examine the applicability and effects of Cogmed WMT (as compared to pharmacotherapy) in an everyday clinical practice. Ninety consecutively referred children and adolescents who were diagnosed with ADHD at our outpatient treatment center participated in this naturalistic trial. Youth and parents were given information about three available interventions: (1) Cogmed WMT, (2) pharmacotherapy with psychostimulant medication, and (3) a combination of Cogmed WMT and pharmacotherapy, after which they were invited to choose one of these treatment options. First of all, we wanted to learn more about the choice for various treatment options for children and adolescents with ADHD: what is the percentage of youth and parents selecting Cogmed WMT and/or pharmacotherapy as intervention(s) and what are the motives for their choice? Further, to evaluate the effects of the three interventions, pre- and post-intervention assessments were conducted that consisted of parent-, teacher-, and self-report rating scales measuring ADHD symptomatology, comorbid problems, and executive functioning, as well as performance-based tests for assessing working memory and attentional processes. Pre- to post-comparisons of parent- and teacher-ratings of ADHD symptoms were considered as the primary outcome measure , and werThe intervention part of the study was conducted between November 2012 and June 2015 at Lucertis (previously Virenze-RIAGG) Maastricht, an outpatient center for children and adolescents with mental health problems. Youth who had been referred to the center were subjected to a standard intake procedure, which consisted of unstructured clinical interviews with the youngster and his/her parents, a semi-structured diagnostic (DSM-IV-based) interview, an observation in the play room (for children in the preschool and primary school age), a contact with the teacher at school, administration of a developmental anamnesis survey and a set of standardized questionnaires , and evN = 97) were approached for participation in the present study. This was done during an advisory conducted by the case manager  who (1) discussed the diagnosis and classification of ADHD, (2) explained why the team thought that the youngster suffered from this condition, and (3) provided basic psycho-education about the disorder. Following this, the youngster and parents were given a leaflet containing information about the background and rationale of the three interventions, their content, and possible disadvantages. The case manager discussed the content of the leaflet orally and also explained that there would be pre- and post-intervention assessment sessions for both the youngster (1 h per session) and the parents (20 min per session) to quantify the effects of the intervention. Then the youngster and the parents were given two weeks to decide on participation and the choice of the intervention.Cases for which ADHD was identified as a condition that required treatment  for this choice, and the level of confidence in the intervention as being helpful for their child . The characteristics of the 90 participating youngsters are displayed in Table SD = 20.39 vs. 138.20, SD = 35.32 and 137.20, SD = 29.93 months; F = 5.71, p < .01]. Further, level of interference associated with ADHD (as rated by parents on the ADIS) was higher in the psychostimulant medication and combined treatment groups as compared to the Cogmed WMT group . Finally, youngsters in the stimulant medication group and the combined treatment group more frequently had a low socio-economic status than youth in the Cogmed WMT group, with percentages being 65.4 and 52.2 versus 25.0%; χ2(1) = 9.98, p < .01.As can be seen in the flowchart presented in Fig. Three youngsters prematurely dropped out of the study , leaving 87 participants for the intent-to-treat analysis . Nine youngsters dropped out during the intervention part of the study: five (15.1%) in the WMT condition, three (10.3%) in the medication condition, and one (4.0%) in the combined intervention condition. Within the latter condition, four participants renounced the Cogmed WMT after having started with the medication treatment and naturally “switched” to the medication condition. Thus, ultimately there were 78 participants for the completer analysis . In passing, it is relevant to note that participants in the WMT conditions  were only considered as completers in case they fully adhered to the Cogmed protocol and conducted all 25 sessions.SD = 12.99, range 9–67; 82% of the children and adolescents reached an index ≥ 17%).The Cogmed WMT was delivered to the children and adolescents at home or (in case that was not possible) at school via the official Pearson website. The program consists of visuospatial (remembering the position of objects in a grid) and verbal  working memory tasks. Children had to perform these working memory exercises during 5 weeks, 45 min–1 h per day, 5 days per week. Parents  were instructed to supervise the children in conducting the daily set of WMT trials. The Cogmed program is developed in such way that the difficulty level of the exercises is automatically adjusted to each individual child: performance on the first trials is taken as the starting level at which the working memory span is trained and gradually improved. The Cogmed WMT was supervised by five psychologists who were officially trained and certified as Cogmed coach by Pearson Netherlands, and who followed the children’s compliance with the intervention and monitored their progress using a special log in facility which enabled them to view the files in which the results of each session conducted by the young participants were stored. In general, the program was successful in enlarging youth’s working memory capacity: the average improvement index was 27.2%  or due to side effects changed to other types of medication.The frequency/duration of the contacts with the Cogmed coaches and the psychiatrists were similar for youth in the Cogmed WMT and stimulant medication groups. There was a starting session during which (a) the psychiatrist conducted a brief medical examination and provided information about the treatment with psychostimulant medication and its procedure, while (b) the Cogmed coaches explained the rational of the WMT training and provided instructions about the use of the program and the role of the parents (or the other person who was going to assist the child in conducting the training). One week later, there was a brief follow-up session  to check whether youth had started with the intervention and to address eventual questions and problems. If indicated, there were additional telephone and email contacts and occasionally even face-to-face sessions during the further course of the intervention. At the end of the training period, there was a closing session in the Cogmed WMT group during which an evaluation of the intervention took place and youth received a certificate for successfully completing the program. Around this time, children and adolescents in the stimulant medication group visited the psychiatrist for a follow-up consult. Youth in the combined treatment group had sessions and follow-up contacts with both the psychiatrist and the Cogmed coaches, and thus received twice as much care as youth in the mono-intervention groups.ADHD-Questionnaire (ADHD-Q ) The Dutch version of the Behavior Rating Inventory of Executive Functioning (BRIEF ) is a 75Verbal and visuospatial working memory were measured with respectively the Digit Span test of the Wechsler Intelligence Scale for Children (WISC ) and theThe Stroop interference task  is a widhttp://www.cotandocumentatie.nl) has concluded that the Bourdon-Vos test has reasonable reliability and validity.The Bourdon-Vos test  is a papThe TEA-Ch  is a neuThe ADHD module of the Anxiety Disorders Interview Schedule for youth  was admiOne year after the post-intervention assessment had taken place, a research assistant contacted the parent(s) of the participating youth by telephone with a number of qualitative follow-up questions pertaining to (1) the current level of ADHD symptoms of the child/adolescent and the degree to which this problem interfered with daily functioning, (2) a retrospective evaluation of the intervention that the child had received for reducing attention-deficit and/or hyperactivity problems , (3) whether the child/adolescent had continued to use the stimulant medication, and or—in case he/she had only received the Cogmed intervention—had started to use this type of medication in the past year, and (4) whether the child/adolescent had received other  interventions targeting ADHD in the past year.d , which in turn was more frequently selected for a positive reason than Cogmed WMT . This imbalance in motives also partly showed itself in participants’ confidence ratings: parents and youth indicated that they expected that medication and the combination intervention  would be more helpful than Cogmed WMT  .When looking at the motives for choosing the three interventions, an interesting pattern emerged. Medication was chosen for a mix of positive and negative reasons. That is, part of the parents/youth (46.7%) selected the treatment with stimulant medication as they considered it as the intervention proven to be most effective for children and adolescents with ADHD. However, other participants chose medication because they deemed the Cogmed WMT program to be too intensive and taxing (53.3%). The choice for Cogmed WMT was mainly negatively motivated: about one-third of the participants (36.7%) preferred the training because they were strongly against the use of medication and/or feared side effects and addiction problems. Other parents/youth (40.4%) considered medication as a too rigorous step and preferred to first try Cogmed WMT. Only a minority (22.9%) chose Cogmed WMT for a positive reason, for example because they thought that this intervention would be effective. The choice for the combination intervention was without exception positively motivated (100%): all parents and youth indicated that they wanted to receive the best possible treatment, and 20% of them explicitly noted that they expected Cogmed WMT to make a significant contribution. Statistical comparisons confirmed that the combination treatment was more often chosen for a positive reason than medication [χd’s between 0.73 and 1.68, all in the medium to very large range) than in the Cogmed WMT group .The series of 3 (groups) × 2 (occasions) ANOVAs performed on the parent and teacher data of the primary outcome measure—the ADHD-Q—revealed significant time effects, indicating a general improvement of youth’s ADHD symptomatology. More importantly, the crucial time × groups interaction effect was also significant and consistently found across all types of ADHD symptoms. As can be seen in Table On the hyperactivity-inattention subscale of the SDQ, a similar pattern was found, but here the significant interaction effect was found in the data of all three informants. Again, youth in the simulant medication and combined treatment groups appeared to have profited more from the intervention than those in the Cogmed WMT group. The SDQ impact ratings yielded comparable results with children and adolescents in the stimulant medication and combined treatment groups demonstrating a greater reduction in the negative impact of symptoms on daily functioning as compared to those in the Cogmed WMT group, although it should also be noted that according to parents and children themselves impact ratings prior to the intervention were already (somewhat) lower in the Cogmed WMT group.On measures of other (comorbid) symptoms as indexed by the SDQ or executive functioning problems only significant time effects were found: these symptoms and problems decreased significantly from pre- to post-treatment, but here improvements were more or less equal across the three intervention groups.d’s between 0.76 and 1.76) and clearly more substantial than those documented in the Cogmed WMT group, which were all in the small to medium range  × 2 (occasions) ANOVAs conducted on the questionnaire data of those who had actually completed various interventions yielded a highly similar picture as the intent-to-treat analysis, which is not that surprising as relatively few participants dropped out or changed group. The crucial interaction effect of groups and occasions was found for most parent- and teacher-rated scales related to ADHD symptoms , for which it was found that the reductions in symptoms were more pronounced in the stimulant medication and combined treatment groups than in the Cogmed WMT group (Table The series of 3 (groups) × 2 (occasions) ANOVAs that were carried out on the performance-based tests first of all revealed significant time effects. In general, participants showed improved working memory on the WISC digit span and the Corsi block-tapping task, less interference on the Stroop test, a faster, more accurate, and more regular performance on the Bourdon-Vos test, and increased attentional capacity on some of the TEA-Ch subtests. A significant groups × occasions interaction effect was documented for the Corsi Block span task. Both the Cogmed WMT and the combined treatment group showed a significant improvement in visual-spatial working memory performance from pre- to post-treatment, which was not present in the stimulant medication group Table . A groupThe 3 (groups) × 2 (occasions) ANOVAs performed on the performance-based tests of the completers yielded a comparable pattern of results. Besides the significant time effect that was found for most of these outcome variables, significant interaction effects of group × occasions were found for both the WISC Digit span and the Corsi Block span tests. Post-hoc comparisons revealed that auditory as well as visual-spatial working memory significantly improved in the Cogmed WMT and the combined treatment groups, whereas it did not in the stimulant medication group Table . A signiThe post-treatment SDQ included some questions evaluating the received intervention. As can be seen in Table The results of the 1-year follow-up interview revealed that parents indicated that stimulant medication and the combined treatment had been more helpful and more effective in reducing ADHD symptoms and improving youth’s daily functioning than the Cogmed WMT. Percentages of youth taking Ritalin or some other stimulant agent were 86.7% in the stimulant medication group and 95.0% in the combined treatment group, indicating that the majority of youth had continued this treatment. About one-third of the youth (31.0%) had started with a new intervention during the past year. Interestingly, most of them were from the Cogmed WMT group of which almost half of the children and adolescents (46.4%) had started with the use of stimulant medication. Examples of other interventions were the use of homeopathic medication , placement in a special school, semi-residential care, and participation in social skills training.This naturalistic study examined treatment preferences for Cogmed WMT versus psychostimulant medication in youth diagnosed with ADHD as well as the clinical effectiveness of these interventions. With regard to the treatment preferences, it can be concluded that Cogmed WMT is a viable treatment option for youth with ADHD and their parents: for 38.9% of the participants in this study Cogmed WMT was selected as the stand-alone intervention, whereas a further 27.8% chose WMT in combination with psychostimulant medication. As no other treatment alternatives  were offered to our participants, the results remain silent about the ‘real’ preference for Cogmed WMT, but at least these findings indicate that a substantial proportion of youth and parents is open to this non-pharmacological treatment of ADHD. Admittedly, when looking at the motives for choosing various interventions, it must also be concluded that Cogmed WMT was frequently chosen for a negative reason: that is, more than three quarters of the participants selected this intervention because they were strongly against the use of medication, feared side-effects or addiction problems, or considered medication as a too rigorous step. This nicely echoes the literature indicating that parents often dismiss psychostimulant medication as a treatment for young people with ADHD  and thatTreatment with stimulant medication was chosen for a mix of positive and negative reasons. Nearly half of the participants selected this intervention because it was considered to be most effective for youth with ADHD. The other participants chose medication because they thought that the Cogmed WMT  would be too intensive and hence too taxing for them to conduct. Indeed some young participants in the Cogmed group reported that the training was taxing and for their parents it was quite difficult to keep these children motivated to perform the  daily exercises. For this reason, researchers have begun to incorporate game elements in WMT to improve the motivation and engagement of youth . MeanwhiWhen looking at the effects produced by the interventions on our primary outcome measure, especially the parent and teacher version of the ADHD-Q, it can first of all be concluded that there was little difference between the results of the intent-to-treat and the completer analyses (probably as a result of the fairly low drop-out rates). In general, all children and adolescents showed significant improvement in ADHD symptomatology from the pre- to post-assessment. This means that in general youth in all three groups displayed lower levels of inattention, hyperactivity, and impulsivity following treatment. It was also noted that reductions in ADHD symptomatology were consistently larger in the stimulant medication and the combined treatment groups than in the Cogmed WMT group. More precisely, the effect sizes found for stimulant medication and combined treatment were all in the medium to very large range, whereas those obtained for Cogmed WMT were in the small to medium range. Admittedly, previous research has yielded variable effect sizes for these interventions in youth with ADHD, probably as a result of variations in population, outcome measures used, type of informant, and study design . However, the results are well in line with the general conclusion of meta-analytic studies indicating that the effects on ADHD symptoms produced by stimulant medication are considerably larger than those produced by cognitive training programs such as Cogmed WMT , 67.Analysis of the data obtained with the self-report version of the ADHD-Q confirmed the general picture that all children and adolescents to some extent profited from the interventions. More precisely, youth themselves also reported to experience reduced levels of ADHD symptomatology following treatment with psychostimulant medication, Cogmed WMT, or the combined intervention. The interaction effects of treatment groups and time  were less robust  when the child-report ADHD-Q was employed as outcome measure. The main reason for this was that—according to youth themselves—reductions of their ADHD symptoms following psychostimulant medication and the combined treatment were smaller than the reductions of these symptoms as observed by parents and teachers. On the one hand, this may be due to youth underreporting these externalizing symptoms , but on The hyperactivity-inattention subscale and the impact supplement of the SDQ generally yielded the same results as those obtained with the ADHD-Q. Thus, these measures also indicated that symptoms of ADHD and their negative impact on youth’s daily functioning decreased from the pre- to post-treatment assessment. In addition, children and adolescents in the stimulant medication and combined treatment groups appeared to profit more from their intervention than youth receiving the Cogmed WMT, and this was most consistently the case when the SDQ hyperactivity-inattention subscale and the impact supplement were completed by the parent and the teacher. For SDQ other problems and BRIEF executive functioning significant time effects were found, indicating that co-occurring psychopathological symptoms and problems with executive functions related to behavior regulation, meta-cognition, and working memory generally were less prominent following all interventions. No significant interaction effects emerged, implying that all treatments were equally effective in reducing comorbid symptoms and improving executive functioning.The analyses conducted on the neuropsychological scores revealed that youth showed improved performance on seven  to eight  out of ten tests. More precisely, following the interventions, youth on average remembered more numbers on the WISC digit span, reproduced a larger sequence of tapping movements on the Corsi Block span, showed less interference on the Stroop color-naming task, were faster and more accurate on the Bourdon-Vos test, and displayed improved selective and divided attention on a number of TEA-Ch tasks. For a number of variables, the interaction of groups by time was also significant. To begin with, it was found that youth in the Cogmed WMT and the combination treatment groups showed a larger improvement in their performance on the WISC digit span  and the Corsi Block span test  as compared to youth in the stimulant medication group. Thus, the interventions that included the WMT component appeared to produce a (somewhat) better effect on indices of verbal and visuospatial working memory, which is in agreement with was has been reported in previous studies , 70–75 aThe subjective evaluations obtained from the three informants at post-treatment were largely in keeping with the data as obtained from our quantitative assessments: that is, in general parents, teachers, and youth themselves evaluated the stimulant medication and combined treatment as considerably more helpful in reducing ADHD symptomatology and making the problem more bearable than Cogmed WMT. At the 1-year follow-up interview with the parents, this picture was unchanged, although it should be admitted that this comparison might have been influenced by the fact that for most youth medication treatment was continued after the post-treatment assessment, whereas the Cogmed training had stopped at that time. The subjective evaluations confirm previous reports indicating that the use of stimulant medication is clinically effective and significantly improves quality of life and functional outcomes in a substantial proportion of the children and adolescents with ADHD , and thaIt should be emphasized that this study was not a randomized controlled trial and that it is not appropriate to use these data to directly compare the effects of Cogmed WMT, stimulant medication, or the combined treatment. For example, because we allowed parents and youth to choose their preferred intervention, the three treatment groups were not fully comparable with regard to levels of symptomatology and problems. That is, according to parents and youth themselves, the participants in the Cogmed WMT group displayed lower  levels of ADHD symptoms, associated interference, comorbid symptoms, and executive functioning at pre-treatment than the participants in the stimulant medication and combined treatment groups. Further, the aforementioned imbalance in motives also accounted for differences in confidence ratings across the three groups, with parents and youth expecting that medication and the combination intervention would be more helpful than Cogmed WMT. On the basis of these inequalities, it is better to view the present study as a naturalistic trial testing the feasibility and effects of Cogmed WMT in common clinical practice, and delimitate its role besides pharmacological interventions for youth with ADHD. Further, when evaluating the treatment effects obtained in this study, one should bear in mind that alongside the described interventions  all young participants and their parents received psychoeducation, which is generally seen as the first step in the standard care for children and adolescents with ADHD , 10. ThuADHD is a debilitating neurodevelopmental disorder causing significant problems in youth’s daily functioning. While there is no curative intervention for ADHD, good care and treatment may help to normalize the behavior of these youngsters and to improve their eventual prognosis. Pharmacotherapy with psychostimulant medication is currently considered as the best treatment option, and the current data confirm this by demonstrating the robust clinical effectiveness of this intervention. However, it is also a fact that many youth and their parents are not eager to adopt this type of treatment and this was the case in our clinical practice where we presented youth with ADHD and their parents with a ‘menu’ of treatment including Cogmed WMT, stimulant medication, and the combination of these interventions. About one-third of the youth with ADHD and their parents chose the non-pharmacological treatment of Cogmed WMT, and the vast majority of them (77.1%) did so because they were either strongly against the use of medication, feared side effects and addiction problems, or considered it as a too rigorous step. Interestingly, it was found that a considerable number of the youth and parents who had initially selected the Cogmed WMT changed their opinion in the year following the intervention and were willing to accept medication treatment. On the one hand, this change may have been due to the fact that the clinical effects produced by Cogmed WMT were quite modest and so for most youth there was still an urge for additional treatment. On the other hand, we also observed that the WMT made parents more aware of the specific problems of their offspring. That is, while conducting the program together with their child, they seemed to get a better picture of its attention problems, hyperactivity, and impulsivity under ‘scholastic’ conditions. Thus, rather than turning Cogmed WMT down as a rather ineffective intervention for youth ADHD, we would like to emphasize that this intervention may have an appropriate role in clinical practice.


Pre-pregnancy BMI was calculated from weight at the last menstrual period and height was extracted from medical records. Gestational weight gain was calculated from pre-pregnancy weight and weight measured at the time of delivery. ADHD symptoms and executive self-regulation behaviors were assessed by maternal report (mean age = 3 years). Multivariable regression methods with inverse probability weighting (IPW) were used to evaluate associations accounting for sample selection bias and confounding. Pre-pregnancy BMI at levels ≥35 was positively associated with higher ADHD symptoms and worse executive self-regulation behaviors (inhibitory control and attention). Compared to adequate GWG, less than adequate GWG was related to more ADHD hyperactive-impulsive symptoms, whereas greater than adequate GWG was related to more problematic behaviors related to working memory and planning. The findings support a link between maternal weight and child neurodevelopment. Continued research that help identify biological mechanisms are needed.This study examines pre-pregnancy Body Mass Index (BMI) and gestational weight gain (GWG) in relation to early childhood Attention Deficit Hyperactivity Disorder (ADHD) symptoms and related executive self-regulation behaviors. The analyses sample ( Globally, more than 10% of the population have a body mass index (BMI) in the obese range BMI ≥ 30) with the prevalence having doubled in 70 countries in the past 25 years 0 with th.Recent studies further suggest that maternal obesity prior to or during pregnancy may also be related to cognitive and neurodevelopmental problems in offspring. For instance, animal studies indicate that an obese state during pregnancy leads to a cascading series of events that affect brain development and subsequent neurodevelopmental functioning. Bilbo and Tsang (2010) showed in rats that gestational obesity produces changes in inflammatory signaling that has downstream effects on fetal microglial functioning, brain development and subsequent offspring spatial learning abilities . In addin = 7 in meta-analysis), but had the highest odds ratio (1.62) associated with pre-pregnancy obesity [Studies of humans align with these findings from studies of animals. Maternal pre-pregnancy obesity has been linked with a number of cognitive and neurodevelopmental outcomes in offspring, such as cognitive/intellectual delay , poorer  obesity . Of note obesity ,17, and  obesity ,19. GiveUnderstanding prenatal and developmental factors associated with ADHD and poor executive self-regulation is important since childhood symptoms in these domains, independent of a clinical diagnosis, can increase the risk for a number of unhealthy behaviors later in adulthood ,21 and hThe purpose of this study was to add additional data to this growing body of literature. First, this study includes assessment of both ADHD symptoms and behaviors in everyday life that depend on executive self-regulation processes . Second, whereas existing studies have focused primarily on school age children, the study population herein is a sample of preschool age children. If associations are present at the preschool age, it may provide further justification for earlier monitoring of behavioral problems among children born to mothers obese prior to and during pregnancy. Third, we examined both continuous and categorical indicators of pre-pregnancy BMI and gestational weight gain (GWG) in order to identify associations at varying levels of exposure. In addition, we used inverse probability weighting (IPW), a robust method for accounting for sample selection bias and confounding in observational studies ,26. In lParticipants were enrolled as part of the Newborn Epigenetics STudy (NEST), a birth cohort designed to identify the effects of early exposures on epigenetic profiles and developmental outcomes. Briefly, 2595 pregnant women were recruited from prenatal clinics serving Duke University Hospital and Durham Regional Hospital Obstetric facilities in Durham, North Carolina, from April 2005 to June 2011. Eligibility criteria was: Age ≥ 18 years, English speaking, pregnant, and intention to use one of the two obstetrics facilities to enable access to labor and birth outcome data. The Institutional Review Board approved the study procedures.n = 1278) were sent a survey by research staff, that included measures of ADHD symptoms and related executive behaviors. Of those who were sent a survey, 223 were undeliverable and 127 were deemed ineligible due to the child’s age at the time the survey was completed. We received 531 surveys (531/(1278 − 127) = 46.4% response rate). Of the 531 returned surveys, 331 had data on all data needed for this study. Main sources of missing data were due to one measure  that was added subsequent to sending and initial set of surveys and missing data on pre-pregnancy weight and data on gestational diabetes from the medical records. The mean gestational age at enrollment for the analysis cohort was 19 weeks (range: 5–42 weeks).Between January 2011 and June 2013, mothers from the NEST study, who had children between the ages of 2 and 6 years of age (n = 331) to the sample who were originally sent surveys minus those who returned the survey (n = 331) and those who returned from mothers who completed the survey after their child turned 6 years of age (n = 127). Compared to eligible mothers who did not return the sent survey, the analytic sample was slightly older , with more college graduates , significantly more Caucasians , and no differences for African Americans , or Hispanics . Fewer mothers reported “Yes” for prenatal smoking status in analysis sample , which were documented as binary variables. The two samples were similar with respect to infant sex  51.7% vs. 50.9%, χ2 = 0.06, p = 0.81). Mean pre-pregnancy BMI was similar , however, mean GWG was greater in the analysis sample . Proportions of women having gestational diabetes were similar in the two samples . The propensity scoring method described below was used to account for non-response selection bias in our sample.We compared our analysis sample (2) from self-reported weight at the last menstrual period prior to the first prenatal visit, and nurse-measured height. World Health Organization (WHO) categories were also constructed . To evaluate the potential recall bias in the sample, we abstracted weight from medical records of 243 women who visited a hospital affiliated clinic on average 6 months prior to their first prenatal visit for the pregnancy that made them eligible for the study. The correlation between periconceptional self-reported and nurse-measured weight was 0.98 (p < 0.0001). When considering only overweight or obese women, the correlation remained significant .All prenatal clinics used the same model of Stadiometer and weight scale  with height being accurate within 1/8 of 1 inch and weight accurate within 0.1 pounds. Pre-pregnancy Body Mass Index (BMI) was computed , and the last weight taken up to seven days before or at delivery from medical records . Categor30 kg/m2 . These rThe Behavior Assessment System for Children (BASC), 2nd edition preschool parent rating scale was used to assess ADHD related symptoms. The BASC is a valid, reliable, 134-item measure of child behavior problems and is appropriate for use in children ages 2 through 5 years 11 months . The meaThe Behavior Rating Inventory of Executive Function (BRIEF)—Preschool Version was used to assess executive behaviors . The BRIThe Adult ADHD Self-Report Scale (ASRS) screener was used to assess ADHD symptoms among the mothers . The ASRAt enrollment (mean gestation age 19 weeks), a self- or interviewer-administered questionnaire solicited information about maternal age, race, educational status, parity, and smoking history (whether they smoked prior to or during pregnancy). Birth weight, gestational weeks, and infant sex were obtained from medical records and child age was calculated from their birth date and the date the mother completed the follow-up survey.p < 0.1. These variables included gestational diabetes, parity, birth weight, the child’s age, sex, mother’s age, race, education, gestational weeks, smoking and mother’s concurrent ADHD. The IPW method used addressed bias from two sources: nonresponse selection and confounding. Following the methods described by Rinsky et al. (2017) [To examine the associations between pre-pregnancy BMI and the two outcomes (ADHD symptoms and executive behaviors), multivariable linear regression with inverse probability weighting (IPW) was used to regress pre-pregnancy BMI as a continuous variable (Model 1) and as a categorical variable using the WHO groups ) on BASC ADHD symptoms and BRIEF scores. IPW is a robust method for addressing confounding in observational studies by simulating a randomized design such that the distribution of confounding variables are balanced across the exposure . Variabl. (2017)  logistic. (2017) ,26. All . (2017) . We did n = 36 (11%) and n = 54 (16%) participants had T-scores of 60 or above  for the BASC HY and BASC AP, respectively. For BRIEF GEC, n = 52 (16%) participants had T-scores of 65 or above . Compared to the sample used to derive population norms, the percentage in the clinical significant range in our study was fairly similar to the norm sample. Specifically, the norm sample used for the BASC-II showed that among children ages 2–6 years, 14–15% for the BASC HY and 14–17% for the BASC AP, were in the clinical range. Meanwhile, norm sample from the BRIEF population showed 8–10% were in the abnormal elevation range for boys and girls at the same age group. Bivariate analyses show that several of the covariates were related to the composite BASC ADHD and BRIEF GEC scores. Further, composite BASC ADHD and BRIEF GEC scores were monotonically related to higher weight categories. Gaining less than or more than the IOM recommendations for weight gain during pregnancy were both associated with statistically higher composite BASC ADHD scores (p < 0.01) and marginally, but not statistically significant, with a higher BRIEF GEC score (p = 0.07).B = 0.17, p = 0.001) and greater hyperactive-impulsive  and attention problems symptoms  (Model 1). As presented in B = 0.38, p = 0.02) (Model 1). B = 0.09, p = 0.04), shift , working memory  and planning and organizing .As seen in Model 2 in B = 0.08, p = 0.046), planning and organizing  and was marginally significantly related to inhibit .As seen in B = 2.04, p = 0.02). With respect to executive behaviors, compared to women with adequate GWG, women with greater than adequate GWG had children with elevated, but not statistically significantly higher scores related to problems inhibiting behavior (p < 0.10).Model 4 in Sensitivity analysis in which we limited the analyses to children born ≥ 37 weeks produced similar results to the main analyses that included children born at ≥ 34 weeks .Our findings demonstrate a consistent relationship between pre-pregnancy BMI ≥ 35 and child ADHD symptoms and executive self-regulation behaviors during the preschool age . GWG, either less than the recommended levels or more than the recommended levels, were also found to be associated with ADHD symptoms and executive self-regulation behaviors with less than recommended levels of weight gain associated with hyperactive-impulsive symptoms and more than recommended levels of weight gain associated with worse working memory, planning and organizing behavior. Of note, the results were significant using a propensity scoring method – a robust method to minimize selection bias and balance confounding across the exposure . Overall, this study contributes additional data to a growing body of research suggesting that maternal weight at conception may influence cognitive and neurodevelopmental outcomes in children and increase the likelihood of ADHD symptoms .The findings are in line previously published results, especially those by Jo et al. (2015) who found that an ADHD diagnosis was significantly higher among children born to mothers with BMI ≥ 35 relative to children born to mothers with a BMI in the normal range . A more The potential biological mechanisms linking these associations remain to be investigated. A prevailing explanation for these associations is that fetal exposure to disruption from inflammatory cytokines among women who have a higher BMI may alter fetal brain development ,39. CytoThis study also adds additional data to this field by examining ADHD symptoms and executive behaviors using well-validated measures among a multiethnic sample of preschool children. The findings from this community-based cohort help support the generalization of findings from previous studies. We also examined a broader range of executive capacities; findings that may help to inform hypotheses of potential mechanisms and aid in the design of early intervention strategies. Specifically, our models revealed consistent deficits in domains of attention and cognitive functions , but not in emotional control. Pre-pregnancy BMI has been associated with emotional intensity and regulation in offspring who were on average 5 years of age . Thus, iThe results should be interpreted within the context of the study’s limitations. First, as is the case with most all studies on this topic, pre-pregnancy weight was based on maternal self-report of weight prior to her last menstrual period. There is some evidence that women who are overweight and/or obese may underreport their weight status . HoweverSecond, we employed dimensional measures of ADHD symptoms and executive function behaviors, which may be related to a number of psychiatric conditions . As differential diagnostic evaluation was not conducted, we are not able to conclude to what extent pre-pregnancy BMI is related to ADHD, as it is clinically defined or to other forms of psychopathology. Since this sample was a community ascertained sample of young children, rather than a clinical sample, the prevalence of ADHD would likely have been low reducing our power to evaluate the hypothesized associations. Additionally, we only have parent questionnaires available for assessment of both ADHD symptoms and executive functioning. Though parents can provide information on their children’s behavior in a naturalistic setting, their report may be limited since parents may be biased in terms of how they report on their children’s behavior. Nevertheless, we did use standardized measures of ADHD and executive behaviors commonly used to assess ADHD. To overcome these measurement challenges, it would be important in future studies to use longitudinal designs with individually administered and performance-based measures . Having multiple informants, such a teachers, would also be warranted in future studies. This was a challenge with this particular study as children were young and not all of them had pre-school or secondary caregivers qualified to provide reports.Finally, it has been suggested that the associations observed between pre-pregnancy BMI and poorer cognitive and neurodevelopmental outcomes may be due to unmeasured confounding factors  ,19. The d effect size for maternal smoking during pregnancy and ADHD is ~0.48  [This study supports a growing body of literature both from animal and human studies that find offspring born of mothers with excess weight prior to or during pregnancy are at increased risk for cognitive and neurodevelopmental problems, including more ADHD and related executive self-regulation problems. Notably, the effect sizes observed here were small. For example, the standardized beta for pre-pregnancy BMI ≥ 35 and ADHD symptoms was 0.21. Small or medium effect sizes would be expected in studies of outcomes, such as ADHD symptoms or executive functioning behaviors, where there are likely multiple causal pathways. To put the effect we observed in perspective, the Cohen’s nalysis) . Howevernalysis) , whereasUnderstanding factors that contribute to early childhood self-regulation problems, such as hyperactive-impulsive symptoms and problems related to attention and poor executive control is important since deficits in these areas can alter the trajectory of health and have a profound impact on their economic burden to society. For instance, Caspi, et al. (2016)  recently


N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia . Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children ( It has been estimated that up to 40% of children diagnosed with clinical ADHD also suffer from reading disability  and vice versa4. The spectrum of affected LRAs in ADHD may, however, also include writing6, spelling8, syntactic10 and phonological10 abilities. Both clinical ADHD and RD are complex childhood-onset neurodevelopmental conditions that affect about 5% and 7% of the general population, respectively12. ADHD is characterised by hyperactive, inattentive and impulsive symptoms13, whereas decoding and/or reading comprehension deficits are prominent in individuals with RD14.Children with Attention-Deficit/Hyperactivity Disorder (ADHD) often experience difficulties mastering literacy-related and/or language-related abilities (LRAs)15. This model is supported by twin studies suggesting that the co-occurrence of ADHD symptoms and reading deficits is, to a large extent, attributable to shared genetic influences18. Further twin research suggests that the genetic covariance between reading difficulties and ADHD is largely independent of genetic factors shared with IQ19, although it is not known whether these findings extend to a wider spectrum of LRAs, beyond reading abilities. Furthermore, the interpretation of polygenic ADHD-LRA overlap using markers on genotyping arrays is more challenging. There is strong evidence that genetically predicted educational attainment (EA)20 shares genetic variability with both ADHD21 and reading abilities23. Genetically predicted EA is a genetic proxy of cognitive abilities, but also socioeconomic status20 including, for example, associations with maternal smoking during pregnancy, parental smoking, household income or watching television24. Thus, observed genetic associations between ADHD and reading abilities may solely reflect shared genetic variation with EA, but not any other, more specific neuro-cognitive mechanisms. In other words, polygenic associations might be inflated or even induced25 by genetically predictable traits that are related to both, ADHD and reading abilities (or other LRAs).To interpret the comorbidity of ADHD and RD, a multiple-deficit model including shared underlying aetiologies has been proposed, involving both genetic and environmental influencesHere, we (a) study polygenic links between clinical ADHD and a wide range of population-ascertained literacy-related and language-related measures as captured by common variation, (b) evaluate to what extent such links reflect a shared genetic basis with EA and (c) assess whether there is support for shared genetic factors between clinical ADHD and LRAs conditional on genetically predicted EA.26, we report here disentangled associations between polygenic ADHD risk and LRA measures and estimate effects independent of and shared with genetically predicted years of schooling, using summary statistics from the Social Science Genetic Association Consortium (SSGAC).Studied ADHD polygenic scores (ADHD-PGS) are based on ADHD genome-wide association study (GWAS) summary statistics from two large independent ADHD samples, the Psychiatric Genomics Consortium (PGC) and the Danish Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), and a combination thereof. Associations between ADHD-PGS and a wide spectrum of population-based literacy-related and language-related measures related to reading, spelling, phonemic awareness, listening comprehension, non-word repetition and verbal intelligence skills, are examined in a sample of children from the UK Avon Longitudinal Study of Parents and Children (ALSPAC). Applying multivariable regression (MVR) techniques, analogous to Mendelian Randomisation (MR) approaches28. Ethical approval was obtained from the ALSPAC Law-and-Ethics Committee (IRB00003312) and the Local Research-Ethics Committees. Written informed consent was obtained from a parent or individual with parental responsibility and assent (and for older children consent) was obtained from the child participants.LRAs were assessed in children and adolescents from ALSPAC, a UK population-based longitudinal pregnancy-ascertained birth cohort , revealing seven independent measures (experiment-wide error rate of 0.007).All LRA scores were rank-transformed to allow for comparisons of genetic effects across different psychological instruments with different distributions ALSPAC participants were genotyped using the Illumina HumanHap550 quad chip genotyping platforms, and genotypes were called using the Illumina GenomeStudio software. Genotyping, imputation and genome-wide association analysis details are described in the Supplementary Psychiatric Genomics Consortium (PGC). GWAS summary statistics were obtained from a mega-analysis of clinical ADHD31, conducted by the PGC  (Table www.med.unc.edu/pgc/).The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). An independent set of ADHD GWAS summary statistics were accessed through the Danish iPSYCH project32  (Table 33.s) Table , using sCombined PGC and iPSYCH ADHD sample (PGC + iPSYCH). To maximise power, we also analysed meta-GWAS summary statistics from an ADHD sample containing both PGC and iPSYCH participants21  (Table www.med.unc.edu/pgc/) and its European-only subset (PGC + iPSYCH(EUR), 19,099 cases, 34,194 controls/pseudo-controls) (Table www.med.unc.edu/pgc/).Detailed sample descriptions are available in Table 20  were obtained from the SSGAC consortium. EA was assessed as years of schooling20. A detailed sample description is available in Table GWAS summary statistics for EA2 and genetic correlations (rg) between LRAs were estimated using Restricted Maximum Likelihood (REML) analyses35 as implemented in Genome-wide Complex Trait Analysis (GCTA) software36, including individuals with a genetic relationship < 0.0534. For this study, we selected only LRAs with evidence for SNP-h2 and sample size N > 4000  regression40 were created in ALSPAC using the independent PGC and iPSYCH GWAS summary statistics, and, to maximise power, also for GWAS summary statistics from the combined PGC + iPSYCH sample  using ordinary least square (OLS) regression . The proportion of phenotypic variance explained is reported as OLS-regression-R2. Beta-coefficients (β) for ADHD-PGS quantify here the change in standard deviation (SD) units of LRA performance per one SD increase in ADHD-PGS.ADHD-PGS26 and controls for collider bias42 through the use of GWAS summary statistics. Technically, it involves the regression of regression estimates from independent samples on each other26 (Supplementary 26 (see below).To study the genetic association between ADHD and LRAs conditional on genetic influences shared with EA, we applied MVR. This technique is analogous to MR methodologiesGenetic variant selection: To disentangle ADHD-LRA associations, we selected two sets of instruments from the most powerful ADHD GWAS summary statistics (PGC + iPSYCH). The first set contained genome-wide significant variants . The second set included variants passing a more lenient P-value threshold  to increase power, consistent with current guidelines for the selection of genetic instruments in MR (F-statistic < 10)43. All sets included independent , well imputed (INFO45 > 0.8) and common (EAF > 0.01) variants. This resulted in 15 conservative and 2689 < NSNPs ≤ 2692 subthreshold ADHD-instruments (Table ts Table .Estimation of ADHD effects: We extracted regression estimates for selected ADHD-instruments (conservative and subthreshold) from ADHD (PGC + iPSYCH), EA (SSGAC) and 13 LRA (ALSPAC) GWAS summary statistics. Analysing each set of variants independently, regression estimates for individual LRA measures (β) were regressed on both ADHD (β as lnOR) and EA regression estimates (β) using an OLS regression framework . Outcomes were (1) a MVR regression estimate quantifying the change in SD units of LRA performance per log odds increase in ADHD risk conditional on years of schooling (ADHD effect independent of EA), and (2) a MVR regression estimate quantifying the change in SD units of LRA performance per year of schooling as captured by ADHD instruments (ADHD effect shared with EA). Latter MVR regression estimates capture here shared genetic effects between ADHD, EA and LRAs, including (1) genetic confounding , (2) mediation  and (3) biological pleiotropy . As ADHD risk and EA are inversely genetically related with each other21, they were reported to quantify change per missing year of schooling. To compare the magnitude of both MVR estimates, we also conducted analyses using fully standardised EA, ADHD and LRA regression estimates  Table  using raAs the directionality of the relationship between ADHD, EA and LRAs cannot be inferred in this study, we also examined the genetic association between EA and LRAs, conditional on ADHD, using MVR. Two sets of EA instruments  and 0.54  (Table 2 = 0.08(SE = 0.03)), iPSYCH (LDSC-h2 = 0.26(SE = 0.02)) and PGC + iPSYCH samples  Table  and gene8) Table  moderatees Table  is consiP = 4.6 × 10-3; iPSYCH: OLS-R² = 1.0%, P < 1 × 10−10), reading accuracy age 9 , and spelling accuracy age 9  using independent ADHD discovery samples . Results were not affected by the exclusion of children with an ADHD diagnosis in ALSPAC , P < 1 × 10−10) between genetically predicted ADHD, as captured by the largest ADHD discovery sample (PGC + iPSYCH), and EA (LDSC-h2 = 0.11(SE = 0.004)), consistent with previous findings21. Likewise, LRAs were moderately to highly positively correlated with EA , P = 3.0 × 10−4; Table 23. Additionally, two independent variants reached genome-wide significance for both ADHD21 and EA20, consistent with biological pleiotropy 47. These findings indicate complex, potentially reciprocal cross-trait relationships   Fig. .ADHD = -0.35(SE = 0.09), P = 9.2 × 10-5, Phet = 0.19), an effect that was considerably stronger than for other LRAs . However, observable effects were smaller in magnitude compared to those captured by conservative ADHD instruments with, for example, a 0.03 SD decrease in pooled reading performance per log-odds increase in ADHD risk (βADHD = -0.03(SE = 0.01), P = 1.4 × 10−6, Table Pmod = 0.016), with stronger ADHD effects on literacy-related abilities, in particular spelling , P = 4.9 × 10−8, Table P = 0.31). Conducting MVR with fully standardised estimates showed that ADHD effects shared with EA were as large as or even larger compared to ADHD-specific effects , revealed a positive genetic association between missingness and polygenic ADHD risk , but also phonological and spelling-related abilities share genetic aetiology with ADHD. These interrelated LRAs may, as hypothesised for RD, arise from a phonological impairment49, which affects decoding and reading skills50, but also spelling abilities51. However, reading abilities can, once developed, also shape phonological skills52.Using independent ADHD discovery samples, these findings show that genetic overlap between ADHD and literacy-related impairments observed in twin and family studies53. Children growing up in disadvantaged environments, genetically predictable through polygenic EA scores54, might be more vulnerable to psychiatric illness including ADHD55 that affects, in turn, their LRAs. In addition, adolescents with ADHD might be more likely to leave school at an earlier age, with lower LRA performance and EA, and pass on an increased genetic load to their own children56.In addition, this study suggests that genetic associations between polygenic ADHD and LRAs reflect, at least partially, shared genetic influences with genetically predictable EA and that, equally likely, genetic associations between polygenic EA and LRAs share genetic influences with ADHD. The magnitude of these shared effects, modelled with different MVR approaches, was comparable with each other. This is consistent with reciprocal genetic influences between EA and ADHD Fig.  and supp42. However, using MVR, the detection of these polygenic associations was strongly governed by the choice of genetic variants. Conservative ADHD instruments identified large ADHD-specific effects on reading as a domain and little evidence for genetic effects that are shared with EA, although they had limited power57. They comprised 15 independent SNPs only, including variation within FOXP2, a gene that has been implicated in childhood apraxia of speech and expressive and receptive language impairments (http://omim.org/entry/602081)58. On the other hand, subthreshold instruments, including thousands of variants, tagged ADHD-specific polygenic links with LRAs  with smaller effects, but with higher predictive accuracy. However, these instruments also captured shared genetic effects with EA, affecting polygenic links between ADHD and all of the LRAs studied. These shared genetic influences were of equal strength and at least equal magnitude compared to ADHD-LRA associations independent of EA. Contrary, a previous twin study showed that the genetic covariance between ADHD and reading difficulties was largely independent of genetic effects shared with IQ19, suggesting that our findings may also reflect socio-economic influences. Thus, in order to improve reading and, more generally, literacy-related deficits in children with ADHD, there is potentially a need for further intervention programmes targeting EA-independent underlying neurocognitive deficits, beyond general training programmes aiming at schooling outcomes59.Here, we demonstrate that disentangling multivariate genetic interrelationships between ADHD, EA and LRAs using MVR can aid the interpretation of genetic overlap, while controlling for collider bias60 model of complex trait architectures, compatible with a general factor model of psychopathology61, including ADHD62. The omnigenic model construes that only the largest-effect variants will reflect ADHD specificity, and may thus tag the most trait-specific associations between ADHD and reading, independent of EA. The majority of variants, however, will capture pleiotropic (omnigenic) influences pointing to highly interconnected neural networks60 that give rise to genetic confounding. Consequently, the majority of subthreshold variants, captured by both ADHD and EA subthreshold variants, are likely to represent highly powerful cross-trait genetic predictors that may enhance and induce genetic overlap.In general, our findings are consistent with an omnigenic64.Finally, the methodological framework within this work has not only relevance for studies investigating polygenic links between ADHD and LRAs, but for many studies examining multivariate trait interrelationships that involve shared genetic effects with a genetically predictable confounder. Specifically, our findings suggest that lower variant selection thresholds can introduce genetic variance sharing that is unspecific and needs to be accounted for before identified associations can be interpreted in terms of underlying mechanisms, including shared genetic aetiologies. This is especially important as current guidelines for studying polygenic links with allelic scores recommend aggregating genetic variants across less stringent significance thresholds to maximise genetic association between discovery and target samples66. Sensitivity analyses showed that this is unlikely to bias our findings based on conservative instruments. However, links identified using subthreshold ADHD variants, might have been underestimated given that individuals with a genetic predisposition to ADHD  are more likely to drop out66. Secondly, the strength of the genetic overlap between polygenic ADHD risk and LRAs may vary according to ADHD symptom domain levels, implicating especially inattentiveness67, as well as the nature of the literacy-related or language-related ability involved . It is conceivable that also other verbal abilities, not investigated in this study, such as grammar, expressive vocabulary or pragmatic skills, may genetically overlap with ADHD. Furthermore, we only studied the extent to which shared genetic variance with EA affects the genetic association between ADHD and LRAs. However, we found little evidence for the presence of additional unaccounted for genetic influences using these instruments, i.e., effects that are not yet captured by either genetically predicted ADHD or EA. Finally, the power of available LRA GWAS summary statistics is still too low to generate genetic instruments supporting reverse models. Larger and more detailed clinical and population-based samples, as well as extensive multivariate variance analyses of the spectrum of LRAs  will help to further characterise the overlap between ADHD and literacy-related and language-related cognitive processes.This study has several limitations. Firstly, ALSPAC, as other cohort studies, suffers from attritionPolygenic associations of clinical ADHD and a range of LRAs are to a large extent attributable to genetic effects that are also shared with EA, especially when investigated with genetic variants typically selected for polygenic scoring approaches. Adjusting for these unspecific genetic effects reveals an ADHD-specific association profile that primarily involves literacy-related impairments.Supplementary Information


Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder, characterized by age inappropriate and impairing levels of inattention and/or hyperactivity/impulsivity. Pharmacotherapy is an important part of the ADHD multimodal treatment. The extent to which ADHD is pharmacologically over or under treated worldwide is controversial. We aimed to estimate the pooled worldwide rate of ADHD pharmacological treatment in individuals with and without the disorder.We will include published or unpublished studies reporting the rates of ADHD pharmacological treatment in participants with and without ADHD of any age group. Population-based, cohort, or follow-up studies, as well as data from insurance health system and third-party reimbursements will be eligible. Searches will be performed in a large number of electronic databases, including Medline, Embase, CINAHL, Cochrane, PsycINFO, Web of Science, and Scopus. The primary outcome will be the prevalence of ADHD pharmacological treatment in individuals with ADHD and without ADHD. Two independent reviewers will perform the screening, and data extraction process. Study quality/bias will be assessed with the Newcastle–Ottawa scale by 2 independent reviewers. To test the robustness of the findings, we will perform a series of sensitivity and meta-regression analysis. Analyses will be performed with R and STATA software.No IRB approval will be necessary. The results of this systematic review and meta-analysis will be presented at international conferences and published in peer-reviewed journals. Luca Tessari's degree should just be MD and Dr. Glaucia Chiyoko Akutagava-Martins’ degree should just be PhD.The abstract should be:The below funding information should appear as:This study was supported by Fundo de Incentivo à Pesquisa of Hospital de Clínicas de Porto Alegre (FIPE/HCPA), and Programa de Pós-Graduação em Ciências Médicas: Psiquiatria from Federal University of Rio Grande do Sul (PPG-P/UFRGS).FC receives scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).RM receives scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).LT, and SC have no competing interests.In section 3.3.1, the second sentence should appear as “Selected titles will have the full text included for a careful reading by 4 independent reviewers .”In section 3.3.2, the second sentence should appear as “Independent reviewers working in pairs  will collect and compare the data extraction sheets.”The following references should have appeared as:https://caddra.ca/pdfs/caddraGuidelines2011.pdf. Accessed May 5, 2018.[9] Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines. In: CADDRA, ed. Third Edition ed. Toronto ON2011: CADDRA. Available at: [17] National Collaborating Centre for Mental Health. Attention Deficit Hyperactivity Disorder: Diagnosis and Management of ADHD in Children, Young People and Adults. Leicester (UK): The British Psychological Society 2009.


Whilst preterm-born individuals have an increased risk of developing attention-deficit/hyperactivity disorder (ADHD), and are reported to have ADHD-like attention and arousal impairments, direct group comparisons are scarce.n = 186) to term-born adolescents with ADHD (n = 69), and term-born controls (n = 135), aged 11–23, on cognitive-performance, event-related potential and skin conductance level (SCL) measures associated with attention and arousal. The measures are from baseline and fast-incentive conditions of a four-choice reaction time task, previously shown to discriminate between the individuals with ADHD and controls. We aimed to establish whether preterm-born adolescents show: (a) identical cognitive-neurophysiological impairments to term-born adolescents with ADHD (b) possible additional impairments, and whether (c) the observed impairments correlate with ADHD symptom scores.We directly compared preterm-born adolescents  and reaction time variability (RTV) in the baseline condition, and attenuated contingent negative variation (CNV) amplitude (response preparation) in the fast-incentive condition. The preterm group, only, did not show significant within-group adjustments in P3 amplitude  and SCL . Dimensional analyses showed that ADHD symptoms scores correlated significantly with MRT, RTV and CNV amplitude only.We find impairments in cognition and brain function in preterm-born adolescents that are linked to increased ADHD symptoms, as well as further impairments, in lack of malleability in neurophysiological processes. Our findings indicate that such impairments extend at least to adolescence. Future studies should extend these investigations into adulthood. From EEG data we can extract event-related potentials (ERPs), which are electrical potentials generated by the brain in response to events, and allow the direct measurement of covert brain processes , this study reported impairments  only among term and preterm-born children with ADHD, compared with term-born controls and preterm-born participants without ADHD.We recently reported findings from a comparison between preterm-born adolescents and term-born ADHD adolescents on the cued continuous performance test (CPT): while we observed response preparation [the ERP index of contingent negative variation (CNV)] and response inhibition (NoGo-P3) impairments in both groups, compared witth a term-born control group, the preterm group showed an additional impairment in executive response control (GoP3), which was not associated with ADHD symptoms, suggestive of more wide-ranging neurophysiological deficits in the preterm group , ERP  and skin conductance (SCL) measures, which help to identify biomarkers for the underlying processes. In order to understand more about impaired brain processes in preterm-born individuals which may relate to ADHD, we now compare the data from ADHD and control participants (now including only term-born participants) to new data on identical Fast Task measures obtained from preterm-born individuals. We aim to establish, first, whether preterm-born adolescents show identical cognitive-neurophysiological impairments to those observed in term-born adolescents with ADHD. Second, we investigate whether any additional impairments are observed in the preterm group only. Third, for any impairments observed in the preterm group, we will examine their association with ADHD symptoms and clinical impairment.The sample initially consisted of preterm-born participants, participants with and without ADHD and their siblings. Exclusion criteria for all groups were IQ of <70, cerebral palsy or any other medical condition that affects motor coordination including epilepsy, as well as brain disorders and any genetic or medical disorder that might mimic ADHD. In addition, preterm birth was an exclusion criterion in the ADHD and control groups, because this study aimed to establish whether the cognitive impairments associated with preterm birth reflect identical neurophysiological impairments in term-born individuals with ADHD.n = 8), see online Supplementary Material II).The preterm group was recruited from secondary schools in Southeast England. All preterm participants had one full sibling available for ascertainment and were born before 37 weeks’ gestation. Siblings of preterm-born individuals were included in the preterm group if they were also born preterm (before 37 weeks’ gestation), to maximize the number of participants in the preterm group. Term-born siblings of preterm-born individuals were not included in this analysis. Most preterm-born participants were of European white descent (84.6%). Since here preterm birth is investigated as a potential risk factor for ADHD, preterm-born individuals who demonstrated high levels of ADHD symptoms were not excluded from the analysis , 69 participants with ADHD  and 135 controls . The groups differed significantly in terms of age, IQ, sex distribution, GA  and ADHD symptom scores     condition consists of 72 trials, which followed a standard warned four-choice RT task. Four empty circles  first appeared for 8 s, after which one of them (the target) was coloured in. Participants were asked to press the response key that directly corresponded to the position of the target stimulus. Following a response, the stimuli disappeared from the screen and a fixed inter-trial interval of 2.5 s followed. Speed and accuracy were emphasized equally in the task instructions. A comparison condition of 80 trials with a fast event rate (fore-period of 1 s) and incentives followed the baseline condition , with a 500 Hz sampling rate, impedances kept under 10 kΩ, and FCz as the recording reference electrode. The electro-oculograms (EOGs) were recorded from electrodes above and below the left eye and at the outer canthi. The EEG data were analysed using Brain Vision Analyzer (2.0) . After down-sampling the data to 256 Hz, the EEG data were re-referenced to the average and filtered offline with digital band-pass  Butterworth filters. Ocular artefacts were identified from the data using Independent Component Analysis . Stimulus onset and participant response events were recorded on a common timeline, which enabled SC activity to be stimulus-locked. SC data values were calculated using a SC system, which is based on an SC sigmoid-exponential model that allows the tonic measure of SCL to be disentangled from phasic, stimulus-associated, SC responses (SCR), and further allows the decomposition of overlapping SCRs  . We investigated if groups differed in the slope from the baseline to fast-incentive condition, by controlling for differences in the baseline condition, indexing the degree of change. To investigate if the impairments observed in the preterm group are related to ADHD symptoms and clinical impairment, Pearson correlations were calculated between the cognitive-neurophysiological measures showing impairment in the preterm group and ADHD symptom scores and ADHD-related impairment. Correlations were run for impairments observed in the baseline condition, fast-incentive condition, and the slope from the baseline to the fast-incentive condition. If impairments were observed in both the baseline and fast-incentive condition for the same variable, correlations were run using the baseline condition only – which is more sensitive to ADHD  in STATA version 11.1 . All analyses controlled for gender, but we additionally reran analyses on a male-only subsample . In addition, we reran all analyses on an age-matched subsample (aged between 14 and 19 years) due to the significant group mean differences in age and the possibility of age effects on ERP measures . All analyses were also re-run with IQ as an additional covariate . Data were analysed using random intercept models in STATA, to control for non-independence of the data (i.e. data coming from siblings of one family), using a ‘robust cluster’ to estimate standard errors  and a main effect of group , but no significant group-by-condition interaction . The within-group difference in MRT from the baseline to the fast-incentive condition was significant in the term-born ADHD and control group . Within-group difference in MRT was also significant in the preterm group . Compared with the term-born control group, the slope in MRT, indexing the extent of change from the baseline to fast-incentive condition, was significantly greater in the term-born ADHD group . For the preterm group, the slope in MRT was not significantly different compared with the term-born ADHD group , but was significantly greater compared with the term-born control group   .Fig. 1.z = −13.40, p < 0.01), a main effect of group  and a significant group-by-condition interaction . Similar to previous analyses  and fast-incentive  conditions. The within-group difference in RTV from the baseline to fast-incentive condition was significant in the term-born ADHD  and term-born control  groups, and the slope in RTV was significantly greater in the term-born ADHD group  compared with the term-born control group.For RTV data for all groups b, a randt = −2.05, p < 0.05), but significantly increased RTV compared with the term-born control group  , but showed significantly increased RTV compared with the term-born control group . The within-group difference in RTV was significant in the preterm group . The slope in RTV in the preterm group was, at a trend level of significance, less steep compared with the term-born ADHD group , but was significantly greater than in the term-born control group   . In the  < 0.05) .Table 1z = −16.61, p < 0.01), a significant main effect of group  and a significant group-by-condition interaction . Similar to previous analyses , but showed significantly reduced CNV amplitude in the fast-incentive condition . The within-group difference in CNV amplitude from the baseline to fast-incentive condition was significant in both the term-born ADHD  and term-born control  group, with a significantly less steep CNV slope in the term-born ADHD group  compared with the term-born control group.For CNV amplitude for all groups c, a randt = −1.48, p = 0.14) or the term-born control group  , but had a significantly reduced CNV amplitude compared with the term-born control group   group. The slope in CNV amplitude in the preterm group was significantly less steep compared with both the term-born ADHD  and control  groups  , Fig. 2a < 0.01) , Fig. 2c) groups .Fig. 2.z = 2.01, p < 0.05), a main effect of group  and a significant group-by-condition interaction emerged . Similar to previous analyses , but they did not differ in the fast-incentive condition   and term-born control  group. The slope in P3 amplitude did not differ between the term-born ADHD and control group .For P3 amplitude for all groups d, a rand = 0.14) , Fig. 2bt = −0.34, p = 0.73) or control  group. In the fast-incentive condition, the preterm group showed significantly decreased P3 amplitude compared both to the term-born ADHD  and term-born control  groups . The slope in P3 amplitude in the preterm group was less steep compared with both the term-born ADHD  and term-born control  groups  groups .z = −5.74, p < 0.01), but no main effect of group , and a trend towards a group-by-condition interaction . Similar to previous analyses , but not in the fast-incentive condition . The within-group difference in SCL from the baseline to fast-incentive condition was significant in the term-born ADHD  and term-born control  groups. The slope in SCL was significantly steeper in the term-born ADHD group compared with the term-born control group .For SCL for all groups e, a randt = 4.01, p < 0.01), but did not differ from the term-born control group . In the fast-incentive condition, the preterm group was not significantly different compared with the term-born ADHD group  or compared with the term-born control group . The within-group difference in SCL from the baseline to fast-incentive condition was not significant in the preterm group . The slope in SCL in the preterm group was less steep compared with both the term-born ADHD  and term-born control  groups , did not change the significance of the results.n = 186) to investigate if the cognitive-neurophysiological differences observed in the preterm group, compared with term-born controls, are related to ADHD symptoms and ADHD-related clinical impairments. In order to reduce the number of statistical comparisons, correlations were run using the baseline condition only - which is more sensitive to ADHD  and in response preparation (CNV in fast-incentive condition). These findings from group comparisons were further confirmed by within-group analyses that showed how each of these impairments correlated with the continuum of ADHD symptoms (and impairments) in individuals born preterm. Second, the adolescents born preterm did not show ADHD-like impairments in the ERP index of attention allocation (P3) or skin conductance-measured arousal (SCL) in the baseline condition, but were unlike either the ADHD or control group in showing an unusual lack of malleability in P3 amplitude and SCL from baseline to fast-incentive condition, indicating a lack of malleability in attention allocation and arousal from the baseline to fast-incentive condition in the individuals born preterm. Overall, we show how specific impairments in cognitive and brain function observed among preterm-born individuals relate to their increased ADHD symptoms, whereas their additional impairments were not significantly associated with ADHD symptoms. Our findings provide further evidence, in line with other studies, that preterm birth is a risk factor for developing some ADHD-related cognitive-neurophysiological impairments  shows an ADHD-like impairment in adolescents born preterm replicates our previous CNV finding on the CPT in the same sample  and peripheral arousal (SCL) indicate that preterm birth is associated with only some, and not all, impairments seen in ADHD, as well as with further unique impairments not associated with ADHD. The adolescents born preterm did not show the ADHD-like impairment in attention allocation (P3) and peripheral hypo-arousal (SCL) in the baseline condition. Yet subtle impairments in P3 amplitude and SCL were observed in the preterm group in the lack of adjustment and malleability from the baseline to fast-incentive condition that are seen in the other groups. For response preparation (CNV), both preterm and ADHD groups showed the reduced change between task conditions, compared with controls, but the lack of adjustment was significantly stronger for the preterm than term-born ADHD group. Overall, the reduced neurophysiological sensitivity to the effects of incentives and a faster event rate in the individuals born preterm is intriguing, calling for a further investigation in future research.n = 8): whilst we controlled for gender, we could not directly examine sex differences between the groups. We were also unable to investigate whether risk factors for being born preterm  might account for the findings in our sample. We show, however, that the impairments are not due to IQ, as controlling for IQ did not change the results.A limitation of our study is the small sample of females in the ADHD group (In conclusion, our investigation of preterm-born adolescents indicates both impairments in cognition and brain function that are linked to increased ADHD symptoms as well as further, subtle impairments in lack of malleability in specific neurophysiological processes. We show how such impairments in individuals born preterm extend to at least adolescence, even in a well-functioning sample recruited from mainstream schools. Greater awareness of the risk of developing ADHD-like and wider-ranging impairments in preterm-born individuals could lead to earlier identification and intervention strategies. Future studies should extend these investigations into adulthood.