Background. Animal toxicity tests and epidemiological studies suggest that exposure to PBDEs can alter attention behavior, yet few studies have examined their association with diagnosis of attention deficit hyperactivity disorder (ADHD) in adolescents. Methods. Logistic regression was used to examine the cross-sectional association between ADHD and lipid and non-lipid adjusted blood serum concentrations of 2′,4-tribromodiphenyl ether (BDE-28), 2,2′,4,4′-tetrabromodiphenylether (BDE-47), 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99), 2,2′,4,4′,5,5′-pentabromodiphenyl ether (BDE-100), 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE-153), serum PBDEs, above/below the 75th percentile of serum PBDEs, and tertiles of serum PBDE in 12–15-year-olds (N = 292) using the National Health and Nutrition Examination Survey (NHANES) 2003-2004. Results. The ADHD weighted prevalence was 13.57%. The weighted adjusted odds ratios (AOR) and 95% confidence interval (CI) between ADHD diagnosis and lipid adjusted BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, serum total PBDE, serum PBDE concentrations above the 75th percentile, and serum PBDE concentrations in the second or third tertile were 1.16 , 1.36 , 1.51 , 1.53 , 1.43 , 1.41 , 0.59 , 6.16 , and 0.99 . Conclusions. We observed no association between serum PBDE concentrations and ADHD in US youths. Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children characterized by forgetfulness, excessive daydreaming, making careless mistakes, and excessive fidgeting . In 2011While the etiology of ADHD is unknown, both environmental and genetic factors are thought to contribute to the development of ADHD . SpecifiThe studies provide some evidence that prenatal exposure to PBDEs is related to ADHD-related behaviors and inattentive behaviors in young children. Yet little is known about the relationship between PBDE exposure and attention and hyperactivity levels in older children. Furthermore, data from experimental studies in rodents exposed to PBDEs during development showed that memory and learning alterations worsened with age, indicating that, even after a delay in exposure, PBDEs may have a lasting effect , 14. GivThis cross-sectional study used data collected in the 2003-2004 of National Health and Nutrition Examination Survey (NHANES). NHANES collects data from a US noninstitutionalized sample population. Participants are selected by a complex multistage, probability design which oversamples certain underrepresented subgroups to increase the generalizability of survey results. The National Center for Health Statistics research ethics review board approved all study protocols and informed consent was obtained from all survey participants.n = 369) which restricted this analysis to children 12 to 15 years old. Additionally, 79 individuals had missing PBDE values due to inadequate serum sample or suspected contamination of sample, leaving 302 individuals who had complete data on all covariates and PBDE measurements. One individual had information missing on both birthweight and preschool attendance, 3 individuals had information missing on both prenatal smoke exposure and BMI, and 2 individuals had missing data on current smoke exposure, resulting in 292 individuals with complete information  were assessed only in children 0 to 15 years old which excluded children aged 16–19 ?” Refusal to answer or “don't know” responses were coded as missing. No missing data for ADHD diagnosis was present in the subpopulation used in this analysis.Serum brominated flame retardants levels were only measured in one-third of the blood samples collected in participants 12 years old and older. Detailed laboratory analysis methods are described elsewhere . BrieflyEach PBDE congener contained left-censored data but 60% or more of the subjects had values above the limit of detection (LOD). However, due to concerns that substituting values with the LOD/√2 may lead to bias, we used multiple imputation to substitute values for left-censored chemical data , 17. BriRisk factors for ADHD identified in previous studies were considered to be potential confounders in this analysis. These included sex, age, race , blood lp value < 0.2. Additionally, lead  was included as a covariate because of its strong positive association with ADHD [Stata 13  was usedith ADHD , 23, 24.Analysis was conducted using the lipid-adjusted and wet weight PBDE concentrations.We compared select characteristics of youths 12–15 years old who had their blood analyzed for PBDEs to those of youths who did not have their blood analyzed for PBDEs to evaluate whether the included sample was representative of all youths in this age range. There were no significant differences in the sociodemographic, environmental factors or ADHD diagnosis in youth 12–15 years old who had their blood serum analyzed for PBDEs compared to youth 12–15 years old who did not have their blood serum analyzed for PBDEs .N = 2) that were not covered by health insurance; therefore, health insurance was not included as a covariate in the final full model.The weighted prevalence of parent-reported clinical ADHD diagnosis by a health care provided in this sample of youth aged 12–15 years was 13.57% . Several risk factors for ADHD were identified in this sample. Prenatal ETS exposure, health insurance, attendance in preschool or daycare, and BMI were significantly associated with higher prevalence of ADHD . HoweverThe geometric mean, detection frequency, and range of the individual PBDEs in youth aged 12–15 years in NHANES 2003-2004 are presented in The bivariate relationships between PBDE exposures and parental reported ADHD are presented in In this subpopulation of US youths, the prevalence of ADHD was 13.57% which was higher than the anticipated prevalence even when accounting for the weighting that addresses the complex survey design of NHANES. This weighted prevalence is greater than the 9.5% weighted prevalence of ADHD diagnosis among children 4 to 17 years old in 2007 from the National Survey of Children's Health . However in vitro model [Animal toxicity testing  and studro model  have sugro model , scores ro model , and eduro model  in childro model . Third, ro model . Fourth,ro model . Additio in utero exposure to PBDEs is a risk factor for attention behavior disorders in younger children. Subsequently, more research is needed to determine if there is a critical window during development for PBDE toxicity or if PBDE exposure remains a risk factor for ADHD as children get older.Youths aged 12 to 15 years residing in the United States are exposed to several brominated flame retardants. While this cross-sectional study did not support an association between brominated flame retardants and ADHD in these youth 12 to 15 years old, previous research has provided some evidence that


Research investigating cognition and behaviour in Sotos syndrome has been sporadic and to date, there is no published overview of study findings.A systematic review of all published literature (1964–2015) presenting empirical data on cognition and behaviour in Sotos syndrome. Thirty four journal articles met inclusion criteria. Within this literature, data relating to cognition and/or behaviour in 247 individuals with a diagnosis of Sotos syndrome were reported. Ten papers reported group data on cognition and/or behaviour. The remaining papers employed a case study design.Intelligence quotient (IQ) scores were reported in twenty five studies. Intellectual disability (IQ < 70) or borderline intellectual functioning (IQ 70–84) was present in the vast majority of individuals with Sotos syndrome. Seven studies reported performance on subscales of intelligence tests. Data from these studies indicate that verbal IQ scores are consistently higher than performance IQ scores. Fourteen papers provided data on behavioural features of individuals with Sotos syndrome. Key themes that emerged in the behavioural literature were overlap with ASD, ADHD, anxiety and high prevalence of aggression/tantrums.Although a range of studies have provided insight into cognition and behaviour in Sotos syndrome, specific profiles have not yet been fully specified. Recommendations for future research are provided. Sotos syndrome is a congenital overgrowth disorder with an incidence of approximately 1 in 14,000 live births  who obseUntil 2002, diagnosis was based on clinical assessment. The four major diagnostic criteria were confirmed by Cole & Hughes  in a samThe identification of a genetic mutation responsible for Sotos syndrome was first established in a Japanese population . The autIt has since been suggested that mutations of the NSD1 gene are responsible for approximately 90% of cases of Sotos syndrome . The remIn NSD1-positive individuals, research has investigated specific genotype-phenotype correlations associated with the different NSD1 abnormalities –18. BroaThe purpose of this review was to synthesise and critically evaluate all published literature providing data on cognition and behaviour in individuals with Sotos syndrome in order to establish current understanding of these facets of the syndrome. The specific research questions were to establish: 1) the degree of intellectual disability in individuals with Sotos syndrome; 2) whether there is evidence for a profile of verbal and non-verbal cognitive abilities; 3) whether there are common behavioural problems associated with Sotos. Behavioural problems included psychiatric and psychological issues, as well as problems with temperament.The quality of the published research in these areas was assessed using an objective assessment tool . This waThe review was written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRSIMA) Checklist .Four electronic databases were systematically searched for relevant studies: Web of Science (1964–2015), Scopus (1964–2015), PsycINFO (1964–2015) and PubMed (1964–2015). The first paper to recognise Sotos as a specific syndrome was published in 1964, so the searches were started from this date. The databases were searched using the terms “Sotos” AND “syndrome”, OR “cerebral” AND “gigantism”. The terms ‘Sotos syndrome’ and ‘cerebral gigantism’ have been used interchangeably within the literature so both were included in the database search.In Scopus and Web of Science, the title/abstract/keywords of the journal articles were searched using the key search terms. In PsycINFO, the abstract/title/key concepts were searched and in PubMed, the title/abstract were searched. Differences in the search strategies implemented were due to the unique search system of each database. The search was conducted in August 2015. In addition to the database search, bibliographies and citations of all papers included in the review were hand-searched to ensure that all relevant papers had been identified.Predetermined inclusion criteria were used to assess whether the articles identified in the initial search were relevant. As an aim of this review was to provide an overview of findings from published research, only articles published in peer reviewed journals and written in English language were included in the review. In addition, only primary research was included in order to ensure that the same methodology and findings were not reviewed multiple times. Finally, the study was required to provide data relating to cognitive ability and/or behaviour in an individual or individuals with a diagnosis of Sotos syndrome.When screening the abstracts, papers were considered relevant if they included the term ‘intelligence’ or if they included terms relating to specific aspects of cognition, such as ‘language’, ‘memory’, ‘attention’, ‘executive function’ or ‘logic/problem-solving’. Abstracts were also considered relevant if they mentioned any behavioural or psychiatric problems, such as ‘ASD’, ‘ADHD’, ‘psychosis’, ‘anxiety’ or ‘aggression/tantrums’. Full text articles that met all inclusion criteria were then selected for the review.Data were extracted from articles that met inclusion criteria. This information included sample size (number of participants with Sotos), demographic information (age and gender), cognitive or behavioural assessments used and key findings from these measures. In order to satisfy the key aims of this review, studies that reported IQ scores of individuals with Sotos are summarised in A quality checklist  was usedThe literature search yielded 1304 results. Once duplicate results had been removed, a total of 917 articles were screened for inclusion in the review. The abstracts of these papers were read and papers were considered to be relevant if the abstract met all inclusion criteria. After the abstracts had been screened, fifty five full articles were read to assess eligibility for the review. Eighteen articles were excluded on the basis that the means of assessment for cognitive or behavioural data were not reported, two were excluded because no primary research was reported and one was excluded due to not being published in English. As a result, a total of thirty four articles met inclusion criteria see . CrucialSD = 1.67) and scores ranged from 1.7–9.5. This highlights that there is considerable variation within the quality of the published literature, providing data on cognition and/or behaviour in Sotos syndrome.Each article was assessed by the first author in order to establish the quality of the research. The articles were assessed in relation to specific criteria based on objectives, methodology, results and conclusions. The score for each article is provided in Tables A small number of studies (n = 10) have used a group study design to assess cognitive and/or behavioural features of individuals with Sotos syndrome. The use of cohorts of individuals has allowed comparisons to be made between participants, providing an insight into common cognitive and behavioural phenotypes. A case study design was implemented in more than half of the studies (n = 24). This means that a significant proportion of the data reported in relation to cognition and behaviour in individuals with Sotos were based on very small samples. The use of case study design makes it is difficult to establish whether there is a consistent cognitive or behavioural pattern associated with the syndrome as the findings often lack generalisability. However, data from case studies are useful in providing a detailed analysis of cognition and behaviour in individuals with Sotos.Cognitive abilities were assessed, using standardised measures of IQ, in a total of 172 participants, across twenty five studies see . Of thesOf the six group studies that reported FSIQ scores, four reported the range of these scores. These were 47–105 , 21–103 In addition to FSIQ scores, seven studies ,25,30–34Other than reporting performance IQ and verbal IQ scores, only one study  reportedIn summary, the focus of previous research has been to investigate degree of intellectual functioning in individuals with Sotos syndrome. This has identified that the majority of individuals with Sotos syndrome have intellectual disability (IQ <70) or are in the borderline range (IQ = 70–84). In addition, the profile of intellectual functioning suggests that individuals achieve higher verbal IQ scores, compared to performance IQ scores. At present, only one case study  has repoLanguage abilities were reported in thirteen studies see . FineganIn contrast, other research has found that individuals with Sotos display relative language impairment. Delays in speech and communication were reported in four studies ,4,37,38,Although speech and language delays have been reported in eleven of the thirteen studies that assessed language abilities, two studies ,36 did nAggressive behaviour and/or tantrums were reported in six studies ,38,43–45It is important to note that all of the participants reported to have these behavioural issues were children. Consequently, no research has investigated whether these behavioural issues persist during adulthood. As children with Sotos are often large for their age, behavioural issues may be considered more problematic by others when the child is compared to another child of similar age and/or size. None of the studies used a control group so it is difficult to establish whether children with Sotos display significantly more aggressive behaviour and/or tantrums than other children of similar intellectual ability.Autistic features were reported in four studies see . One stuOf the group studies that assessed behaviour, two reported a high prevalence of ADHD see . FineganAnxiety has been reported in two studies see . SarimskOne of the cardinal features of Sotos syndrome is developmental delay and children with the syndrome may follow a distinct developmental trajectory. In order to identify the progression of cognitive development in individuals with Sotos, it is important to investigate developmental changes, over time. One study  providedWithin the thirty four studies that were included in this review, cognitive abilities and/or behavioural features were reported for a total of 247 participants. Of the studies that reported group data, none of the participants were adults. Cognitive and/or behavioural data were presented in seven case reports of adults with Sotos ,41,42,49Less than half of the studies (n = 14) were published after identification of the genetic abnormality associated with Sotos syndrome. Of these studies, eight ,42,49–51SD = 1.69) and scores ranged from 1.7–9.5. The findings from the published literature were extracted and summarised in order to provide a comprehensive overview of current understanding of cognition and behaviour in Sotos syndrome.The primary of this review was to synthesise and critically evaluate all published literature providing data on cognition and behaviour in individuals with Sotos syndrome in order to establish current understanding of these facets of the syndrome. The specific research questions were to establish: 1) the degree of intellectual disability in individuals with Sotos syndrome; 2) whether there is evidence for a profile of verbal and non-verbal cognitive abilities; 3) whether there are common behavioural problems associated with Sotos, such as psychiatric problems and issues with temperament. The quality of the identified research was assessed using a standardised checklist and scores were rated out of 10. The mean score was 6.8  or are in the borderline range (IQ = 70–84) and this evidence supports the inclusion of intellectual disability as one of the main diagnostic criteria of the syndrome. In addition, findings from research using intelligence tests indicate that verbal IQ scores are consistently higher than performance IQ scores. Language abilities are relative to general level of intellectual functioning . LanguagThe cognitive literature identified that almost all of the reported cases of Sotos syndrome have a degree of intellectual disability. This ranged from mild to severe. The International Statistical Classification of Diseases and Related Health Problems (ICD-10) suggests the following guidelines for classification of the degree of intellectual impairment: borderline intellectual functioning (70–84), mild intellectual disability (IQ = 50–69), moderate intellectual disability (IQ = 35 and 49) and severe intellectual disability (IQ = 20–34). Most of the cognitive data were presented in the form of an IQ score and the research to date has focused on the use of intelligence tests to measure cognition. The informative value of a full scale IQ score alone is limited in terms of its contribution to identifying ability in specific cognitive domains. Although this can provide a general indication of intellectual ability, it does not provide any information relating to strengths or weaknesses in different aspects of cognition. Thus, in order to establish whether individuals diagnosed with Sotos syndrome have a consistent cognitive profile, it will be necessary to investigate patterns of ability and disability in specific cognitive domains using a standardised battery of cognitive tests.Behavioural problems such as aggression/tantrums, ASD, ADHD and anxiety have been reported in fourteen studies of individuals with Sotos syndrome. More than half of these were cases studies and as a result, the findings within the behavioural literature are based on a limited sample size. It has been suggested that children with Sotos may display more behavioural problems, compared to typically developing children ,29. ThisThis review only included published studies as an aim of the review was to establish the current understanding of literature reporting data on cognition and behaviour in Sotos syndrome. It is important to note that a limitation of this approach is that the review is subject to publication bias. In addition, only papers published in English language were reviewed which means that findings from data published in other languages were automatically excluded from the review.More than half of the studies included in this review were published prior to identification of the NSD1 genetic abnormality which was identified in 2002 . It is tAs stated by Cole & Hughes , a numbeA fundamental methodological issue present in most of the studies included in this review is the limited sample size. As Sotos syndrome has a relatively low incidence, there is a limited population from which to recruit participants. It is therefore important for future research to utilise all available recruitment strategies in order to collect a large and representative data set. A further methodological problem, identified in more than half of the studies, was a failure to use standardised measures to assess cognition and/or behaviour or, in some cases, a failure to report which measures were used. Findings from these studies lack validity as it is not clear whether the results were obtained using standardised measures. As a result, these studies tended to score lower on the quality assessment checklist.A number of cognitive and behavioural features have been identified in individuals with Sotos syndrome such as language difficulties , ADHD 2 and ASD The suggestion that verbal IQ scores are higher than performance IQ scores in Sotos is particularly interesting as the opposite is often reported in individuals with ASD ,53. As AFuture research could combine genetic information with both cognitive and behavioural data, in order to establish a comprehensive understanding of genotype-phenotype correlations within this population. This could include individuals with NSD1 deletions or NSD1 mutations and individuals who are considered to be Sotos-like, who may have abnormalities of the NFIX protein.Cognitive and behavioural phenotyping of disorders and syndromes associated with intellectual disability can be extremely beneficial for individuals. For example, research has established specific cognitive profiles associated with Williams syndrome  and DownIn summary, during the fifty one years since the initial recognition of Sotos syndrome, a total of thirty four papers reporting data on cognition and/or behaviour in Sotos syndrome have been published in peer-reviewed journals. The current literature supports the view that a significant number of individuals with Sotos syndrome have an associated intellectual disability (IQ < 70) and nearly all participants had an FSIQ score < 100. The highest reported FSIQ score was 113  and the S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.


Attention-deficit/hyperactivity disorder (ADHD) is more frequent in males than in females. The “female protective effect” posits that females undergo greater exposure to etiological factors than males in order to develop ADHD, leading to the prediction that relatives of females with ADHD will display more ADHD behaviors. We thus tested whether cotwins of females displaying extreme ADHD traits would display more ADHD traits than cotwins of males displaying extreme ADHD traits.Parents of approximately 7,000 pairs of nonidentical twins in Sweden, and approximately 4,000 pairs of twins in England and Wales, completed dimensional assessments of ADHD traits. Probands were selected on the basis of scoring within the highest 10% of the distribution in each sample. Dimensional scores of cotwins of probands, as well as the categorical recurrence rate, were investigated by proband sex.p < .01) and when the 2 samples were merged into a single, larger sample (p < .001). When the samples were merged, there was also a significant association between proband sex and cotwin’s categorical status, with more cotwins of female probands also being probands than cotwins of male probands.Cotwins of female probands displayed higher mean ADHD trait scores (mean = 0.62−0.79) than cotwins of male probands (mean = 0.38−0.55) in both samples. This trend was significant in the Swedish sample (These findings support a female protective effect against ADHD behaviors, suggesting that females require greater exposure to genetic and environmental factors associated with ADHD in order to develop the condition. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by excessive hyperactivity and impulsivity, inattentiveness, or a combination of these symptoms.4A number of twin studies have established that ADHD is among the most heritable of neuropsychiatric conditions.One possible explanation for the sharp sex discrepancy in ADHD prevalence is a putative “female protective effect” model. Under this model, females would be predicted to require greater exposure than males to genetic and environmental factors associated with ADHD in order to display sufficient ADHD behaviors to warrant a diagnosis, thus meaning that fewer females than males would be expected to be diagnosed with ADHD.Very few studies have tested for the existence of a female protective effect against ADHD. A recent Swedish investigation suggested that merely having a female cotwin is associated with displaying a greater degree of ADHD traits than having a male cotwin, although this study did not take account of the degree to which the index twin displayed ADHD symptoms.As a consequence, we aimed to test for the existence of a female protective effect against ADHD behaviors in 2 independent, large-scale European twin samples. We first tested whether the cotwins of females displaying extreme degrees of ADHD traits would exhibit more continuous ADHD traits than the cotwins of high-scoring males. Second, we sought to test whether high-scoring female twins would be more likely to have a high-scoring cotwin than high-scoring male twins. The 1 previous study documenting this effect reported that the effect size was small14Data were collected from participants in 2 representative, community-based twin studies. The Child and Adolescent Twin Study in Sweden (CATSS) is a study of twins born in Sweden since 1992. Initially, the twins were contacted in connection with their ninth birthdays.16Both CATSS and TEDS comprise both monozygotic (MZ) and dizygotic (DZ) twins, although only DZ twins were included in this study owing to the fact that the genetic resemblance of 2 DZ twins within a pair is the same as the resemblance between 2 singleton siblings (approximately 50% of their segregating DNA code on average). Both same-sex and opposite-sex DZ twins were included. In CATSS, families of 6,817 pairs of DZ twins returned data, whereas 4,309 participating families in TEDS returned data. In CATSS, exclusions were conducted for known brain injuries and chromosomal syndromes (n = 113), leaving 6,704 DZ twin pairs. Participants in TEDS were excluded for genetic and chromosomal syndromes, extreme perinatal complications, and missing first contact data (n = 254), leaving 4,055 pairs of DZ twins. Combined, there were 10,759 DZ twin pairs across the 2 samples.CATSS has ethical approval from the Karolinska Institutet Ethical Review Board, and TEDS has ethical approval from the King’s College London, Institute of Psychiatry, Psychology and Neuroscience Ethics Committee.DSM-IV criteria for ADHD.In CATSS, the ADHD modules of the Autism-Tics, ADHD, and Other Comorbidities inventory (A-TAC)DSM-IV criteria for ADHD.Parents of twins participating in TEDS completed the ADHD subscale of the Conners’ Parent Rating Scale–Revised (Conners ADHD).In both samples, 1 twin was randomly selected as the “index twin.” All other twins were cotwins. Probands were selected as the index twins scoring within the highest 10% of the A-TAC and Conners ADHD distributions, with such a cut-off designed to maximize statistical power while capturing severe-enough cases. Thus, probands in CATSS were selected on the basis of A-TAC scores of 6.5 or more, whereas TEDS probands were defined as index twins scoring at least 23 on the Conners ADHD. Subsequently, analyses were repeated using more conservative cut-offs of 9.5 on the A-TAC and 28 on the Conners ADHD. These cut-offs were designed to capture the highest scoring 5% of each sample, thus testing for a female protective effect in relation to even more extreme scores. Due to the lack of sex-specific diagnostic criteria for ADHD, the same cut-offs were used to select probands, regardless of sex. The number of probands, split by sex, is given in p values were adjusted for multiple comparisons within each sample using the Bonferroni correction. All reported p values are adjusted in this manner. Effect sizes were summarized using Cohen’s d. Effect sizes were interpreted using Cohen’s criteria,d of 0.20 to 0.49 considered a small effect, 0.50 to 0.79 medium, and greater than 0.80 large.To test whether cotwins of female probands would display higher ADHD trait scores than cotwins of male probands, 3×2 between-subjects analysis of variance (ANOVA) was used. Proband status of the index twin  was the grouping variable, with cotwins’ ADHD trait scores acting as the outcome variable. An omnibus test initially compared scores across cotwins of male probands, female probands, and controls, before planned comparisons compared the scores of cotwins of male and female probands. Individual 2 tests of association were used to test whether cotwin status was significantly associated with proband sex. Effect sizes were summarized using odds ratios (ORs).To test whether the sex of the probands was associated with whether or not their cotwin would also be a proband, categorical analyses were used. Using the above identified cut-offs, cotwins were classified as either “affected”  or “unaffected” . Then χAnalyses were first conducted separately in CATSS and TEDS. To bolster statistical power, a third set of analyses was performed on the 2 samples combined. The Conners ADHD and A-TAC were both heavily, positively skewed and were therefore log transformed before analysis . All cotp values were not adjusted for multiple comparisons.Post hoc analyses subsequently tested for a female protective effect against specific ADHD behaviors. All of the analyses detailed above were repeated on the Hyperactivity/Impulsivity and Inattention subscales of the A-TAC and Conners ADHD. Because these analyses were post hoc, Descriptive statistics for the A-TAC and Conners ADHD are given in F2,6688 = 79.35, p < .01), with cotwins of female probands scoring highest (mean = 0.62), followed by cotwins of male probands (mean = 0.38), and cotwins of controls (mean = −0.05). Specifically, cotwins of female probands displayed significantly higher A-TAC scores than cotwins of male probands , with a modest effect size of d = 0.07.Mean standardized scores of cotwins of male probands, female probands, and controls are all shown in F2,4040 = 102.30, p < .001). Planned contrasts, however, indicated that mean Conners ADHD scores were not significantly elevated in cotwins of female probands relative to cotwins of male probands , despite a trend in this direction.Similarly in TEDS, Conners ADHD scores differed significantly across cotwins of male probands (mean = 0.55), cotwins of female probands (mean = 0.79), and cotwins of controls (mean = −0.07) , with cotwins of female probands showing the highest ADHD trait scores (mean = 0.69), followed by cotwins of male probands (mean = 0.45), and controls (mean = −0.06). The planned contrast confirmed that mean ADHD trait scores were significantly higher for cotwins of female probands than cotwins of male probands .Merging the 2 samples produced the same pattern; mean ADHD trait scores differed significantly in the 3 groups , with cotwins of female probands displaying the highest ADHD trait scores (mean = 0.73), followed by cotwins of male probands (mean 0.51) and controls (mean = −0.03). Mean ADHD trait scores were significantly elevated in cotwins of female probands compared with cotwins of male probands .All mean ADHD trait scores for cotwins of probands selected under the more severe, 5% cut-offs are given in F2,6688 = 46.39, p < .01); however, mean A-TAC scores for cotwins of female probands were not significantly higher than mean A-TAC scores for cotwins of male probands . The same result emerged for TEDS. Although the main effect of index twin status was significant , with cotwins of female probands showing the highest mean Conners ADHD scores (mean = 0.79), followed by cotwins of male probands (mean = 0.62) and controls (−0.04), mean Conners ADHD scores for cotwins of female probands were not significantly higher than mean scores for cotwins of male probands .Using a 5% cut-off, the same pattern emerged in each individual sample. In CATSS, mean A-TAC scores differed significantly across cotwins of male probands (mean = 0.43), female probands (mean = 0.69), and controls (mean = −0.03) , with a greater proportion of cotwins of female probands (29%) than cotwins of male probands (22%) showing higher ADHD trait scores.21 = 4.67, p = .06, OR = 0.57 [95% CI: 0.34/0.92]). Similarly in TEDS, 38% of cotwins of female probands scored above the 10% cut-off compared with 29% of cotwins of male probands, although this association was again small and failed to reach significance .In CATSS, a greater proportion of cotwins of female probands scoring above the 10% also scored above the cut-off . The association was small and nonsignificant, however , with a greater proportion of cotwins of female probands (26%) than cotwins of male probands (16%) showing a pronounced degree of ADHD traits. In CATSS alone, more cotwins of female probands (21%) than cotwins of male probands (12%) were affected, yet this association was not significant . The same was true of TEDS: more cotwins of female probands (33%) than cotwins of male probands (22%) were affected, yet this seeming association was not significant .The findings followed the same pattern when a cut-off that selected 5% of index twins as probands was used. When CATSS and TEDS were merged, there was a significant association between proband sex and cotwin status (χp < .05).p < .05).Inattention followed the same pattern, as shown in These results are shown in full in This investigation sought to test whether a female protective effect can account for the substantially elevated prevalence of ADHD in males relative to females.Our findings provide a platform for future research into the genetic basis of ADHD to build upon. Although twin studies of ADHD have consistently supported its high heritability,Indeed, although our study did not investigate any specific etiological mechanisms associated with ADHD, our findings suggest that investigating the degree of exposure to etiological factors associated with ADHD in males and females with the condition may be a worthwhile future research direction. Although the above example mentioned larger, rarer copy number variants, one might also test whether females with ADHD exhibit a greater number of smaller, common genetic variants. Indeed, in using polygenic scores, which have yielded useful insights in the genetic architecture of ADHD,One could also extend this to causal environmental factors. Although twin studies indicate that genetic factors seem to outweigh environmental factors in the etiology of ADHD,The presence of a female protective effect against ADHD behaviors also has implications for clinical practice. If clinicians take account of family history when diagnosing ADHD, it may be beneficial also to take into account the sex of any previously affected relatives, under the assumption that relatives of females with ADHD are more likely to exhibit ADHD symptoms than relatives of males with ADHD. The caveat to this assertion, however, is that our findings are based only on twin data. The female protective effect against ADHD needs to be replicated in alternative, non-twin samples before such a conclusion can be decisively drawn. For instance, a recent study of ASD found that siblings of female non-twins with ASD were more likely to have ASD than siblings of male non-twins.It does need to be noted that the overall sizes of the effects reported here, where significant, were weak. The effect reported in this article is less than half the size of the female protective effect in relation to autism reported in a similar study.DSM-IV criteria for ADHD, upon which our measures were based, are based exclusively on observations of males.31The small female protective effect seen here does, nevertheless, stress the need not to discount alternative explanations for the increased number of males with ADHD relative to females. There is very limited research considering phenotypic differences between males and females with ADHD. For instance, 1 study investigated sex differences in ADHD across 10 European countries, and reported that females with ADHD displayed more emotional difficulties.Two further possibilities cannot be discounted from our study. Although our findings lend support to the notion of a female protective effect against ADHD, it is not mutually exclusive to the hypothesis that males have more risk factors for ADHD. It is also, in theory, possible that rater contrast effects drove the higher scores seen in cotwins of female probands. Rater contrast effects refer to the scenario whereby parent ratings of 1 twin are influenced by how they view their cotwin.In addition to the caveat regarding the small effect size, our study did have further limitations that need taking into account. Proband status was ascertained through the use of dimensional questionnaire measures, as opposed to in-depth assessments of ADHD. The use of this approach would, however, have come at the cost of the large sample size. As mentioned above, only twins were used in this study. Although we removed MZ twins to ensure that the genetic relatedness of the relatives in our sample was similar to that of fraternal siblings, it is important to know whether these findings extend to non-twin relatives in the future. In defense of our use of a twin sample, on the other hand, there is evidence to indicate that ADHD traits are not elevated in twins’ relatives to singletons.Finally, our study did not take comorbidity into account. Females with ADHD are more likely to present with additional disorders, such as anxiety and depression, than males with ADHD.To a certain degree, this study indicates that females are protected against behaviors characteristic of ADHD. Although our findings do not speak to any specific mechanisms through which this effect may operate, this study indicates that further research on the female protective effect model is warranted in relation to ADHD, with a view to identify the specific biological basis of this effect. If the effect holds across multiple epidemiological methods, then it represents a plausible explanation for why fewer females than males develop ADHD, as well as assisting in the diagnostic process.


Attention deficit hyperactivity disorder (ADHD) is associated with lower than average intelligence quotient (IQ) scores. However, research done on this disorder often excludes participants based on lower than average IQ’s . The purpose of this paper is to alert researchers to the consequences of excluding participants based on IQ’s within this range and to highlight the importance of providing a clear rationale when choosing to exclude participants based on IQ. Next, we offer recommendations for researching ADHD and their relative benefits and drawbacks of these approaches. Overall this paper emphasizes that including participants who have lower than average IQ in research on ADHD may promote a more realistic understanding of the condition and in turn improve our ability to treat it. Attention deficit hyperactivity disorder (ADHD) is characterized by age inappropriate levels of inattention and/or hyperactivity and impulsivity . It affeIt is common practice to exclude participants with and without ADHD who have IQ’s that are one to two standard deviations below average . However, excluding participants who are above one or two standard deviations above average  is rarely seen and a rational is rarely provided in either scenario e.g., . While tOn the other hand, it is important to recognize that depending on the cognitive or behavioral tasks at hand an IQ cut-off of 80 or 85 may be reasonable given the complexity of the task. If this is the case, however, the rationale should be provided by the researchers. This form of rationale is suitably discussed when the researcher is interpreting the results . This is because the IQ cut-off may be influential in the interpretation of the studies outcomes in addition to addressing limitations. For example, in a study where the tasks are relatively demanding and the IQ cut-off needs to be higher it can be explained in this section of the research paper that the results may not apply to individuals with ADHD who have lower IQ’s. In addition to providing a rationale the limitations that may result from the IQ cut-off, such as limited generalizability, need to be addressed in the Discussion section of the research paper. Unfortunately, this is not common practice.A meta-analytic examination of differences in full scale IQ among adults with and without ADHD by Similarly, matching participants with and without ADHD on IQ is a common practice . HoweverAs highlighted, individuals with ADHD score on average 9 points lower on standardized measures of IQ . Thus, aThe detrimental impact of excluding those with lower IQ can be demonstrated by a number of studies. One example, centers on prescribing Atomoxetine, a non-stimulant selective norepinephrine transporter inhibitor. Atomoxetine shows to be effective across gender, ADHD subtypes and age . FurtherThis scenario is not an isolated one, Excluding ADHD participants who have lower IQ’s may also prevent the development of our understanding of how ADHD may co-exist with other conditions and/or evolve into secondary conditions. This is best elucidated through discussing the relationship ADHD has with other comorbid disorders. It is understood that ADHD frequently co-exists with learning disabilities (LD’s) and sluggish cognitive tempo . Both slTaking into account how ADHD and IQ influence one another is also necessary. For instance, the symptoms of ADHD may put individuals with ADHD at an increased risk for lower IQ scores compared to their peers without ADHD . Rommel It is also possible that there are subgroups among those with ADHD who are more resilient to the compromising effects ADHD symptoms can have on the skills and knowledge typically acquired through education. For instance, Overall, we have limited understanding of ADHD in low IQ populations as a result of not including those with lower than average IQ in studies. Thus, a significant research gap exists: through failure to study ADHD in low IQ populations  we do not know (1) the base rate of symptoms within this population and (2) whether a distinct diagnostic algorithm would be suitable to those individuals with lower than average IQ who also potentially may have ADHD. Consequently, making inferences about the ADHD population from samples excluding participants with mild intellectual impairments is problematic. It would be remiss not to address the notion that it may be difficult to distinguish between ADHD and behaviors similar to ADHD that occur in response to environmental demands among low IQ populations. However, when a diagnosis of ADHD is made, environmental factors are taken into account. Thus, researchers can be reasonably assured when studying populations with ADHD that the diagnosis is accurate. Next, we make recommendations to help solve the problems that may arise from excluding those with ADHD who have lower IQ’s.One method is to include participants with mild intellectual impairment but report their results separately. In other words, research samples should be broken down into separate IQ categories , and the results should be reported, respectively. Reporting results in this way would acknowledge the intellectual diversity of the ADHD population and help us capture the differences and similarities that exist between individuals who have ADHD with or without intellectual impairment. Eventually, if the research shows that individuals with average IQ’s  and below average IQ’s but not significantly developmentally delayed  are overwhelmingly similar, then we can simply merge these IQ groups. On the other hand, if differences are observed, then these results would attest to the importance of continuing to examine how IQ and ADHD interact to cause differences in cognitive,behavioral, and emotional outcomes. However, this approach may have drawbacks. Specifically, there may be a reduction in statistical power. Nevertheless in many forms of analyses categorization is inevitable and in turn recruiting large sample sizes is necessary.One form of an example of this method is through the use of IQ as a moderating variable. For instance, dichotomizing a continuous IQ variable, such that an experimental and control group are subdivided into high and low IQ groups. This approach is taken in Opposed to an approach where IQ is a moderator or is arbitrarily identified as high or low for the purpose of a given study, acceptable exclusion/inclusion cut-off points will vary depending on the particular issue under investigation. Specifically, there will be different IQ cut-off points for different forms of ADHD studies. For example, in studies where participants need to be able to understand relatively complex tasks researchers may need to put thought into an IQ cut-off. Alternatively, in the event that the tasks involved in a study do not need to be understood we may not need to enforce an IQ cut-off point, such as in studies examining the neuroanatomy of the brain, the genetic basis of ADHD, or studies assessing the efficacy of medications. In such studies, low intellectual functioning is much less likely to interfere with the individual’s full participation in the study. Given that there are many areas of research involving ADHD, rather than propose a specific IQ cut-off point across all studies, we recommend that researchers do not choose an arbitrary cut-off point, but instead justify the cut-offs they choose, and also be open to critiquing others when appropriate justifications are not offered. Over time, consensus will develop over the appropriate cut-offs for each area of research, and their use will become standard practice.The purpose of this paper is three-fold: (1) to alert researchers to the potential caveats of current exclusionary criteria when studying ADHD, specifically IQ; (2) to have a clear rationale and make note of the limitations given the lack of standards for exclusionary IQ criteria in studies involving participants with ADHD and (3) to provide recommendations to researchers on methods that can be used to include individuals with lower than average IQ’s into studies where ADHD is under scrutiny. Overall, we urge researchers to carefully consider what potential participants they exclude and why they do so. This practice in turn may provide insight into the reality of the complexity of intelligence for clinicians and educators who provide services to clients and/or students with ADHD, leading to more informed diagnoses and treatment in lower IQ cohorts.GM: Came up with the original idea for the paper, wrote the majority of the paper, and found most of the articles used in this mini review. EW: Came up with the idea of adding a recommendations section, thought of the recommendations to offer researchers, and wrote the majority of the recommendations section (including doing the research and finding relevant articles). Contributed to the entire paper through revisions and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To study the course of ADHD during childhood and analyze possible personal and family predictor variables of the results.Conners' Rating Scales. The groups were compared on ADHD characteristics (symptoms of ADHD and impairment), child psychopathology, executive functioning  and parenting characteristics  at baseline.Sixty-one children with ADHD who were between 6 and 12 years old at the baseline assessment were evaluated 30 months later . Status of ADHD in follow-up was identified as persistent (met DSM-IV-TR criteria according to parents’ and teachers’ ratings), contextually persistent  and remitted ADHD . Associated psychological disorders of the three groups were analyzed in the follow-up with the At the follow-up, 55.7% of the children continued to meet the DSM-IV-TR criteria for ADHD, 29.5% showed contextual persistence, and 14.8% presented remission of the disorder. The persistent and contextually persistent ADHD groups showed more associated psychological disorders. Inattention, oppositional problems, cognitive problems and impairment at baseline distinguished the remitted ADHD children from the persistent and contextually persistent ADHD children. Moreover, the persistent groups had significantly more emotional liability and higher parental stress than the group in remission, while no differences in EF where found among the groups.ADHD children continue to present symptoms, as well as comorbid psychological problems, during adolescence and early adulthood. These findings confirm that persistence of ADHD is associated with child psychopathology, parental stress and impairment in childhood. Currently, follow-up studies show the persistence of the attention deficit hyperactivity disorder (ADHD) in the transition period from childhood to early adolescence, with a variation in the percentages ranging from 45%-55% –3, to 70In addition to its chronic nature, another worrisome issue is the high comorbidity that characterizes the course of ADHD. More than half of the children with an ADHD diagnosis continue to present other disorders, particularly behavior and anxiety disorders –14 and iThis alarming situation has stimulated research on the determinants of the course of ADHD. Genetic studies show the relationship between the DRD4 ,24, DAT1In addition to the biomarkers, the explanatory socio-ecological ADHD models highlight the contribution of environmental factors to the behavioral expression and different developmental trajectories of the disorder . The basIn recent years, another research area has involved analyzing the relationship between executive functioning (EF) and the course of ADHD, with mixed research results. A systematic review based on eighteen studies concluded that persisters and remitters did not differ on higher or lower level neurocognitive functions, although both had worse performance than controls . These fRegarding factors related to the family context, a recent review that focused on the relationship between parenting and functional impairments showed that ADHD is associated with greater stress within the family, higher rates of parental psychopathology, and conflicted parent—child relationships . Recent The research by the Biederman and Faraone group is of particular relevance in examining ADHD persistence, as they include different types of factors in their analyses. The researchers followed boys and girls with ADHD from childhood to adulthood. In adolescence (4-year follow-up) they found significant differences between the remittent and persistent groups at baseline, not only on child factors , but also on the psychosocial and family adversity of the disorder . In the In summary, many children with ADHD remain symptomatic. Understanding what characterizes this persistent ADHD group and identifying factors associated with differential developmental outcomes have important repercussions in the clinical setting. The early identification of children who are likely to have a worse course of the disorder will make it possible to perform interventions using more appropriate strategies.Hence, the present study, which is part of a longitudinal study that followed the course of children with an ADHD diagnosis, proposed two specific objectives. The first was to study the ADHD course during childhood, determining the rates of children who presented persistent, contextually persistent and remitted ADHD, and analyze possible differences among the groups on associated psychological disorders. The second objective was to compare the persistent, contextually persistent and remitted groups on baseline measures related to ADHD characteristics (ADHD symptoms and impairment), child psychopathology, executive functions  and parenting characteristics . We hypothesized that the different outcomes would be influenced by the effects of personal and family risk characteristics. Based on the proposals of a multifactorial model, we hypothesized that the persistent groups, especially if the persistence was cross-contextual, would have more severe ADHD symptoms and related child psychopathologies, greater impairments in executive functions, and worse results on parenting measures at baseline than the ADHD remitted group.In the present follow-up study, the participants were 61 children with a clinical diagnosis of combined-subtype ADHD and their families, who formed part of the sample of Spanish families from the International Multicenter ADHD Genetic Project (IMAGE) , a genetThe participants were evaluated at the beginning of the study, between 2003 and 2005 (baseline), and 30 months later, between 2006 and 2008 (follow-up). To identify the initial sample, the records from the Neuropediatric Service of La Fe Children’s Hospital were reviewed with the help of the service’s clinical psychologist, in order to identify children who had received an ADHD combined subtype diagnosis. In addition, neuro-pediatricians and pediatricians from the regions of Castellon and Valencia were contacted, as well as private specialists and psychology clinics. Through these procedures, a total of 321 possible participants were identified. Of these children, 109 were eliminated due to presenting manifestations of a possible ADHD subtype other than the combined subtype or neurological disorders (mainly epilepsy). When the 212 families were contacted, 147 agreed to participate in the study. In the individualized evaluation performed, children were excluded from the study if they presented an estimated intelligence quotient (IQ) of less than 70, suffered neurological or sensorial damage or motor impairments, or had a diagnosis of schizophrenia or generalized developmental disorder. Finally, 81 children met the strict diagnostic criteria for ADHD combined subtype (ADHD-C) from the revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) , based oMoreover, these 81 children met the requirements for the IMAGE study protocol to confirm the ADHD combined subtype diagnosis using the ADHD-section of the Parental Account of Childhood Symptom (PACS), a semi-structured interview that covers ADHD related behavior in different situations . The parents have to rate the frequency or severity of their child’s hyperactivity, inattention and impulsive behaviors . A speciWechsler Intelligence Scale for children- revised (WISC-R) [At baseline, the participants were between 6 and 12 years old (mean = 8.70 ± 1.97) and had an equivalent IQ within the ranges of normality (mean IQ = 105.98 ± 16.48), estimated by the sum of the scale scores for Vocabulary and Block Design on the (WISC-R) , using t(WISC-R) .t (79) = -0.90, p = .366; hyperactivity-impulsivity: t (79) = -0.87, p = .389; DSM-total: t (79) = -0.60, p = .549) and teachers’ ratings (inattention: t (79) = 1.12, p = .266; hyperactivity-impulsivity: t (79) = -0.72, p = .476; DSM-total: t (79) = 0.37, p = .712). There were no differences in other child characteristics assessed at the study baseline either. At follow-up, participants were between 8 and 14 years old (mean = 10.98 ± 2.19). Of the total sample, 58 were boys (95.1%), and 3 were girls (4.9%). A clinical psychologist with more than 10 years of experience, under the supervision of a senior investigator, again evaluated the ADHD symptomatology. Attention was paid to the concordance between parents’ and teachers’ ratings on the DSM-IV-TR criteria for the ADHD diagnosis and information about indicators of the children’s functional impairment, which was collected in the interviews with the family.Thirty months later the participants were again contacted. Due to the sample loss that often occurs in longitudinal studies, the follow-up included the participation of 61 of the 81 families who had participated at baseline, that is, 75% of the original sample. The other 25% did not participate for different reasons: 9 children (11%) did not participate because of loss of their localization (changes in the family address or contact telephone), and 11 participants declined to attend to the evaluations (14%). There were no differences in baseline ADHD severity between the 61 children who continued in the follow-up and the 20 who did not participate, based on the parents’  [CRS—R:L) . This isCRS—R:L) . There aStrengths and Difficulties Questionnaire for Parents (SDQ) [ts (SDQ) . This veWISC-R Digit-Span Subtest, backward [Temporo- Spatial Retrieval Task (TSRT) [Continuous Performance Test (CPT) [Three aspects of executive functioning were assessed: verbal working memory, visuo-spatial working memory and inhibition. Verbal working memory was evaluated with the backward , where tk (TSRT) . This isst (CPT)  was selest (CPT) . On thisThe Parenting Stress Index (PSI) [ex (PSI)  is a 126Parents rate each item on a 5-point Likert scale (1 = strongly disagree to 5 strongly agree). The scores are added up to obtain a total stress score that assesses the overall magnitude of parental stress. Scores from the PSI have acceptable internal consistency (α = 0.95) and test-retest reliability (r = 0.71–0.82) . In the The Parenting Scale [ng Scale . This 30The scale has adequate reliability (0.84) and discriminates between parents of clinical and non-clinical children. It correlates with self-report measures of child behavior, marital discord and depressive symptoms, and also with observational measures of dysfunctional discipline and child behavior .At baseline, participants with a diagnosis of combined subtype ADHD were selected, and behavioral , neuropsychological  and family  measures were collected.Hospital La Fe and Ministerio de Educación y Ciencia of Spain). To make sure treatment did not mask the experimental results, all the children had their medication withdrawn 48 hours before the sessions.The follow-up evaluation took place a mean of 30 months after the initial evaluation. After giving the participants a complete description of the study, written informed consent was obtained from the parents and the children, based on the procedures approved by the clinical research ethical committee : 1) subjects with a persistent status, when both informants positively rated the presence of 6 or more criteria from the DSM-IV- TR; 2) subjects with a contextually persistent status, who met the ADHD criteria according to the ratings of one evaluator, whether parents or teachers, and had social and/or academic impairments, recorded as affirmative responses to the SDQ-Impact Supplemental questions “Do you think your child has difficulties in one or more of the following areas: emotions, concentration, behavior or being able to get on with other people?”, “Do the difficulties upset or distress your child?”, and interference in at least one of the child's everyday life areas (home life/friendships/classroom learning/leisure activities); and 3) subjects with a remission status, who did not meet criteria for the disorder according to either the parents’ or teachers’ ratings.Data analysis was conducted with the SPSS statistical package, version 19.00. To compare the groups’ associated psychological disorders in the follow-up, Multivariate Analysis of Covariance (MANCOVA) was used. Four MANCOVAs were conducted to compare the data obtained at baseline  among the subjects with remission, persistence, or a status of contextual persistence of ADHD. The age of the participants was included as a covariate to avoid interpreting the differences due to the broad age range of the participants as effects of development. Post-hoc analysis with Bonferroni correction was performed. The degrees of freedom are not the same in all the MANCOVAs, due to the lack of data from some participants on the neurocognitive tests and on the family variables. The proportion of total variance accounted for by the independent variables was calculated using the partial eta squared . Only 14.8% presented remission of the disorder at the follow-up, meeting less than six inattention and hyperactivity-impulsivity criteria according to the ratings of both parents and teachers. Finally, in the remaining 29.5%, the group with contextual persistence, there was no agreement between the parents’ and teachers’ ratings, so that only one of the evaluators determined that the diagnostic criteria were met for one of the ADHD subtypes, even though the child had a functional impairment .12,104 = 3.97, p < .001, η2p = .314). Specifically, the differences were statistically significant on all the Conners’ variables used, except Emotional Lability: Oppositional , Cognitive Problems , Anxious/shy , Social Problems  and Global Index . Bonferroni’s post hoc test revealed statistically significant differences between the remitted group and both the persistent and contextually persistent groups on Oppositional , Cognitive problems , Social Problems  and Conners’ Global Index . In these cases, the persistent and contextually persistent ADHD groups presented significantly higher scores than the remitted group. On the Anxious/shy variable, only the remitted group showed significantly lower scores than the contextually persistent group (p = .042). Finally, the persistent and contextually persistent groups presented significant differences on the Cognitive Problems variable (p = .032), as the persistent group showed greater problematicity  presented statistically significant differences in associated psychological disorders at the follow-up . In fact, 33.3% of the children in the remitted group had taken medication at some point in their lives, while in the case of the persistent and contextually persistent ADHD groups, this percentage rose to 76.5% and 77.8%, respectively. Moreover, 47.1% of the persistent ADHD group consistently took medication during the time period between baseline and follow-up, while the remaining 29.4% of the subjects had taken medication for less time. In the ADHD group with contextual persistence, the rates were 55.6% and 22.2%, respectively. In the remitted ADHD group, 11.1% took medication continuously between baseline and follow-up, and 22.2% for a shorter period of time.The three groups were also significantly different from each other in the use of pharmacological treatment  (χ2 (2) = 7.02, To study the factors that influence the persistence of ADHD, the group with a remitted status, was compared to the group with a contextually persistent and a persistent status on ADHD characteristics, child psychopathology, executive functions and parenting characteristics rated at baseline, using age as covariate.6,102 = 4.30, p = .001, η2p = .202). Specifically, statistically significant differences were found on the variables: inattention  and impairment , but not on the symptomatology of hyperactivity/impulsivity  and Impairment variables . In both cases, the remitted ADHD had better scores than the other two groups.The results of the first MANCOVA showed that overall there were statistically significant differences among the three groups on baseline ADHD characteristics . Specifically, the differences were statistically significant on Oppositional , Cognitive Problems , Emotional Lability  and the Conners Global Index , but not on Anxiety and Social Problems , Cognitive problems  and Conners’ Global Index . Moreover, the ADHD persistent group presented significantly higher scores on Emotional Lability than the remitted group (p = .028).The three groups also showed differences in child psychopathology . The same analyses were performed with the family variables of parenting stress and dysfunctional discipline style, with the results of the MANCOVA showing statistically significant differences . The posterior ANCOVAS showed differences on the total stress variable , but not on discipline style (p = .006).The MANCOVA conducted to evaluate the differences in the executive functioning variables did not show statistically significant differences (Wilks Lambda = .94, Fne style . In thisThis longitudinal study had two specific aims. The first objective consisted of providing estimates of the course of ADHD and mapping its correlates over time. The second objective was to identify risk factors at baseline associated with differential outcomes of persistence/remission, related to the psychopathology of the child, EF and parenting.Our data support the “diagnostic stability” of ADHD. Thus, at the follow-up, nearly 60% of the children continued to meet the diagnostic criteria for one of the subtypes of the disorder, while only 14.8% could be assigned the status of remitted. Moreover, when adding the contextually persistent category, the percentage rose to 85.2%, similar to the 78% found by Biederman et al  in an 11The core manifestations of ADHD changed over time, as 33.9% of the combined subtype participants moved toward the predominantly inattentive subtype. This movement is consistent with the trajectories of the symptoms from early childhood to adolescence  and withIn addition, about 50% of the participants in the persistent and contextually persistent groups took medication continuously, compared to about 10% of the remitted group. This finding suggests that at the follow-up, the greater severity of the symptomatology of the persistent and contextually persistent groups, who present significantly more oppositional problems, cognitive problems, social problems and more general problematicity, has required a prolonged administration of medication over time. In another recent study, more adolescents with persistent ADHD were treated with methylphenidate before and at that time than adolescents with non-persistent ADHD [The persistent and contextually persistent groups present a similar profile of associated psychological disorders in the follow-up. However, there are differences on the level of cognitive problems, even though both groups present more problems than the remitted group. It is necessary to further analyze what occurs with the learning disabilities at these ages, as the persistent group probably presents more severe problems in reading, writing or mathematics than the other two groups.When the differences in baseline variables among the participants who presented complete persistence, contextual persistence and remitted symptoms were analyzed, the results showed that the two groups with persistence presented a worse profile of child psychopathology variables at baseline; however, no differences were found among the three groups on any of the executive functions evaluated. Thus, the results show the influence of the psychological disorders ,6,9,61 aThe family variables were also found to have an important role in the persistence of the disorder. Our results complement the information on the stress experienced by parents of children with ADHD , indicatFurthermore, the parents of the children with remitted ADHD did not seem to apply different discipline styles from those reported by parents of children with persistent or contextually persistent ADHD. As other studies have shown, it is likely that parents of children with ADHD in our sample present more dysfunctional discipline styles than parents of children with typical development . TherefoFinally, the expectation that children with remitted symptoms would show better EF at baseline was not fulfilled. Even though EF impairments in the preschool stage seem to be a good predictor of ADHD symptomatology in the beginning school stage , our resThe limitations affecting this study must be considered. First, the small sample size and the fact that it is composed of children with a clinical diagnosis of combined subtype ADHD may affect the generalization of the results, which cannot be extrapolated to a non-clinical sample. It is also important to note that many of our participants come basically from middle-low class families with no social marginalization; therefore, our findings may be more generalizable to the middle-class. Other limitations have to do with the broad age range of the participants, from 6 to 12 years old in the first evaluation, as well as the long follow-up period, 30 months. It is necessary to replicate the results with more specific age ranges and longer time periods that extend into late adolescence and early adulthood.The evaluation of executive functioning is another limitation of this study. Although the selection was based on the result of ad hoc reviews that point to inhibition and working memory as the executive functions most involved in ADHD, in future studies it would be advisable to include neuropsychological tasks such as the Stop Signal or the Go/No-go, in order to evaluate other basic ADHD parameters such as performance variability, or contemplate other executive functions such as planning and cognitive flexibility, in addition to using more ecological executive functioning measures.The attention deficit with hyperactivity disorder has a chronic nature. A large percentage of children with ADHD continue to present symptoms, as well as comorbid psychological problems, during adolescence and early adulthood. Therefore, understanding the personal and environmental factors that can worsen the severity of ADHD is a particularly critical issue for detecting and planning early efficacious actions that can attenuate the consequences of the disorder throughout the life cycle. For example, guidance programs for parents must go beyond a model based only on medication or behavior modification. Along with these components, parents should be offered information that: reduces their insecurity and feelings of guilt; provides them with strategies to reduce the level of stress that their children’s behavior can cause; teaches them to identify and value progress, even when limited; helps them to promote a clear distribution of responsibilities and roles; and constructs a democratic educational style that is neither coercive nor over-protective .In addition to its great relevance in the clinical setting, as it can help in designing appropriate treatment strategies to speed up remission, better knowledge about the predictors of ADHD persistence will make it possible to concentrate the scant economic resources on the cases with the greatest risk of persistence.One of the most interesting findings from the present study is that the ADHD cases that become contextually persistent have just as many associated psychological disorders as the cases with complete persistence. Related studies with adults indicate that individuals with partially-remitted ADHD showed similar substance use to those with current ADHD, whereas those in full remission were comparable to normal controls. In summary, although ADHD symptoms may remit with time, individuals who retain persisting or partial symptoms have considerable needs that must be addressed throughout their development.


Little is known about the extent of genetic diversity contained in any of them and its relation to contemporary varieties, since to date rye genetic diversity studies had a very limited scope, analyzing few loci and/ or few accessions. Development of high throughput genotyping methods for rye opened the possibility for genome wide characterizations of large accessions sets. In this study we used 1054 Diversity Array Technology (DArT) markers with defined chromosomal location to characterize genetic diversity and population structure in a collection of 379 rye accessions including wild species, landraces, cultivated materials, historical and contemporary rye varieties.Numerous rye accessions are stored in Secale germplasm. We revealed a relatively limited diversity in improved rye accessions, both historical and contemporary, as well as lack of correlation between clustering of improved accessions and geographic origin, suggesting common genetic background of rye accessions from diverse geographic regions and extensive germplasm exchange. Moreover, contemporary varieties were distinct from the remaining accessions.Average genetic similarity (GS) coefficients and average polymorphic information content (PIC) values varied among chromosomes. Comparison of chromosome specific average GS within and between germplasm sub-groups indicated regions of chromosomes 1R and 4R as being targeted by selection in current breeding programs. Bayesian clustering, principal coordinate analysis and Neighbor Joining clustering demonstrated that source and improvement status contributed significantly to the structure observed in the analyzed set of ex situ collections for broadening the genetic diversity in rye breeding programs. Obtained data show that DArT markers provide a realistic picture of the genetic diversity and population structure present in the collection of 379 rye accessions and are an effective platform for rye germplasm characterization and association mapping studies.Our results point to an influence of reproduction methods on the observed diversity patterns and indicate potential of  Secale cereale L.; 2n = 14, RR) is an out-crossing, wind-pollinated temperate zone cereal with low water and soil fertility requirements and good tolerance for biotic and abiotic stresses. It is an important crop in several Eastern, Central and Northern European countries with cultivation area of approximately 5 Million hectares worldwide in 2011 [http://faostat.fao.org]. The primary uses of rye include bread making, alcohol production, and animal feed. Recently it is also gaining attention as a biomass crop. Rye products are a valuable diet component due to high dietary fiber content and rye bread was shown to have beneficial influence on human healthet al...et al.[cessions and in tcessions. Our resBeadChip. Apart fBeadChip. AdditioBeadChip,42.ex situ collections for broadening the genetic diversity in current rye breeding programs.We conducted the largest and most comprehensive study of genetic diversity in rye to date and revealed a relatively limited diversity in improved rye accessions, both historical and contemporary, as well as lack of correlation between clustering of improved accessions and geographic origin, suggesting common genetic background of rye accessions from diverse geographic regions that probably results from extensive germplasm exchange. Genetic distinctness of contemporary varieties from the rest of accession that was also observed indicates a great genetic potential of One of the more interesting findings of our study is the identification of accession source as a major determinant of population structure. Our result point to possible influence of reproduction methods on the observed diversity pattern. Further studies involving accessions from different genebanks would be desirable to verify our findings concerning the source of population structure in rye.We also revealed differences in distribution of genetic polymorphism among rye chromosomes that could be indicative of genome regions targeted by selection during domestication and improvement programs.Obtained data indicate that DArT markers provide a realistic picture of the genetic diversity and population structure present in the collection of 379 rye accessions and are currently a method of choice for rye germplasm characterization and association mapping studies.AK is an employee of Diversity Arrays Technology Pty. Ltd., which offers genome profiling service using the technology described in this report. This fact, however, has not interfered whatsoever with the full, objective, transparent and unbiased presentation of the research results described in the manuscript nor alters the authors’ adherence to all the BMC policies on data and material release.HBB conceived and designed the experiments, wrote the manuscript. HBB, MT performed the experiments. HBB, AK, LB analyzed the data. HBB, AK, LB, MT, MRT contributed reagents/materials/analysis tools. HBB, MT, MRT contributed to the selection and preparation of germplasm. All authors read and approved the final version of the manuscript.Excel spreadsheet containing detailed information on rye used in the study and their genotypic DArT marker data.Click here for fileExcel spreadsheet containing mean PIC values for groups of accessions created according to source and type of germplasm.Click here for file(Portable Document File). Delta K values for K values (number of populations assumed) ranging from 1 to 20.Click here for file(Portable Document File). Principal coordinate analysis of 379 rye accessions based on 1054 DArT markers with defined chromosomal location. Accessions were labeled according to the geographic origin of accessions: panel a: only cultivated materials and varieties from PAS BG are shown; panel b: only landraces are shown.Click here for filePT analyses for accession source and improvement status, and for region of origin.Excel spreadsheet containing results of AMOVA and pairwise population PhClick here for file


HIGHLIGHTSBoth spatial and temporal analyses of the Center of Pressure demonstrate that children with ADHD have poorer postural control than typically developing sex-, age-, and IQ-matched children.Poor sensory integration in postural control could partially explained the deficits in postural stability in children with ADHD.MPH treatment improves postural performance in both spatial and temporal domains in children with ADHD.MPH improves postural control specifically when visual and proprioceptive inputs are misleading.Such improvement could be due to MPH effects on neurons, facilitating cerebellar processing of postural control.The aim of this study was to examine postural control in children with ADHD and explore the effect of methylphenidate (MPH), using spatial and temporal analyses of the center of pressure (CoP). Thirty-eight children with ADHD (mean age 9.82 ± 0.37 years) and 38 sex- age- and IQ-matched children with typically development were examined. Postural stability was evaluated using the Multitest Equilibre machine  at inclusion and after 1 month of MPH in children with ADHD. Postural stability was assessed by recording under several conditions: with eyes open and fixed on a target, with eyes closed and with vision perturbed by optokinetic stimulation, on stable and unstable platforms. At inclusion, we observed poor spatial and temporal postural stability in children with ADHD. The spectral power index was higher in children with ADHD than in controls. Canceling time was shorter at low and medium frequencies of oscillation and longer at higher frequencies in children with ADHD. After 1 month of MPH, the surface area and mean velocity of the CoP decreased significantly under the most complex conditions . The spectral power index decreased significantly after MPH while the canceling time did not change. Poor postural control in children with ADHD supports the hypothesis of cerebellar dysfunction in this disorder. Postural control could be improved by a more efficient processing of sensory inputs (a high-level process), as suggested by the decrease in spectral power index after MPH without changes in the canceling time (a low-level process). Attention deficit hyperactivity disorder (ADHD) is characterized by abnormal behavioral patterns, including inattention, hyperactivity, and impulsivity. ADHD affects ~5% of children in Western countries  is commonly used to treat patients with ADHD  and 38 IQ-, sex-, and age-matched TD children were enrolled in the study at the Child and Adolescent Psychiatry Department, Robert Debré Hospital, . Trained child psychiatrists assessed all subjects. The diagnosis of ADHD according to DSM-5 criteria  = 1.02, p = 0.3 and F = 1.45, p = 0.10 for the similarities and matrix reasoning tests, respectively]. The clinical characteristics of children with ADHD and controls are summarized in Table Controls were directly interviewed to confirm the absence of ADHD. To be included in our study, controls also needed to have a total score ≤ 10 on the ADHD-RS  were also examined 1 month after MPH treatment was started.The investigation adhered to the principles of the Declaration of Helsinki and was approved by our Institutional Human Experimentation Committee . Written informed consent was obtained from the participants' parents after the nature of the procedure had been explained.www.framiral.fr). The platform consists in a force plate mounted on a translator, which allows a translation of the subject in the antero-posterior (y) or the medio-lateral direction (x). A computer-controlled mechanism allows sinusoidal displacements of 62 mm amplitude with adjustable velocities and frequencies. In our experimental conditions, the ramp mode allowed forward and backward translations of the force plate, with constant linear velocities of 0.03 and 0.07 m/s. For the sinusoidal mode, the frequency was 0.25 Hz. The displacement of the CoP was sampled at 40 and 100 Hz under static and dynamic conditions, respectively, and digitized with 16-bit precision  and an unstable (U) platform, under three different visual conditions: eyes open and fixed on a target (EO), eyes closed (EC), and eyes open but with perturbed vision . The child was asked to stay as stable as possible. During the EO condition, the child had to focus on a small red light at a distance of 2.5 m. The optokinetic stimulation was performed using an optokinetic ball. The ball was projected on a wall at a distance of 2.5 m from the child's eyes and turned at an angular speed of 158° per second  and its mean velocity (mm/s) were analyzed in order to quantify postural performance. The surface area is an efficient measure of CoP spatial variability, corresponding to an ellipse including 90% of CoP excursions . Individual Student's t-tests were used to compare postural values obtained before and 1 month after MPH treatment. The effect of a factor was considered significant when the p-value was below 0.05.Statistical analysis using two-way ANOVA was carried out in order to compare the postural control of the two groups of children under the different visual and postural conditions . F = 31.9, p < 0.001], a significant postural condition effect   and a significant visual condition effect . Post-hoc analysis revealed that the smallest value of the surface area of the CoP was reported in the EO condition while the largest was observed in the OPTO condition .The surface area of the CoP Figure  and its F = 35.33, p < 0.001]. There was also a significant postural condition effect  , and a significant visual condition effect . Post-hoc comparisons revealed that the mean velocity of the CoP in the EO condition was lower than that reported in the EC and OPTO conditions (p < 0.001 for both).ANOVA also showed significant differences in the mean velocity of the CoP between groups and experimental conditions Figure . IndepenTo summarize, children with ADHD have poor postural control that is worsened in a dynamic environment and when visual information is perturbed or absent.F = 37.16, p < 0.001], a significant postural condition effect , and a significant visual condition effect . Post-hoc comparisons showed that the spectral power index in the EO condition was smaller than that reported in the EC and OPTO conditions (p < 0.001 for both). ANOVA also revealed a significant frequency effect . Post-hoc comparisons showed that the highest spectral power index was recorded for low frequencies while the lowest was recorded for high frequencies .Using wavelet transformation, the spectral power index was significantly larger in children with ADHD, independent of experimental conditions Figure . ANOVA rF = 247, p < 0.001]. The canceling time recorded for medium frequencies was significantly higher than those reported for lower and higher frequencies . Interestingly, there was a significant interaction between postural and visual conditions  and between groups and frequency . Post-hoc comparisons revealed that the canceling time was longer in the stable EO condition than in the other conditions . In contrast, the canceling time recorded with visual perturbation was similar in both stable and unstable conditions. Furthermore, children with ADHD showed significantly shorter canceling times than TD children for low and medium frequency bands (both p < 0.001) but longer canceling times for the high frequency band (p < 0.001).The canceling time in the anteroposterior direction was not different between the two groups of children examined Figure . ANOVA sIn conclusion, both static and dynamic analyses of CoP displacement reveal differences in postural control between children with ADHD and TD children: postural stability in children with ADHD is deficient with respect to control children.t-test revealed that the decrease in the surface area of the CoP after MPH treatment was significant in all but one condition (EO_S); the mean velocity of the CoP also decreased significantly in the majority of conditions tested .Figure t-test showed that the decrease in the spectral power index after MPH treatment was significant for the EC_S condition for the low frequency band and for the majority of conditions on the unstable platform .Figure t-test).After 4 weeks of MPH treatment, children with ADHD increased their canceling time  postural control is weak in ADHD children compared sex-, age-, and IQ-matched TD children. The deficit occurred mainly for medium frequencies, pointing to a cerebellar dysfunction in ADHD. (ii) MPH significantly improved postural control, especially in unstable conditions, apparently by the more efficient processing of sensory inputs (a high-level process), as suggested by the decrease in the spectral power index, but induced no significant changes in canceling time (a low-level process).The present study confirms and expands previous findings showing poor postural control in children with ADHD. Indeed, the spatial analysis of postural measures revealed a greater surface area and velocity of the CoP in ADHD children, in line with previous studies summarized in the Introduction. The stability of the body appeared to depend on somatosensory as well as visual inputs. In our study, whatever the status of the children, stability was better on a stable platform with eyes open, while it was worse on an unstable platform when vision was perturbed by optokinetic stimulation. This finding paralleled previous observations by our group showing that healthy 4-year-old children already use both visual and somatosensory information to control their postural stability  and EC conditions (p < 0.025). Temporal analysis of the CoP confirmed results from the static spatial analysis, but provided new and relevant information concerning the mechanisms used to compensate for the postural deficit. The frequency of body sway was significantly higher in children with ADHD. These children spent more muscular energy in controlling their stability, independently of the postural and visual conditions tested.The deficit in postural stability was correlated with the severity of ADHD. Specifically, we observed that the surface area covered by the CoP was significantly correlated with the inattention sub-score on the ADHD-RS, on an unstable platform in both EO  to obtain postural stability, particularly when they are on an unstable platform, when somatosensory inputs are missing or when visual inputs are absent and/or disturbed by optokinetic stimulation. Under such conditions, cerebellar processing is needed to compensate for all these deficits and to provide efficient postural control. Peterka  have alsThe present finding suggesting a deficiency in sensory processing by the cerebellum in children with ADHD is based on behavioral study in which cerebellar activity is indirectly observed. However, postural measures could be a promising opportunity for easily testing cerebellar performance in children with ADHD with a good acceptability. This study was conducted on a limited number of patients, and further research on a larger number of ADHD children with different doses of MPH would be useful in order to improve our understanding.In the present study, we show that postural measures could be a promising method with which to indirectly observe cerebellar performance in ADHD children. The results of this study suggest that the deficit in postural stability in children with ADHD compared to normally developing age-matched children could be due to a deficit in sensory processing by the cerebellum. MPH treatment improves postural control through adaptive strategies involving the cerebellum.MB conceptualized and designed the study. CS, EA, HP, RD selected patients. MB coordinated and supervised data collection. MB drafted the initial manuscript. MB, CS, EA, HP, RD reviewed and revised the manuscript, and approved the final manuscript as submitted.The authors thank the eyeBRAIN society for promoting the study. MB was supported by the Académie des Sciences, Fondation NRJ - Institut de France. The authors are also grateful to the Fondation Yves Cotrel - Institut de France for the financial support.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.