There is an ongoing debate as to whether attention-deficit hyperactivity disorder (ADHD) in highly intelligent individuals has a similar presentation as in average intelligent individuals. The aim of this study was to examine the cognitive correlates of ADHD in highly intelligent children and adolescents with ADHD.N = 204 and N = 84) of (1) high intelligence quotient (IQ) (IQ ≥ 120) children and adolescents with ADHD were used, carefully matched on age, gender, ADHD severity, and IQ with (2) control participants with high intelligence, (3) participants with ADHD with an average intelligence (IQ 90–110), and (4) control participants with an average intelligence. These samples were selected from the Dutch node of the International Multicenter ADHD Genetics (NeuroIMAGE) and Tracking Adolescents’ Individual Lives Survey (TRAILS) cohorts, respectively, in which a large battery of cognitive tasks was administered. Linear mixed models were used to examine the main effects of ADHD and IQ and their interaction on cognitive performance.Two independent samples  control group. Attention-deficit hyperactivity disorder (ADHD) is defined by high levels of inattention, impulsiveness, and/or hyperactivity that significantly impair daily functioning and are pervasive across situations . A stronPreviously, it has been argued that high intelligence “mimics” ADHD , 11. Acc. These conclusions were further supported in a large population-based sample where intelligence levels were inversely related to ADHD (and comorbid) symptoms [In contrast, in a recent systematic review on the relationship between intelligence and ADHD, high intelligence level was found to be strongly protective against ADHD symptoms and related cognitive problems . Resultssymptoms . MoreoveFinally, it has been argued that the cognitive correlates of highly intelligent individuals with ADHD are similar in type and severity as those in average intelligent individuals with ADHD , 20 but The only way to examine these three hypotheses is by using a four-group design, with both average and highly intelligent ADHD cases and controls, to examine whether group differences are equally large in average versus highly intelligent groups. To the best of our knowledge, no prior study has used this design. The few studies that have examined the cognitive correlates of highly intelligent individuals with ADHD mostly compared highly intelligent ADHD cases with highly intelligent controls, sometimes in combination to population norms , 22, 24.N = 204) and a population-based sample (N = 84). In both cohorts, a wide range of cognitive parameters was available, including response inhibition, verbal working memory, timing variability, sustained attention, and social cognition. The key question that was examined was whether a diagnosis by IQ interaction was present. If the mimicing symptoms-hypothesis was supported, an interaction effect was expected where ADHD-control differences would only be found in average intelligent but not in highly intelligent participants. If the strongly atypical-hypothesis was confirmed, an interaction effect was expected where ADHD-control differences would be larger in highly intelligent participants. Finally, if the compensating-hypothesis was confirmed, no interaction effect was expected and ADHD-control differences would be equally large in average versus highly intelligent groups.The aim of this study was therefore to examine the cognitive correlates of ADHD in highly intelligent individuals with ADHD using a carefully individually matched four-group design consisting of average intelligent (IQ 90–110) and highly intelligent (IQ ≥ 120) ADHD cases and controls. The cutoff point of an IQ ≥ 120 is in line with previous studies on this topic , 8, 24 awww.neuroimage.nl), a longitudinal sample with three measurement waves between 2003 and 2015 . The NeuroIMAGE cohort consists of probands with ADHD, their biological parents, and full biological siblings. Participants were usually assessed in more than one wave. The description of the sample, the measurements, and the recruitment procedure have been described in detail in previous papers [N = 204 assessments in total, of which n = 140 represented unique participants. Repeated assessments included n = 20 participants with data collected in two different waves/time points ; n = 1 participant was measured in two waves and within one of those waves in two quartets (n = 3 data points). In addition, data was duplicated for n = 6 and triplicated for n = 3 participants, respectively (not participants with ADHD and an IQ ≥ 120), to be used for individual matching purposes when no other participants fulfilled the strict matching criteria (n = 21 data points). To correct for the relatedness of measurements between waves for one participant as well as for duplication of data, sensitivity analyses were performed excluding these extra data points. For more information, see Table The sample originated from the Dutch node of the International Multicenter ADHD Genetics (IMAGE) study . The recruitment procedure has been described in other papers  originating from the population-based cohort and n = 19 had a confirmed ADHD diagnosis based on structured diagnostic interview originating from the clinical cohort. The quantitative ADHD symptom severity scores of these n = 2 participants (M = 12) were at the same average score of the n = 19 participants with a confirmed ADHD diagnosis (M = 11.78), indicating ADHD symptom severity was comparable. These participants were matched in the same manner as described for participants in cohort 1, resulting in 21 quartets, comprising N = 84 unique participants , a Dutch cohort study following 2230 children from the general population and 540 children referred to an outpatient clinic before the age of 11, from early adolescence (age range 10–12) to young adulthood . Br. Brwww.tT-scores ≥ 63 on the Conners or DSM-IV ADHD subscales inattention, hyperactivity/impulsivity, and/or total symptoms were considered clinically significant. Those participants who scored clinically on any of these subscales were administered the Parental Account of Children’s Symptoms (PACS) [The Conners long-version parent and teacher questionnaires , 28 (yous (PACS)  wave 1)s (PACS)  (waves 2s (PACS) ). The mas (PACS) For the assessment of ADHD, the Diagnostic Interview Schedule for Children (DISC-IV) was used . In the Full-scale IQ of all youth was estimated using four subtests  of the Wechsler Intelligence Scale for Children or Wechsler Adult Intelligence Scale-III (WISC/WAIS-III) , 34. TheFull-scale IQ was estimated using two subtests (vocabulary and block design) of the WISC/WAIS-III , 34.The cognitive tasks used on this sample have been described in previous papers , 37. TheComplete description of the cognitive assessment is available in previous papers . The tasCognitive assessment took place in a quiet room, and small breaks were provided. Psychostimulants were discontinued for at least 48 h before testing took place. Both studies had medical/ethical approval.t tests compared the performance of the group with ADHD and high intelligence with the control groups with average IQ and high intelligence, in order to illustrate the effect of comparing highly intelligent individuals with ADHD with IQ-matched versus average intelligence controls. Lastly, in order to consider the overall pattern of results, a principal component analysis was carried out to create a single composite score of cognitive performance. Correction for false discovery rates (FDR) for multiple testing was carried out.In both cohorts, analyses were separately carried out using the Statistical Package for the Social Sciences (SPSS) version 23. The percentage of missing data for the cognitive assessments ranged between 0 and 23% for the dependent variables for cohort 1 and between 0 and 2% for cohort 2. Missing data were replaced by using the Estimation Maximization procedure . AnalyseNo significant interaction effects were found  = 0.87, p = 0.35; F  = 0.49, p = 0.49)  = 8.71, p < 0.01, d = 0.58) and IQ  = 3.81, p < 0.05, d = 0.38) was found. In cohort 2, only a significant main effect of IQ was found  = 10.35, p < 0.01, d = 0.97). Post hoc t tests indicated that the highly intelligent group with ADHD performed at the same level as the average intelligent control group .Linear mixed models on the two aggregated scores revealed no significant and no trend significant ADHD by IQ interaction effects . Principal component analysis and an ANOVA were carried out. Results remained similar to the original analyses, with one main component explaining around the 40% of the variance and a significant main effect for ADHD only  = 8.62, p < 0.01, d = 0.58) but not for IQ  = 4.64, p = 0.32) or an ADHD × IQ interaction  = 0.34, p = 0.54). The same procedure was carried out using only the n = 140 unique participants. The main results remained identical, with one main component explaining 42% of the variance and no ADHD × IQ interaction was found  = 0.05, p = 0.81).Additional analyses were carried out in the NeuroIMAGE cohort in order to control for the effect of repeated assessments. As a first step, for participants who had repeated assessments in different waves of the cohort, only the first assessment was kept for analyses. This resulted in The aim of this study was to examine the cognitive correlates of ADHD in highly intelligent children and adolescents with ADHD. Two independent cohorts were used, comprising of (1) 51 and 21 highly intelligent (IQ ≥ 120) individuals with ADHD, respectively, carefully matched on age, gender, ADHD subtype, and IQ with (2) control participants with high intelligence, (3) participants with ADHD with average intelligence (IQ 90–110), and (4) control participants with average intelligence. In both cohorts, a battery of cognitive tasks was administered. Results indicate that ADHD-control group differences were not moderated by IQ; similarly, large ADHD-control cognitive performance differences were found in high versus average intelligent groups. The small moderating effects that were found when multiple testing was not corrected for mostly indicated somewhat milder cognitive problems in highly intelligent individuals with ADHD. However, on several tasks, a moderate to large effect of IQ was found: highly intelligent participants (regardless of having ADHD or not) performed better than average intelligence participants. Highly intelligent individuals with ADHD generally performed at the level of average intelligence controls.compensating-hypothesis where ADHD-related deficits are compensated by the high intelligence of highly intelligent individuals with ADHD . Even then, however, the ADHD symptoms might affect the working attitude and possibly lead to an IQ score that does not represent the intellectual abilities of the testee. The psychologist needs to have knowledge about ADHD as well as knowledge about possible problems caused by giftedness to be able to interpret the data.> 120). Using an IQ ≥ 130, a cutoff also often applied to study subjects with “high intellectual abilities” or “giftedness”  or four (cohort 1) subtests only. However, the subtests used are known to highly correlate with the full-scale IQ  and suit or four  example , 14) may example , 14, 18 In summary, our findings indicate the cognitive profile of ADHD is similar in highly versus average intelligent individuals with ADHD, although ADHD-related cognitive deficits may be easily overlooked in the high intelligence population when compared to the typical  control group.Additional file 1: Table S1. Description of cognitive assessment.Additional file 2: Table S2. Results of Cognitive correlates in relation to ADHD and high intelligence.


Adherence to attention deficit hyperactivity disorder (ADHD) medication can prevent serious consequences, possibly with lifelong effects. Numerous factors have been observed that influence adherent behaviour, but the impact of personality traits has been inadequately explored. The purpose of this study was to explore the associations between personality traits and adherence to ADHD medication, beliefs about the medication, and perceptions of ADHD.n = 99) on ADHD medication were administered: Health-Relevant Personality Traits Five-Factor Inventory, Medication Adherence Report Scale, Beliefs about Medicines Specific and Brief Illness Perceptions Questionnaires.Adolescents  and perceived personal control of ADHD . Negative Affectivity correlated with beliefs regarding necessity , concerns , and experienced side effects of medication , alongside perceptions regarding duration , identity , being emotionally affected , personal control  and concerns about ADHD . Impulsivity correlated with perceived consequences  and personal control of ADHD . Hedonic Capacity correlated with concerns about medication  and perceived identification with ADHD .The personality trait Antagonism correlated with adherence behaviour (Personality traits are related to adherence, beliefs about ADHD medicines and perceptions of ADHD. Antagonism is associated with adherence, especially intentional non-adherence, while Negative Affectivity correlates with numerous perceptions of ADHD and beliefs about medications. Personality assessments could be useful in the care and treatment of adolescents with ADHD. Personality traits may influence behaviour through beliefs and attitudes , which iPersonality traits may be defined as “dimensions of individual differences in tendencies to show consistent patterns of thoughts, feelings and actions” (p.25) . One of Interestingly, both low Conscientiousness , 8 and hWith regard to the fact that the five personality traits are supposed to mature up to the age of 30 years  and therThere is a growing body of knowledge regarding consequences of attention deficit hyperactivity disorder (ADHD) on a person’s life including negative effects on quality of life and sleep , risks oThe reported prevalence rates of adherence to ADHD medication vary widely, with a range of 21–81% in adolescents , 31. In Adherence in general is postulated to be a multidimensional phenomenon involving therapy, the healthcare system, diseases and socioeconomic and patient-related factors such as personality traits and the patient’s beliefs . PreviouGiven that high Neuroticism/negative Emotionality and low Agreeableness and Conscientiousness are associated with non-adherence behaviour in somatic disorders , 11–13, In general, there is little research available regarding the influence of personality on illness perception or beliefs about medications , 38 and The Health-Relevant Personality Traits Five-Factor Inventory (HP5i) has some advantages for assessing the role of personality in clinical situations in that it is short and easily filled in and captures the five health-relevant facets of The Big Five . Also, sThe aim of this study was to explore possible associations between personality traits and adherence to long-term ADHD medication, beliefs about the medication, and perceptions of ADHD among adolescents. A second aim was to investigate whether personality traits are associated with adherence through beliefs about the medication.Adolescents aged 13–17 years) who had received ADHD medication for at least 6 months at two Swedish child and adolescent psychiatric clinics (CAP) were offered to take part in the study between March 2014 and June 2015. In addition to language difficulties, exclusions criteria also included autism spectrum-, intellectual developmental- and neurological disorders. Information was enclosed in a letter given prior to a scheduled appointment for a regular follow up which occurred twice a year. After the adolescent and the parent/guardian assigned informed consent, a battery of self-reports was handed out which was comprised of sociodemographic questions, Hp5i –17 years, BMQ-SpeThe Regional Ethical Review Board in Linköping (D-nr 2013/402–31) approved this study. The ethical standards of The Helsinki Declaration of 1964  were fol± 1.36 years and 64 (64.6%) were males and 35 (35.4%) females. The ADHD diagnosis was based on the DSM-IV criteria and was determined before treatment started by an experienced specialist in child and adolescent psychiatry after a thorough diagnostic investigation. This included neuropsychological and clinical examination, relevant questionnaires and the results of the QbTest (Qbtech. Quantitative behaviour technology. https://www.qbtech.com/. Accessed 26 February 2019), which supported the diagnosis in 93% (92/99) of cases. All adolescents were found to have the combined type of ADHD. The females showed a tendency to be older (p = 0.073) and to have been on ADHD medication for a shorter period of time (p = 0.068) but the mean time on medication was 51.3 (SD: 29.2) months. The majority, or eighty-one (80.9%) of adolescents had long-acting methylphenidate (MPH) formulations and nine (9.0%) atomoxetine (ATX) added to the ten who had the combination treatment of ATX (10.1%) and MPH. An attrition analysis did not reveal any significant differences regarding gender, age at the start of medication, or time on medication when the 49 non-respondents were compared to the 99 participants [Out of the 160 adolescents invited to participate, 148 (92.5%) accepted and 99 (68.9%) completed all questionnaires. Their mean age was 15.6 icipants .Negative Affectivity (a facet of Neuroticism), Impulsivity (an opposite facet to Conscientiousness), Hedonic Capacity (a facet of Extraversion), Alexithymia (an opposite facet to Openness to experiences) and Antagonism (an opposite facet to Agreeableness). The inventory has 20 items that are scored between 1 and 4. Each personality trait is covered by four items [The HP5i assess five health-relevant facets of the Big Five’s personality traits including; ur items . The invur items . In the In order to assess adherent behaviour to prescribed ADHD medication, the MARS questionnaire was used. The first of its five statements evaluates unintentional non-adherence (item 1: “I forgot to take them”) and the remaining four address intentional non-adherence  . The iteThe BMQ-Specific investigates beliefs about the prescribed medication and consists of eleven questions that are clustered into three subscales. The items are scored on a 5-point scale covering the interval between “strongly disagree” =1 to “strongly agree” =5 , 43. TheThe adolescents´ perceptions regarding ADHD were investigated using a nine items self-report, B-IPQ. The first eight items of the inventory are scored between 0 and 10 whereas a higher score implies a stronger perception of the respective dimension of ADHD. B-IPQ consists of cognitive dimensions that are measured by five of its items (timeline (chronic vs. acute), identity, consequences, and personal and treatment control of ADHD). In addition, emotional dimensions are assessed by two items  and the last dimension is measured by one item, comprehensibility of ADHD . Finallyr = 0.1, medium if r = 0.3 and large if r = 0.5 [n = 57, males n = 34, females n = 23) and Swedish normative controls  aged 16 to 19 years [p level < 0.10 with any of the HP5i personality traits. Two different models were created in which the scores of a) the total MARS questionnaire, and b) intentional subscales were dependent variables. The independent variables in model a) were Antagonism, “the BMQ-Specific-Necessity”, “the BMQ-Specific-Concerns”, “the BMQ-Necessity-Concerns differential” and “the BMQ-unpleasant side-effects”. In model b), the independent variables were as follows: the personality trait of Antagonism, “the BMQ-Specific-Concerns”, “the BMQ-Necessity-Concerns differential” and “the BMQ-unpleasant side-effects”. The effect size for R2 was classified as small if R2 = 0.02, medium if R2 = 0.13 and large if R2 = 0.26 [The Statistical Package for the Social Sciences (SPSS) 21.0 was employed for data analysis. Descriptive statistics consisted of frequencies, means and standard deviation calculations. Pearson’s correlation coefficient was utilised to explore associations between personality traits (HP5i) and the variables age, perceptions about ADHD (B-IPQ), beliefs about medication (BMQ-Specific) and adherence behaviour . The effect size for Pearson’s r was classified as small if  r = 0.5 . The Man r = 0.5 –47 was e r = 0.5 –47 was u19 years . A media19 years . Two ste19 years –47, 50 w2 = 0.26 .Detailed information regarding the results of MARS, BMQ-Specific and B-IPQ are given in a prior publication by Emilsson et al. .p < 0.001) and Impulsivity (p = 0.019) than the males (Table p = 0.003) higher Impulsivity while the males with ADHD reported significantly (p = 0.005) higher Hedonic Capacity.HP5i personality traits were not significantly correlated to age in the ADHD population. The females reported higher Negative Affectivity p < 0.00 and Impup = 0.050) and its intentional non-adherence subscale (p = 0.043). Both findings remained  in a consecutive gender analysis solely in the males. In addition, Negative Affectivity showed a tendency for a negative correlation with scores for the total MARS questionnaire (p = 0.063) and its intentional non-adherence subscale (p = 0.058). See Tables The HP5i Antagonism scores correlated negatively with scores for the total MARS questionnaire ( p = 0.04. Both fip = 0.001), concerns (p = 0.001) and “I get unpleasant side-effects from my ADHD medicines” (p = 0.001). In a separate gender analysis, Negative Affectivity correlated positively to the necessity scores (p = 0.003) and the item “I get unpleasant side-effects from my ADHD medicines” (p = 0.006) in males and to the concerns scores in both males (p = 0.030) and females (p = 0.037). Antagonism correlated positively to the necessity scores (p = 0.037) in males. Hedonic Capacity correlated negatively to the concerns scores (p = 0.030) in the total group , identity (p < 0.001), concerns (p < 0.001) and emotional response (p < 0.001), but negatively with the personal control scores (p = 0.004). Antagonism was negatively correlated with the personal control (p = 0.007) and comprehensibility (p = 0.016) scores. Impulsivity correlated negatively with the personal control (p < 0.001) and consequences (p = 0.025) but positively with emotional response scores (p = 0.001). Hedonic Capacity correlated negatively with the identity scores (p = 0.045). Alexithymia correlated negatively with personal control (p = 0.031) scores.The HP5i personality traits were significantly linked to seven of the eight B-IPQ items exploring perceptions of ADHD (see Tables R2 = 0.48) was significantly explained by the personality trait Antagonism, along with the necessity-concern differential and BMQ side-effects item. An increment in Antagonism by one point was predictive of a 0.41-point decrease in the intentional non-adherence scores (p = 0.047). A one-point increment in the BMQ’s necessity–concern differential was predictive of a 0.11-point increment in the intentional non-adherence (p < 0.001). A one-point increase in BMQ’s “experienced side effects” was predictive of a 0.35-point decrease in the intentional non-adherence (p = 0.017).In a stepwise multiple regression model Table , the varR2 = 0.46) between the personality trait Antagonism and the total MARS score (dependent variable) (Table p < 0.001). A one-point increase in the “experienced side effects” score decreased the total MARS score by 0.43 (p = 0.016).In a stepwise multiple regression model, no association was found R2 = 0.6 betweenThe main results were that the personality trait Antagonism correlated significantly with adherence to ADHD medication by adolescents. Negative Affectivity only showed a tendency to correlate with adherence, despite widespread correlations with perceptions about ADHD and beliefs about medication, including side effects.These findings provide evidence that personality plays a role in health-related behaviour , 51, espThere was no gender difference regarding Antagonism. However, the relation between Antagonism and adherence behaviour was only replicated in males, congruent with findings from young people with asthma , suggestThe results suggest that assessments of personality may be useful in the clinical work to ascertain adherence in young people with ADHD by more directed surveillance and information about the medications for those with high Antagonism.Other HP5i personality traits showed no significant associations with adherence, which contradicts prior research on somatic disorders, especially regarding Conscientiousness and Neuroticism , 11–13. Negative Affectivity correlated with numerous beliefs about ADHD medication and perceptions about ADHD, some of which are of interest for adherence . The uneThe higher Negative Affectivity (a facet of Neuroticism) and Impulsivity in females with ADHD compared to males parallels research on adolescents with substance misuse problems  and has Impulsivity was associated with perceiving more consequences of having ADHD, less personal control over ADHD and being more emotionally affected by ADHD. This is in line with the definition of Impulsivity which describes individuals with limited thoughtfulness, reliability, ability to plan and carefulness . Hence, Higher Hedonic Capacity was accompanied by low concerns about medication, which harmonises with the positive nature of Hedonic Capacity .Several limitations should be mentioned. We cannot exclude the possibility that medication has an impact on the personality outcomes but existing literature is conflicting. Miller et al.  detectedDespite giving informed consent, a substantial proportion of the recruited individuals did not return the questionnaires, plausibly due to a tendency for cooperativeness in the presence of caregivers that did not persist after returning home. Furthermore, insufficient support to fill in the questionnaires may have increased the attrition since the caregivers may have similar disabilities. Nevertheless, it is possible that those adolescents who chose not to participate may have more prominent personality deviations. Consequently, the attrition may have limited the study’s ability to elucidate the impact of personality traits on attitudes to ADHD and medication and on adherence , 11–13. The adherence results may be inaccurate because self-reports such as MARS are indirect assessments that tend to report greater adherence than direct patient observations or pharmacological analyses . In addiThis is an exploratory study and therefore no adjustments were made for mass significance, despite the risk of alpha error. In order to avoid overfitting, a stepwise regression was considered more suitable compared to other alternative multiple regression methods, such as the enter , forwardSince HP5i data from a normal 13–15-year-old population were not available, comparisons with the age- and gender-matched norm population were only performed on participants ≥16 years. Compared to the normal population, the females with ADHD revealed higher Impulsivity while the males with ADHD revealed higher Hedonic Capacity. Higher Impulsivity of the ADHD females is in accordance with previous studies , 37; howA strength of the investigation is the well-characterised sample, because it was possible to identify all suitable patients at the participating clinics, and the solid diagnostic work. The HP5i inventory is validated for Swedish adolescents , which eThe present results provide evidence for the involvement of personality traits in perceptions about ADHD, beliefs about ADHD medication and adherence in adolescents. Antagonism is associated with adherence to ADHD medication, especially intentional non-adherence behaviour in adolescent males. This suggests that it is important to identify the Antagonism personality trait in the caretaking of ADHD adolescents in order to promote their adherence to medication by means of more information and support.


Attention Deficit Hyperactivity Disorder (ADHD) is associated with a range of adverse outcomes in adult life. However it is unclear whether the risk pathways to adverse adult outcomes are established during childhood or whether associations are driven by concurrent ADHD symptoms that have persisted to adulthood.We examined associations between broadly defined child-limited (remitted) and persistent ADHD  with social outcomes  at age 25 years in a UK longitudinal population sample ALPSAC : total N=6439.-05) and receiving state benefits  at age 25 years compared to those without ADHD. We did not find strong evidence of associations between child-limited ADHD and social outcomes . Persistent ADHD associations with negative social outcomes were observed across family-of-origin income groups, sex and were not explained by comorbidity.Up to 20% of young-people with less favourable social outcomes at age 25 had persistent ADHD. Persistent ADHD was associated with an increased likelihood of being not in education, employment or training (NEET: OR=3.71, 95% CI=2.06 to 6.67, p=1x10Our findings highlight the importance of continued monitoring and management of ADHD symptoms and related social as well as clinical outcomes across development into adulthood. Future research is needed to identify what factors promote positive social outcomes, including effective treatment of adult ADHD symptoms. Although most affected individuals continue to display some ADHD symptoms and impairment after childhood, others remit before adult life.7. One meta-analysis estimated fivefold higher prevalence of people with ADHD detained in youth prison populations (30.1%) and tenfold in adult prison populations (26.2%) across a number of countries, compared to general population prevalence estimates at equivalent ages.8 ADHD is also associated with an increased likelihood of not completing secondary school or attending tertiary education,9 employment difficulties, homelessness and financial dependence on parents or government/public assistance in adulthood.11 Finally, studies also suggest an association between ADHD and poorer quality social relationships and support in adulthood.13The association between ADHD and higher levels of antisocial behaviour is well established15 substance misuse, cigarette smoking, BMI and coronary artery disease16 may be causal, arising as a direct result of ADHD. If that is the case, then vigorous and effective support/treatment of ADHD would be crucial for preventing adverse adult outcomes.A variety of different research designs have been used to infer causal relationships between ADHD and several different clinical and physical health outcomes; these include time-series investigations of prescription data and Mendelian randomisation approaches. These studies suggest that the relationships between ADHD and some adverse outcomes, including depression,17 The question of what happens to those with ADHD that remits is clinically important: if ADHD appears to have remitted by late adolescence, should these young people be discharged from services or continue to be monitored by adult mental health or primary care services even if this follow-up is provided less frequently than for those with persistent ADHD?For many individuals however, the transition from child to adult mental health services disrupts engagement with clinicians and treatment continuity. That may not be a problem if ADHD has remitted and adverse adult outcomes primarily are influenced by concurrent ADHD symptoms. However, if ADHD symptoms in childhood lead to adversities or disadvantages  across childhood and adolescence, then the risk mechanisms leading to poor adult outcomes have already been set in place. That would support the argument for continued monitoring of those with a history of childhood ADHD even if ADHD symptoms have declined or remitted. One previous study supports the latter hypothesis. In the UK prospective twin cohort E-risk, those with remitted ADHD showed worse outcomes at age 18 years than those who have never had ADHD but not to the same extent as those with persistent ADHD.In this study we utilise a UK longitudinal birth cohort, followed up to age 25 years to address this question. We set out to examine the adult social outcomes at age 25 years associated with broadly defined ADHD, differentiating those that were child-limited (remitted) and persistent. We hypothesised that those with ADHD who had remitted by age 25 years, as well as those with persistent ADHD, would show adverse social outcomes by age 25 years.20 Pregnant women resident in Avon, UK with expected dates of delivery 1st April 1991 to 31st December 1992 were invited to take part in the study. The initial number of pregnancies enrolled is 14,541 (for these at least one questionnaire has been returned or a “Children in Focus” clinic had been attended by 19/07/99). Of these initial pregnancies, there was a total of 14,676 foetuses, resulting in 14,062 live births and 13,988 children who were alive at 1 year of age. When the oldest children were approximately 7 years of age, an attempt was made to bolster the initial sample with eligible cases who had failed to join the study originally. As a result, the total sample size for data collected after the age of seven is therefore 15,454 pregnancies, resulting in 15,589 foetuses. Of these 14,901 were alive at 1 year of age. Part of this data was collected and managed using REDCap electronic data capture tools hosted at the University of Bristol.21 REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies. Ethical approval for the study was obtained from the ALSPAC Law and Ethics Committee and Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Please note that the study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool: http://www.bristol.ac.uk/alspac/researchers/our-data/. Further details of the study, measures and sample can be found elsewhere.20 Where families included multiple births, we included the oldest sibling.We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a well-established prospective, longitudinal UK birth cohort study.22 a well-established screening measure completed by parents about their children at approximately ages 7, 8, 9, 12 and 17, and by self-report at age 25 years. The SDQ ADHD subscale has high validity in identifying DSM-5 ADHD caseness. The category of broadly defined ADHD was applied to participants who scored above the recommended SDQ cut-point for identifying ADHD diagnosis. These cut-points are ≥8 in childhood and adolescence21 and ≥5 for self-reports at age 25 years.23 In-line with previous work24 childhood ADHD was defined as the presence of broadly-defined ADHD at ages 7, 8, 9 or 12 and late adolescent/young-adult ADHD where participants scored above the SDQ-ADHD subscale cut-point at ages 17 or 25. Based on these categories, individuals were categorised as having low ADHD levels (i.e. below the SDQ cut-point in both childhood and late adolescence/young-adulthood), child-limited ADHD (i.e. above the SDQ cut-point in childhood but not in late adolescence/young-adulthood) or persistent ADHD (i.e. above the SDQ cut-point in both childhood and late adolescence/young-adulthood). These groups are shown in ADHD symptoms were assessed using the 5-item ADHD subscale of the Strengths and Difficulties Questionnaire (SDQ: possible range 0-10),Emotional  and instrumental support  were measured by the National Institute of Health (NIH) Toolbox Adult Social Relationship Scales25 (possible ranges 0-32). Low support was defined as the bottom 10% for descriptive purposes. Aggressive and non-aggressive antisocial behaviour were measured using the Edinburgh Study of Youth Transitions and Crime26 which assessed engagement in 12 antisocial activities in the past year (possible range 0-12). Antisocial behaviour was defined as engagement in any of the relevant anti-social activities: the aggressive (4 items) and non-aggressive (8 items) antisocial behaviours (details available on request from the author). Not in Education, Employment or Training (NEET) status was derived in-line with the UK Office for National Statistics definition27 (details available on request from the author). State benefit recipient was defined as receiving unemployment-related benefits, income support, sickness or disability benefits, housing benefits  or tax credits. We included receiving state benefits as an outcome as a proxy measure of socio-economic disadvantage. Homelessness was assessed using one item from a 27-event checklist that asked about events experienced in the previous 12 months.Social outcomes were assessed based on self-reports at age 25 years. Family income was measured by mother-report at approximately child age 11 years as the average household income including social benefits each week on a 10-point scale from <£120 to ≥£800. Four income groups were generated, with lower/higher income defined based on falling below/above the median and the lowest and highest subsequently identified as bottom/top decile.Sensitivity analyses were conducted stratifying by sex and family of origin (“family”) income. Low IQ was defined as IQ<80, measured using the Wechsler Intelligence Scale for Children.28Autism symptoms were measured using the parentrated 12-item Social Communication Disorders Checklist (SCDC)29 at ages 7 years (cut-point ≥9). Conduct problems were assessed using the parent-rated 5-item SDQ22 subscale at age 7 years (cut-point ≥4). Emotional problems were also assessed using the parent-rated 5-item SDQ22 subscale at age 7 years (cut-point ≥5).We also examined whether associations between ADHD and age 25 social outcomes were still present in the absence of child comorbidities. Young-adult emotional problems were also assessed using the self-rated 5-item SDQ22 subscale at age 25 years (cut-point ≥6). Lifetime ADHD medication use  was assessed by self-report at age 25 years.Finally, we examined whether associations between ADHD and age 25 social outcomes were still present in the absence of young-adult emotional problems and when excluding those with ADHD medication use. 30 including individuals with ADHD data available in both childhood and adolescence/adulthood (N=6439): social outcome data were available for N=3591-3654 depending on the variable (details available on request from the author). We used logistic and linear regression to examine associations with social outcomes, with low ADHD symptoms as the reference group to estimate associations for child-limited and persistent ADHD. Sensitivity analyses examined associations stratified by sex, family income, childhood comorbidities , young-adult emotional problems and excluding those with ADHD medication use. Sensitivity analyses based on MI (without IPW), IPW (without MI) and complete-case analyses are available on request from the author. Finally, sensitivity analyses using different definitions of ADHD were conducted (a) defining childhood ADHD as having high ADHD symptoms at multiple times across 7, 8, 9 or 12 , (b) defining high ADHD symptoms at age 25 years using the more stringent cut-point of ≥6 23 and (c) defining persistent ADHD based on the presence of high symptoms at age 25 years only (i.e. rather than age 17 or 25 years). Sensitivity analyses using different definitions of ADHD are also available on request from the author.Analyses were conducted using multiple imputation with inverse probability weighting (IPW/MI),Approximately 89% of the sample were defined as having low ADHD symptom levels, 6% as having child-limited ADHD symptoms and 5% as having persistent symptoms.Estimated social outcome means/proportions by ADHD group are shown in As shown in 05), whereas evidence of association for child-limited ADHD was weaker . The estimated total number of these outcomes by ADHD group are shown in Persistent ADHD was also associated with a higher total number of these adverse social outcomes  compared to those with low ADHD symptoms . Associations stratified by family of origin income also found associations to be generally consistent across income levels, with overlapping confidence intervals across groups.Sensitivity analyses also examined whether associations between ADHD and adult social outcomes were still present in the absence of child comorbidities , young-adult emotional problems and ADHD medication use. Evidence of association between persistent ADHD and lower emotional support, being NEET and receiving state benefits remained when excluding these child comorbidities, young-adult emotional problems and taking ADHD medication although the association with state benefits was somewhat attenuated when excluding those with childhood ASD symptoms and association with lower emotional support was somewhat attenuated when excluding those taking ADHD medication.Missing data sensitivity analyses showed a similar pattern of results across different approaches.Finally, sensitivity analyses using different definitions of ADHD also showed a similar pattern of results, as did those investigating “late-onset” ADHD.This study set out to examine the adult social outcomes at age 25 of ADHD symptoms across childhood and young-adulthood in a longitudinal birth cohort, differentiating those that were child-limited (remitted) and persistent. The findings observed did not support our hypothesis that adults with both remitted and persistent ADHD would show adverse social outcomes by age 25 years. While we found associations with persistent ADHD, we did not find such strong evidence of association with child-limited ADHD.We found ADHD that persisted into young-adulthood was associated with multiple adverse social outcomes including lower levels of emotional support and an increased likelihood of being NEET  and of receiving state benefits (a proxy measure of socio-economic disadvantage). Approximately 20% of young people with NEET status, receiving state benefits and who were homeless had ADHD. This pattern of associations was present across sex, family of origin income level, and when excluding childhood comorbidities, young-adult emotional problems and ADHD medication use. While it is beyond the scope of this paper to investigate the mechanisms linking (persistent) ADHD to these social outcomes, possible explanations include ADHD-related core symptoms and emotional regulation difficulties impacting on the initiation and/or maintenance of supportive relationships and upon educational attainment. Interestingly we did not find strong evidence of association between persistent ADHD and lower instrumental support, which may result from a reliance on (and therefore increase use of) others for practical support. Difficulties in ADHD-service engagement (including during the transition from child to adult services) at a time of formal examinations, transitions out of school and future planning may also contribute to poor social outcomes. We also found persistent ADHD to be associated with an increased number of these negative social outcomes even though the sample is a population-based cohort and we defined ADHD broadly. Around 1 in 4 of this group had more than one of these negative social outcomes. Future research needs to identify what modifiable social factors promote better social outcomes. There also was some evidence that women with ADHD may be more likely to have impairments in social relationships  and men with ADHD to have impairments in employment/training (NEET). Further work would be needed to investigate potentially different pathways for men and women between ADHD and social outcomes.31: but that this effect may not persist into young-adulthood (10-yearfollow-up).32 However our study design cannot differentiate whether associations with outcomes are a causal consequence of ADHD symptoms. For example, evidence suggests that ADHD persistence is associated with ADHD severity and a higher genetic loading than remitted ADHD.33 Also ADHD symptom persistence into young-adulthood does not exclude the possibility that risk mechanisms for social outcomes were set in place earlier in development for this group. Regardless, our findings highlight the importance of ADHD monitoring and management of ADHD symptoms across development, the transition from child to adult services and the variability in adult social outcomes.Our findings suggest that directing resources to supporting those with ADHD and monitoring symptoms across adolescence and young-adulthood may be a beneficial area of focus. This age captures a period of increasing socio-occupational, personal and financial demands, when young people typically graduate from education into the world of further training and/or employment. The absence of strong evidence of association between child-limited ADHD suggests that the risk-mechanisms linking ADHD and social outcomes in young-adulthood are not exclusively set in place in childhood – that effective ADHD treatment and other interventions that reduce symptoms may help prevent adverse adult outcomes. Indeed, previous work has found for example that stimulant medication in young people with ADHD is associated with a decreased risk of subsequent smoking and substance use disorders in adolescence (at 5-year follow-up)17 One explanation is that our study focussed on broadly defined ADHD whereas the previous work17 examined ADHD diagnosis, which means that individuals who were categorised as having remitted ADHD (i.e. did not meet diagnostic threshold at 18 years) may still have had (subthreshold) ADHD symptoms at 18.17 Such individuals would have been categorised as having persistent ADHD symptoms in our study. It could be that our (less common) outcomes were defined more stringently and were more severe. Alternatively, differences could be due to follow-up period: it may be that the familial, social, occupational and personal life events and changes that occur between ages 18 and 25 explain the apparent contrasting findings.Our findings somewhat differ from a previous UK cohort study which showed association between remitted ADHD and life satisfaction, NEET status and criminal convictions  at the age of 18 years.35 We used multiple imputation with inverse probability weighting to try to minimise the effect of missingness and findings were consistent across different approaches. We focused on ADHD symptoms in a population cohort and although evidence suggests that ADHD behaves as a continuously distributed trait without clear-cut thresholds in terms of associations with adverse outcomes,36 our findings may not be able to be generalised to clinical diagnosis or those in clinical services. However our prevalence rates of ADHD are not much higher than the rate of ADHD diagnosis in many population surveys. The use of a population sample also limited our power for detecting association with rarer outcomes such as homelessness. Finally, beyond examining young-adult emotional problems we did not examine the potential impact of presence and treatment of additional comorbid psychiatric disorders in adulthood.Our study findings should be considered in light of limitations. As with many longitudinal population-based samples, ALSPAC also suffers from non-random attrition, with those who drop out more likely to be at elevated risk of psychopathology.Further research using alternative designs such as those that assess causal inference is needed to test whether the associations we found are causal and work is needed to identify potentially modifiable risk mechanisms, groups that are at highest risk and factors that promote positive adult social outcomes. Identification of such moderating and mediating factors as well as those relating to service disengagement is needed to be able to better address the emotional wellbeing and social marginalisation of at-risk young people with ADHD. The effect of the COVID-19 global pandemic on the social outcomes of young people with ADHD is also as yet unknown: the associated additional challenges that this has posed on young people and understanding how they can be best supported as they progress into wider society remains vital.The funding and expansion of support for young-adults with ADHD in educational/occupational establishments and benefit systems may help reduce negative outcomes. Holistic age-specific ADHD resources, interventions, support and services that span the lifespan may be beneficial in addressing the range of adverse outcomes associated with ADHD, as well as core features. Mental health awareness initiatives are increasingly taking place in educational establishments, however specific ADHD-informed interventions are indicated to anticipate and support young people in making choices around goals for further training and/or occupational activity. Understanding individuals with ADHD and matching strengths and interests  with appropriate lines of work may serve to increase the likelihood of increased enjoyment, satisfaction and longer-term engagement in meaningful socio-occupational activity. This may in turn have positive effects on navigating supportive relationships, emotional wellbeing and use of maladaptive coping strategies. Early identification and specific careers guidance by resourced practitioners with increased awareness of ADHD would support and highlight to young people with persistent symptoms the wide range of complimentary, realistic and exciting future opportunities for their diverse skill sets.In conclusion, our study found ADHD that persists to young-adulthood is associated with a range of less favourable social outcomes, including low emotional support, NEET status and receiving state benefits (as an indicator of socio-economic disadvantage) although these adverse outcomes were not inevitable. Strong evidence of association was not found for child-limited ADHD. These findings support the continued monitoring and management of ADHD across development and the transition from child to adult services, including in areas of functional impairment beyond core ADHD features.


Lead is known to be associated with attention-deficit/hyperactivity disorder (ADHD) even at low concentrations. We aimed to evaluate neurocognitive functions associated with lead in the blood and the interactions between lead and dopaminergic or noradrenergic pathway-related genotypes in youths with ADHD.DAT1), dopamine receptor D4 (DRD4), and alpha-2A-adrenergic receptor (ADRA2A) genotypes were investigated. All participants were assessed using the ADHD Rating Scale-IV (ADHD-RS). Participants also completed the continuous performance test (CPT) and Stroop Color-Word Test (SCWT). Analysis of covariance was used for comparison of blood lead levels between ADHD and control groups. A multivariable linear regression model was used to evaluate the associations of blood lead levels with the results of ADHD-RS, CPT, and SCWT; adjusted for intelligence quotient (IQ), age, and sex. A path analysis model was used to identify the mediating effects of neurocognitive functions on the effects of blood lead on ADHD symptoms. To evaluate the effect of the interaction between blood lead and genes on neuropsychological functions, hierarchical regression analyses were performed.A total of 259 youths with ADHD and 96 healthy controls (aged 5–18 years) enrolled in this study. The Korean Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime version was conducted for psychiatric diagnostic evaluation. Blood lead levels were measured, and their interaction with dopaminergic or noradrenergic genotypes for ADHD; namely, the dopamine transporter (p = .005). Blood lead levels showed a positive correlation with scores on omission errors and response time variability  of CPT. In the multivariable linear regression model, blood lead levels were associated with omission errors . Regarding the effects of lead on ADHD symptoms, hyperactivity-impulsivity was mediated by omission errors. An interaction effect was detected between ADRA2A DraI genotype and lead levels on omission errors .There was a significant difference in blood lead levels between the ADHD and control groups (1.4 ± 0.5 vs. 1.3 ± 0.5 μg/dL, Our results indicate that neurocognitive functions at least partly mediate the association between blood lead levels and ADHD symptoms, and that neurocognitive functions are affected by the interaction between blood lead levels and noradrenergic genotype. DAT1) and dopamine D4 receptor (DRD4), are most commonly reported as having positive associations with ADHD [ADRA2A), have been studied in the context of their relationship with symptoms and executive functions in ADHD [Attention-deficit/hyperactivity disorder (ADHD) occurs in 5% of children  and is cith ADHD . Recent ith ADHD . Noradre in ADHD , 10.Genetic risk factors alone cannot explain the course and development of ADHD , 7. AlonDAT1 gene is an ADHD candidate gene reported to be associated with response inhibition [DRD4–7 polymorphism, impaired executive functions were linked to increased lead levels [DAT1 VNTR and DRD4 VNTR variants and ADHD in Koreans [ADRA2A MspI and DraI polymorphisms were reported as predictors of treatment responses in ADHD with blood lead [Lead is a well-known neurotoxicant that can damage multiple organs  and intehibition . A studyhibition . In child levels . A recen Koreans . ADRA2A ood lead . Howeverood lead , it is nDAT1 and DRD4, and norepinephrine-related genes, such as ADRA2A, and that this interplay would affect specific executive functions, such as inattention, impulsivity, and processing speed.In this study, we aimed to evaluate which executive functions mediated the effects of blood lead levels on ADHD symptoms and the specific genes interacting with lead that were correlated with executive functions affected by blood lead levels. Based on previous studies, we hypothesized that lead, as an environmental risk factor, would interact with dopamine-related genes, such as Data from 355 participants comprising 259 patients with ADHD and 96 controls (aged 5–18 years) were pooled from two studies conducted with the same protocol between August 2010 and February 2015 at the child and adolescent psychiatry outpatient clinic of our hospital. In total, 90 patients with ADHD and 33 controls were initially recruited from the first study; after excluding two patients with ADHD and eight controls with missing genetic or environmental data, 88 patients with ADHD and 25 controls were assessed. In the second study, 191 patients with ADHD and 78 controls were initially recruited; after excluding 20 patients with ADHD and seven controls with missing genetic or environmental data, 171 patients with ADHD and 71 controls were assessed. A board-certified child and adolescent psychiatrist performed a psychiatric diagnostic evaluation, consisting of the Korean Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime version (K-SADS-PL), for each participant in both groups. The validity and reliability of the Korean version of the K-SADS-PL have been ascertained . ExclusiThe Korean version of the ADHD Rating Scale-IV (ADHD-RS) was completed by the parents to assess the severity of ADHD symptoms . The ADHFrom each child, 5 mL venous blood samples were collected in metal-free tubes for lead measurements. Matrix modifier reagent composed of Triton X-100 and ammonium hydrogen phosphate dibasic was used for dilution, and the atomic absorption spectrometer–graphite furnace  was used to assay lead concentrations. Using this method, the detection limit for lead was 0.058 μg/dL. The methods for the assay have been described previously .DAT1 on chromosome 5p15.3, was genotyped using T7–5 Long (5′-TGT GGT GTA GGG AAC GGC CTG AG-3′) and T7-3a Long (5′-CTT CCT GGA GGT CAC GGC TCA AGG-3′). The genotypes of the DAT1 variant were grouped according to the number of 10 repeats they carried as 10/10, with a 10, or without 10. The DRD4 exon III VNTR polymorphism comprised 2–10 variable repeat units (1 unit = 48 base pairs) and was generated using the oligonucleotide primers (5′-ACC ACC GGC AGG ACC CTC ATG GCC TTG CGC TC-3′ and 5′-CTT CCT ACC CTG CCC GCT CAT GCT CTA CTG G-3′). The genotypes of the DRD4 variant were grouped into 4/4, with a 4, and without 4. For genotyping of norepinephrine-related genes, G-DEX™ II Genomic DNA Extraction Kit  was used to extract genomic DNA from whole blood lymphocytes. ADRA2A polymorphisms were generated using oligonucleotide primers . The genotypes of the ADRA2A MspI variant were divided into C/C, G/C, and G/G; and those of the ADRA2A DraI variant were divided into C/C, C/T, and T/T. The detailed genotyping processes and the primer sequences used have been described previously [For genotyping of dopamine-related genes, a Genomic DNA Extraction Kit  was used to extract genomic DNA from blood lymphocytes. The 40-base pair VNTR polymorphism, located in the 3′-UTR of eviously .DAT1, DRD4, ADRA2A MspI, and ADRA2A DraI) were analyzed. For each regression, the age, sex, and IQ were entered in the first block; diagnosis  was entered in the second block; genotypes and lead levels were entered in the third block; interaction terms between diagnosis or genotypes and lead levels  were entered in the fourth block; and interaction terms among diagnosis, genotypes, and lead levels  were entered in the fifth block. Multiple linear regression analyses were used to examine the associations of blood lead levels with neuropsychological functions. Regression analyses were performed using a set of covariates that included age, sex, and IQ. To calculate the effect size, Cohen’s d, H or f2 was calculated. A Benjamini–Hochberg test with a false discovery rate threshold of 0.05 was performed to adjust for multiple comparisons for all analyses. All statistical analyses except the path analyses were performed using SPSS 22.0 . Results were considered statistically significant at p < .05 (two-tailed).We compared the blood lead levels between ADHD and control groups using independent-sample t-tests and analysis of covariance (ANCOVA). In the ANCOVA, age, sex, and IQ, which were significantly different between groups, were used as covariates. A Pearson correlation analysis was used to examine the correlation of blood lead level with ADHD symptoms and neuropsychological functions in all participants. To analyze neuropsychological functions and ADHD symptoms on a spectrum, we analyzed the data from all participants concurrently. Pearson correlation analysis confirmed the neuropsychological functions and the symptoms of ADHD are associated with lead. Path analysis, which was performed to test the mediating effect of omission errors and response time variability, confirmed the correlation of the levels of lead and the effect on ADHD symptoms. Path model analysis was performed using the AMOS version 19.0 statistical program . To evaluate the effect of the interaction between blood lead and genes on neuropsychological functions, hierarchical regression analyses were performed. The outcome variable was the CPT omission error; four genes , male ratio , and IQ . All subscales of the ADHD rating scale in the ADHD group were higher than were those in the control group . In CPT, omission errors , commission errors , and response time variability  were higher in the ADHD group than in the control group. There was a significant difference in blood lead levels between the ADHD and control groups . However, after adjusting for age, sex, and IQ, there was no significant difference in blood lead levels between the ADHD and control groups . ANCOVA revealed that sex significantly affected differences in blood lead levels . In analyses of males and females separately, males did not show a significant difference in blood lead levels between the ADHD and control groups . However, in females, average blood lead levels in the ADHD group were significantly higher than were those of the control group . In the whole group of patients and the control group, the lead concentration was higher in males than in females . No differences in any of the genotype frequencies were found between the ADHD and control groups.Table B = 3.748, 95% confidence interval 0.091–7.404, p = .045) and response time , after adjusting for age, sex, and IQ. However, after adjustments for multiple comparisons, these associations were insignificant. . The most related genotype with omission errors was T/T, followed by C/T. The C/C genotype was found to be the least relevant. DAT1 VNTR showed a trend for an association with omission error . However, after adjustments for multiple comparisons, these associations were insignificant. No interactions between lead and genes were associated with response time variability.As shown in Table This study compared blood lead levels in ADHD and control groups. We identified associations among blood lead levels, ADHD symptoms, and brain functions assessed by neuropsychological tests. We identified that a subset of genes, previously associated with ADHD, may impact brain functions through their interactions with lead. This study is the first to reveal that interactions between lead and particular genes affect brain functions mediating the effects of lead on ADHD symptoms.Previous studies have reported associations of blood lead levels with ADHD symptoms or certain cognitive functions. Controversy remains regarding which domain of ADHD symptoms is more affected by lead. Research on patients with ADHD reported associations with hyperactivity-impulsivity , and a sADRA2A DraI and DAT1 (trend level), affected omission errors by interacting with lead. The alpha-2A-adrenergic receptor is involved in executive functions in the prefrontal cortex, such as working memory, attention, and impulse control [p-value were .92 and .825, respectively [With regard to the etiology of ADHD, interactions between environment and genes have been reported , 40. Lea control . Howeverectively . To our ectively . ResultsPrevious studies have reported that lead has effects on cognitive functions and associations with intelligence. While no significant association with intelligence was observed in the present study, recent studies reporting lower average lead levels were able to demonstrate an association . Future In the comparison of blood lead levels in the ADHD and control groups, significantly higher blood lead levels were observed in the ADHD group. However, after correcting for age, sex, and IQ, there was no significant difference. Since the number of males in the ADHD group was greater than that of females, and the average blood lead levels were higher in males than in females overall, the average blood lead levels of the ADHD group were also higher than that of the control group. As previously reported, there was still a significant effect under 5 μg/dL, which is the standard level per Centers for Disease Control and Prevention. In addition, although males did not exhibit differences in blood lead levels between the ADHD and control groups, there was a significant effect on symptoms, suggesting that ADHD pathogenesis is also affected by interactions with other factors such as the genes identified in this study.p-value. It is necessary to be careful in interpreting the results of this study. Since the statistical significance level is affected by the number of samples and variables, it is necessary to analyze with a larger number of samples in subsequent studies and check whether the same results are repeated. Lastly, the studies used as references in this paper did not include recent studies. This also means that research on the interaction of lead and gene expression has not been continued. Therefore, the results should be interpreted with caution. Subsequent studies on the effect of lead and gene interactions on the symptoms of ADHD should be continued. A strength of this study is that we attempted to understand the disorder across the spectrum based on changes in the DSM-5 and to calculate the effect size, Cohen’s d, H or f2 was calculated.First, this study was unable to balance the proportion of males and females and match for age and sex between the ADHD and control groups. This limitation was addressed by using age and sex as covariates in the statistical comparisons between the ADHD and control groups. Because there are differences in genetic variation between races and countries, there are limitations in interpreting the data in this study. Since the distribution of the general population of Korea is not fully understood, the data of the patient population in this study needs to be compared with the genetic distribution of the general population and verified in the future. In addition, in diagnosing ADHD symptoms, the same symptoms are supposed to be identified in two different settings, but this study assessed symptoms from parents only. However, we increased the accuracy of diagnosis by using a structured assessment tool. Further, we did not classify participants by the presence of diagnosis in the analysis of associations between lead and symptoms. Instead, we considered a wide range of symptoms  for the statistical analyses. When considering multiple comparisons, several results were reported without statistical significance. However, the effect size was medium although it was not statistically significant in ADRA2A DraI gene. It is necessary to confirm whether these results are replicable through additional studies on interactions of lead with relevant genes.Blood lead levels influenced ADHD symptoms, including both inattention and hyperactivity-impulsivity, and the effects were mediated by omission errors and response time variability, as measured by CPT. Omission errors were affected by interactions between lead and the Additional file 1: Table S1. Association between Blood Lead Concentration and Clinical Characteristics in the ADHD Group in the Multivariable Linear Regression Analysis.


In Italy, the elections occur often, indeed almost every year the citizens are involved in a democratic choice for deciding leaders of different administrative entities. Sometimes the citizens are called to vote for filling more than one office in more than one administrative body. This phenomenon has occurred 35 times after 1948; it creates the peculiar condition of having the same sample of people expressing decisions on political bases at the same time. Therefore, the Italian contemporaneous ballots constitute the occasion to measure coherence and chaos in the way of expressing political opinion. In this paper, we address all the Italian elections that occurred between 1948 and 2018. We collect the number of votes per party at each administrative level and we treat each election as a manifestation of a complex system. Then, we use the Shannon entropy and the Gini Index to study the degree of disorder manifested during different types of elections at the municipality level. A particular focus is devoted to the contemporaneous elections. Such cases implicate different disorder dynamics in the contemporaneous ballots, when different administrative level are involved. Furthermore, some features that characterize different entropic regimes have emerged. The Italian Ministry of the Interior publishes the electoral data immediately after each Italian election round. The official available data proves the high number of voting turns that occurred over the years; Disordered System’s states and we address the degree of disorder overcoming the assumptions often used in the voters’ behaviours studies. To run such a measurement we employ the b-ary entropy  when thobserved  as well case see ); namelyTangentopoli in 1992 to the beginning of the first Berlusconi’s government, 1994). In the 1996’s ballot, the so-called Legge Mattarella was applied for the first time, it divided the parliamentary seats by different type of electoral systems (mixed system), 75% of the seats were distributed through a majoritarian rule, while the remaining 25% was distributed through the proportional system (with minor corrections). The authors of )Once we get the entropy and the adjusted Gini for each municipality, for each democratic call, we compare the entropy empirical distributions realized in different elections between each other and then we do the same for the Gini empirical distributions. After that, utilizing Pearson’s and Kendall’s correlations, we can assess the relationship between the two measures to validate the findings.The main objective is to study the contemporaneous ballots pairwise  to capture information about the outcome of voters’ decisions in an aggregate fashion. In this way, we look at voters’ choices under a different perspective, particularly extracting information from the distributional features of the manifested chaos in each district. To compare the distributions between each other (not mixing entropy and Gini), we employed the Kolmogorov–Smirnov test (see an illustrative example in  or 54]))54]) betSometimes, the contemporaneous rounds of voting involved just subsets of zones of Italy , therefore, running the KS test on the overall data requires a further check to exclude spatial effects. To pursue such a scope, we have run the test a second time but selecting just the municipalities for which the data is present in all the elections that occurred contemporaneously . For example, for the case of April 2000, we have selected the municipalities present for the Regional elections as well as for the municipal ones and we have compared their entropies via the KS test. Therefore, we have two KS test statistics, one for the entropy comparison and another for the Gini comparison.In this section, we report the result of the entropic and inequality analysis performed on the Italian elections between 1948 and 2018. The section is divided into four parts, the first two where we present the general dynamics of the b-ary entropy and the Gini coefficient along the years for the majority of the ballots and the last two in which the results for the contemporaneous elections are reported.A summary of the entropy calculated with the election results coming from Italian municipalities for each ballot in the dataset is reported in Table 4. To better summarize the outcomes, we have divided the time into three chunks.Figures 4–6 are helpful to clarify the changes in entropy that occurred along the years for the European elections, Chamber of Deputies and Senate of the Republic. The other types of democratic calls are not suitable for such a representation because on certain dates they have involved just a part of the country.The maximum entropies for the Municipal elections are recorded in northern towns characterized by low population. All of them reached in recent elections (after 1995).For the Provincial cases, we have the three highest entropies that occurred in the Veneto region, namely Domegge di Cadore, La Valle Agordina and Sedico, with respectively 0.957, 0.942 and 0.934. If one extends the analysis to the top ten entropy levels, it is possible to notice that they also fall into northern regions, particularly in towns characterized by low population. However, most of them were recorded during the 2004 election.On the other hand, for the municipality with the minimum level of entropy, one cannot see a particular trend apart from noticing that most of them occurred in 2009 and 2004 ballots.The Regional elections manifest a maximum in Campobasso on 16/10/2011 with 0.95. In descending order, the following are Pietrabbondante (Molise), Cugnoli (Abruzzo) and Sant’Agapito (Molise). All of them have a low population and they got, respectively, 0.948, 0.944 and 0.942 on 23/04/1995. Extending the analysis to the most entropic municipalities, one finds mostly town and villages belonging to the Molise region.The minimum entropic municipality in the Regional ballots is Sizzano with zero entropy obtained on 16/04/2000. It is quite an interesting case because Sizzano had 1266 potential voters, 972 of them showed up at the cabinets and all of them spoiled the votes  or left voting papers white. To find some ideas for justifying such a behaviour, see . The autThe lowest entropic municipalities just before Sizzano are Castelpizzuto with 0.095 on 8/06/1980, Morterone with 0.11 on 8/6/1980 and, finally, Aquila di Arroscia with 0.116 on 7/6/1970. They all referred to quite old ballots.Talking about the Italian parliamentary elections (Chamber of Deputies), the three highest positions for their entropy levels are held by Saint-Pierre, Cogne and Saint-Denis  with one obtained on 19/05/1968. Interestingly, all the top 10 positions are held by towns from Valle d’Aosta, which got their outcomes on 19/05/1968 or 28/4/1963.The Chamber of Deputies ballot has zero as the minimum level of entropy. It is reached by Valsavarenche  and Massa di Somma on 14/06/1987 (no data available), Staiti , Santa Maria la Carità (there is no data for 3/06/1979) and Spera, where all the 303 valid votes have been expressed in favour of “Democrazia Cristiana” on 18/04/1948.The Senate of the Republic ballots present a maximum entropy in Saint-Pierre with one obtained in 1968. It is followed by other towns from the Italian’s northern regions . These municipalities got high levels of entropies (around one) during the 1948, 1968 and 1996 elections.The Municipality with the maximum entropy for the European election is Salza di Pinerolo 13/06/1999 with 0.93. Then Ribordone with 0.899 in 13/06/1999 followed by Noasca and Issiglio with 0.897 and 0.894, respectively, all of them on 13/06/1999. It is interesting to notice that all of them belong to the Piemonte region and they have a population below 500 people. The lowest entropy level for the European election occurs in the Trentino Alto Adige region, in a small town, during the 1979 and 1984 elections. The municipalities are Selva dei Molini with 0.035, Terento with 0.042 and Verano with 0.042 as well. All the first lowest level of entropies are held by municipalities of Trentino Alto Adige.The summary of the results are presented in Table 4, columns G. Their comparison with the columns H can be consistently done jointly with a visual inspection of Figures 4–6. These graphs report the b-ary entropy (upper) and adjusted Gini (lower) along the years for the European elections, Chamber of Deputies and Senate of the Republic. As already mentioned, the other types of democratic calls are not suitable for representing the phenomenon along the years because certain ballots have partially involved the country.n-th electoral turn.To verify the validity of outcomes presented in With European and Municipal (5 times);Chamber of Deputies and Senate of the Republic (18 times);Chamber of Deputies and Regional, Senate of the Republic with Regional (2 times each couple);Chamber of Deputies and Provincial, Senate of the Republic and Provincial (once per each couple);Chamber of Deputies and Municipal, Senate of the Republic and Municipal (2 times each couple);Regional and European (once), Regional and Provincial (2 times), Regional and Municipal (6 times);Provincial and European (2 times), Provincial and Municipal (9 times).To compare the entropy distributions calculated with parties’ performances at the municipality level, we have run a Kolmogorov–Smirnov test for each couple of contemporaneous elections. The compared ballots along the years are:Every date in which there have been overlapping elections and the municipalities involved were less than 100 have been removed from the analysis . Such a distinction is particularly useful when the local elections  are compared to European or National. If one does not consider just the intersection, spatial effects/biases could be introduced. It is important to remark that in the “Intersection” comparisons, if the resulting number of common municipalities is inferior to 100, the KS test has not been performed. Anyway, in the paper, we report just the comparison for the interception.For example, in the recent ballot of 04/03/2018, when the The 10 highest and lowest KS statistics with their respective information in Table 3. It is interesting to notice the number of times local elections are involved in the highest KS statistics subtable. In most of the cases, the Municipal elections are involved introducing the main source of difference. Indeed, on the other hand, looking at the lowest KS statistics list , it is immediately clear that the closest distributions are those coming from the entropic behaviours of the Chamber of Deputies and Senate of Republic voters.“Mani Pulite” [The comparison between the Chamber of Deputies and Senate of Republic is the most common. Indeed, Italy has a bicameral system and the respective offices have always been filled thanks to democratic calls that occurred on the same days.  Pulite” ,57.n-th electoral turn.To compare the outcome coming from the two measures in each ballot, we have calculated the Pearson correlation between the b-ary entropy levels and the adjusted Gini in each election.The correlation is statistically significant at the 5% of confidence level in almost all the cases . FurtheIn addition, based on the figures presented in Municipal—The highest entropies are recorded in the northern Italian area, most of them in recent elections, namely between 1995 and 2016. The minimum entropy level is zero and many municipalities resulted with it. For example, San Didero, Bosio and Berzano di Tortona are very small villages where the citizens have voted for the unique party in competition. Most of the cases having zero entropy are like these. Others are affected by different voters behaviours, e.g., all made invalid their votes or data issues.Provincial—The highest levels of entropy have occurred in central-northern regions mainly during the 2009 and 2004 elections. The towns involved are all quite small apart from Bologna. The 10 municipalities with the lowest levels of entropy are small and they recorded such results during the 2009 and 2004 elections. This is due to the high variability within the country.Regional—Such cases present a different situation. The 10 highest entropies are obtained by municipalities of centre-south of Italy involved in the elections of 2011 and 1995. The lowest levels are again obtained from municipalities characterized by low population, the results of which have been mainly obtained in 1970 and 1980.Chamber of Deputies—The most entropic municipalities belong to Valle d’Aosta region and they are all very small. Their entropy values have been recorded during the 1968 and 1963 elections. There are six small municipalities with entropy equal to zero. They are peculiar cases of missing data, votes wrongly expressed or spoiled, as happened in the other cases.Senate of the Republic—The highest position is held by Saint-Pierre, which is the same town having the first position for the Chamber of Deputies. The other municipalities occupy the first 10 positions because their entropic figures come from the northern area. The elections involved are 1948, 1968 and 1996.European—The most entropic municipalities are tiny and they belong to the Piemonte region. Their electoral outcomes come from the 1999 election. The 10 municipalities with the lowest entropies come from the north of Italy, specifically from Trentino Alto Adige region. The towns in this case are slightly bigger and their results have been collected during two elections: 17/06/1984 and 10/6/1979.One can see that the elections’ entropies at the municipality level presents some trends or paths that open different research questions, for example, has found a relationship between the Italian political instability in December 2011–January 2012 and during February 2013 , and theTalking about the contemporaneous elections, the most interesting part of the analysis to be commented is the one performed over the interception of municipalities across the synchronised elections. Most of the highest statistics in Between the highest KS statistics of Concluding, the entropic analysis on the votes at the municipality level allows looking at the electoral results from a different perspective, highlighting salient facts and trends in the manifested chaos from the voters’ preference expressions. The specific focus on the concurrent elections by using the Kolmogorov–Smirnov test permits to measure the magnitude of the different disorder realized over the years, it consents to capture differences between National and local ballots dynamics and to capture heterogeneity within the country.


This narrative review describes an overview of the multiple effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD) and its potential neurobiological targets. It addressed the following aspects: 1) MPH effects on attention and executive functions in ADHD; 2) the relation between MPH efficacy and dopamine transporter gene (DAT) polymorphism; and 3) the role of MPH as an epigenetic modulator in ADHD. Literature analysis showed that MPH, the most commonly used psychostimulant in the therapy of ADHD, acts on multiple components of the disorder. Marked improvements in attentional and executive dysfunction have been observed in children with ADHD during treatment with MPH, as well as reductions in neurological soft signs. MPH efficacy may be influenced by polymorphisms in the DAT, and better responses to treatment were associated with the 10/10 genotype. Innovative lines of research have suggested that ADHD etiopathogenesis and its neuropsychological phenotypes also depend on the expression levels of human endogenous retrovirus (HERV). In particular, several studies have revealed that ADHD is associated with HERV-H over-expression and that MPH administration results in decreased expression levels of this retroviral family and a reduction in the main symptoms of the disorder. In conclusion, there is a confirmed role for MPH as an elective drug in the therapy of ADHD alone or in association with behavioral therapy. Its effectiveness can vary based on DAT polymorphisms and can act as a modulator of HERV-H gene expression, pointing to targets for a precision medicine approach. Attention-deficit/hyperactivity disorder (ADHD) represents one of the most common neurodevelopmental disorders with onset in early childhood, high heritability and documented brain abnormalities . ADHD isSince the 1990s, neuroimaging studies , 6 and gA variable number of tandem repeats (VNTR) in the DAT 3’-untranslated region (3’UTR) has been the most investigated polymorphism of this gene. The three most common alleles are represented by the 10/10 genotype, 9/10 genotype, and 9/9 genotype, and each has been reported with differential gene expression, influencing DAT availability , 15. StuThis narrative review addresses the following aspects: 1) MPH impact on attention and executive functions (EFs) in ADHD; 2) the relation between MPH efficacy and DAT polymorphism; and 3) the role of MPH as an epigenetic modulator in ADHD. We decided to perform a narrative review because our aim was to focus on precision medicine approaches and available studies did not permit to reach this goal with a systematic review.Sustained attention is the capacity to direct attention to one or more sources of information over a relatively long and unbroken period of time; vigilance, as a type of sustained attention, is the ability to maintain attention over a prolonged period during which infrequent response-demanding events occur –24. SeleAttentional functions are mediated by several cortical and subcortical networks; however, the processing of specific functions is related to specific brain regions. Alertness functions are supported by the reticular formation, dorsolateral prefrontal cortex and inferior parietal cortex . The retAttentional dysfunction is one of the main symptoms of ADHD. Regarding attention deficits, parents and teachers say that patients with ADHD have difficulties concentrating, paying attention to details and sustaining attention for a prolonged period of time . DisturbSonuga-Barke and Castellanos postulated that deficient regulation of the default network by cognitive and attention networks highlights intrusions in their interplay that manifest as phasic lapses of attention or in impulsive behaviors . This hySeveral studies have shown that DA and norepinephrine participate in the processes of attention and inhibition , 43, andMPH treatment has been shown to decrease reaction time and its variability  and to iTaken together, these studies underscore MPH positive effects on the attentional functioning of patients with ADHD , 56. HowEFs refer to a set of mental control cognitive processes that permit the use of goal-directed behaviors and are represented by five main domains: response inhibition, planning, working memory, verbal fluency, and cognitive flexibility/shifting , 58. ThiEFs have been conceptualized as a means of behavioral self-regulation that modulates behavior in a manner that is adaptive to the dynamic contexts of the situation at hand . NeuroanIn addition to the three main clinical symptom dimensions , children with ADHD also exhibit executive functioning deficits , 71, andIt is known that the VNTR in the 3’UTR of DAT may influence the variability in the therapeutic response to MPH in individuals with ADHD , 80. In Neurological soft signs (NSSs) have been interpreted as minor neurological abnormalities in motor, sensory, and integrative functions . Some auNSS are mainly represented by overflow movements (OMs) and dysrhythmia. OMs are defined as co-movements of body parts not specifically needed to efficiently complete a motor task . There aOMs likely reflect dysfunction within motor and premotor circuits that are important for the preparation and execution of motor responses . A functA study on the correlation between NSS and attentional dysfunction revealed that patients with ADHD were impaired in several attentional processes and reported a greater number of NSS compared to healthy children. Moreover, significant correlations between disturbances in attention and motor abnormalities were described in the clinical sample. Indeed, deficits in alertness (in terms of increased variability in reaction time) and sustained attention (in terms of an increase in reaction time and number of omission errors) interfered with speed-timed activities. Dysfunction of selective attention (in terms of increased number of omission errors) and divided attention  significantly correlated with dysrhythmia. Impairments in sustained attention (in terms of increased number of omission errors) significantly correlated with OM. Taken together, these results suggested that attentional processes could be involved in the pathophysiology of NSS .MPH treatment has been associated with the improvement or complete resolution of NSS and, in particular, of OM in patients with ADHD . It is kThe persistence of OM in patients with ADHD supports the hypothesis that the brain abnormalities in children suffering from this disorder have a developmental origin. Oligodendroglial abnormalities may be due to dysfunction of the DA system . MPH theHuman endogenous retroviruses (HERVs) represent remnants from ancient germ line infections with exogenous retroviruses. During evolution, HERVs were amplified and spread throughout the human genome by repeated events of retrotransposition and/or reinfection, and they are integrated as provirus in chromosomal DNA . Their iin vitro, HERV-H expression increased, while no changes in the expression levels were found in ADHD patients undergoing therapy. This suggests that MPH could affect HERV-H activity .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.