What are recent trends in adult attention-deficit/hyperactivity disorder (ADHD) prevalence and incidence among racial and ethnic groups in the United States?In this cohort study of 5 282 877 patients who identified as African American or black, Native American, Pacific Islander, Latino or Hispanic, non-Hispanic white, Asian American, or other and were cared for at Kaiser Permanente Northern California, the annual adult ADHD prevalence and incidence rates significantly increased over a 10-year period for every race/ethnicity except Native American; rates remained highest among white patients throughout. The presence of other psychiatric diagnoses was found to be a major factor associated with likelihood of adult ADHD diagnosis.The prevalence and incidence of adults diagnosed with ADHD are increasing, although pronounced racial/ethnic inequalities in rates of diagnosis remain. This cohort study examines trends, including associated demographic characteristics, psychiatric diagnoses, and negative outcomes, in the prevalence and incidence of attention-deficit/hyperactivity disorder (ADHD) diagnosis among 7 racial/ethnic groups in the United States during a 10-year period. An increasing prevalence of adult attention-deficit/hyperactivity disorder (ADHD) diagnosis and treatment has been reported in clinical settings and administrative data in the United States. However, there are limited data on recent trends of adult ADHD diagnosis among racial/ethnic subgroups.To examine trends, including associated demographic characteristics, psychiatric diagnoses, and negative outcomes, in the prevalence and incidence of adult ADHD diagnosis among 7 racial/ethnic groups during a 10-year period.This cohort study investigated trends in the diagnosis of ADHD in adults who identified as African American or black, Native American, Pacific Islander, Latino or Hispanic, non-Hispanic white, Asian American, or other using the Kaiser Permanente Northern California health plan medical records. A total of 5 282 877 adult patients and 867 453 children aged 5 to 11 years who received care at Kaiser Permanente Northern California from January 1, 2007, to December 31, 2016, were included. Data analysis was performed from January 2017 through September 2019.Period of ADHD diagnosis.Prevalence and incidence of licensed mental health clinician–diagnosed ADHD in adults and prevalence of licensed mental health clinician–diagnosed ADHD in children aged 5 to 11 years.P < .001), male sex , white race , being divorced , being employed , and having a higher median education level  were positively associated with odds of ADHD diagnosis. Having an eating disorder , depressive disorder , bipolar disorder , or anxiety disorder  was associated with higher odds of receiving an ADHD diagnosis. Adults with ADHD had significantly higher odds of frequent health care utilization  and sexually transmitted infections  compared with adults with no ADHD diagnosis.Of 5 282 877 adult patients , 59 371 (1.12%) received diagnoses of ADHD. Prevalence increased from 0.43% in 2007 to 0.96% in 2016. Among 867 453 children aged 5 to 11 years , prevalence increased from 2.96% in 2007 to 3.74% in 2016. During the study period, annual adult ADHD prevalence increased for every race/ethnicity, but white individuals consistently had the highest prevalence rates . Incidence of ADHD diagnosis per 10 000 person-years increased from 9.43 in 2007 to 13.49 in 2016. Younger age (eg, >65 years vs 18-24 years: odds ratio [OR], 0.094; 95% CI, 0.088-0.101; This study confirmed the reported increases in rates of ADHD diagnosis among adults, showing substantially lower rates of detection among minority racial/ethnic subgroups in the United States. Higher odds of negative outcomes reflect the economic and personal consequences that substantiate the need to improve assessment and treatment of ADHD in adults. The growing number of negative outcomes associated with ADHD in adulthood  highlight the importance of detecting and treating the disorder. However, questions remain about the diagnostic process and true prevalence of ADHD among adults as well as factors that may impede its detection.Interest in the phenomenology and continuity of attention-deficit/hyperactivity disorder (ADHD) across the life span has been increasing. Initially motivated by findings of clinical symptoms of ADHD in adults with minimal brain dysfunction,5 was 2.8%, with greater rates in higher-income countries. Prevalence estimates of ADHD in nationally representative household surveys of adults in the United States were 5.2% in the National Comorbidity Survey Replication6 and 2.5% for the combined subtype of ADHD in the National Epidemiologic Survey on Alcohol and Related Conditions.7 The consistency in sociodemographic correlates of adult ADHD in the 2 community surveys of nationally representative samples of adults in the United States8 provides a basis to investigate disparities in the recognition and treatment of ADHD in clinical settings; specifically, male sex, higher education level, divorced marital status, and non-Hispanic white race/ethnicity have been associated with a greater likelihood of diagnosis in 1 or more studies.8Estimates of the prevalence of ADHD in adults have been derived from community and clinical samples. The aggregate prevalence of ADHD in adults in 20 countries from the World Mental Health Surveys10 employer health insurance,11 Medicaid,12 and primary care.13 These studies have demonstrated consistent increases in the number of adults in the United States diagnosed with and treated for ADHD. In the largest study of a nationally representative sample of primary care physicians, Fairman et al13 reported a 36% increase in the prevalence of ADHD between 2008-2009 and 2012-2013. A parallel increase has been documented in the Scandinavian registries, a setting in which patients have universal health care,15 so the increase is unlikely to be attributable solely to changes in health insurance coverage.The cross-sectional nature of household surveys precludes exploration of time trends in the magnitude of adult ADHD. Instead, indirect estimates of ADHD prevalence and time trends in the United States have been derived from administrative databases, including managed care settings,9 Additionally, few studies have considered differences in diagnostic trends observed among a broad range of racial/ethnic groups. We evaluated the electronic medical record system of Kaiser Permanente Northern California (KPNC) for the period of January 1, 2007, to December 31, 2016, to quantify trends in the prevalence and incidence of ADHD diagnosis in adults among 7 racial/ethnic groups. Specifically, we tested the following hypotheses: (1) that diagnosis of ADHD in adults is increasing, possibly at a higher rate than among children aged 5 to 11 years, (2) that significant differences in prevalence and incidence by sex and race/ethnicity persist, (3) that diagnosis of ADHD in adults is associated with other diagnosed mental disorders, and (4) that ADHD is negatively associated with selected health outcomes.Despite growing insight into adult ADHD in the general population, it has been difficult to comprehensively characterize trends in the diagnosis and treatment of ADHD among adults because of differences in sampling and methods. Studies differ markedly in design and sample characteristics and have used divergent diagnostic methods and criteria for ADHD, ranging from formal categorical approaches to dimensional symptom checklists.16 Medical records were used to extract demographic and clinical information, including age, sex, race/ethnicity, marital status, occupational status, medical diagnoses from outpatient and inpatient visits, and pharmacy use. Median family household income and education level were not directly available, so census tract–based median family household income and education level were calculated based on the 2010 US Census and 2006-2010 American Community Survey. The study design was reviewed and approved by the KPNC Region institutional review board, including a waiver of informed consent because the research involved no more than a minimal risk to participants. Our report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.Kaiser Permanente Northern California is a large, integrated health care delivery system that provides comprehensive medical care to more than 4 million individuals. The population of KPNC members is generally representative of the overall regional population, although income distribution extremes may be underrepresented.International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes (314.x) and ICD-10 diagnostic codes (F90.x). Diagnosis of ADHD in the KPNC system is typically based on the following: medical history; chief or presenting concerns; mental status examination; and functional ability and structured clinical interview by a qualified, licensed mental health clinician. For those newly diagnosed as adults, childhood onset of symptoms must be reported. In pilot work with 50 participants conducted in preparation for the study, 47 adults (94%) diagnosed with ADHD during the study period were assessed by a licensed psychiatrist, psychologist, or psychiatric nurse practitioner and were subsequently treated with ADHD medications. To facilitate comparison with other databases and to determine the specificity of trends in adults, we also obtained medical records for children aged 5 to 11 years to estimate corresponding prevalences.The primary study cohort consisted of 5 282 877 adult patients who received care at KPNC between January 1, 2007, and December 31, 2016. We identified ADHD diagnoses from electronic medical records of inpatient and outpatient encounters based on 17Covariates included sex, age, race/ethnicity, census tract–based median family household income and education level, marital status, employment status, health care utilization, and psychiatric and physical comorbidities. Race/ethnicity was self-identified as 1 of the following: African American or black (black), American Indian or Alaska Native (AIAN), Native Hawaiian or other Pacific Islander (NHPI), Latino or Hispanic (Hispanic), non-Hispanic white (white), Asian American (Asian), or other. Psychiatric comorbidities were identified based on diagnostic codes from outpatient and inpatient visits. We calculated a dichotomous variable for whether participants had 1 or more health care visits (inpatient or outpatient) per year during the study period as a measure of health care utilization.18 we examined health care utilization as defined earlier. Second, motivated by consistent reports of increased accidental injury rates among individuals with ADHD,19 we examined whether participants with ADHD were more likely to have frequent emergency department (ED) visits . Finally, findings from a 2018 national longitudinal cohort reaffirmed prior assertions that STIs are more frequent in individuals with ADHD.20 Therefore, we used ICD-9 or ICD-10 codes to examine differences in the proportion affected by 1 or more STI diagnosis during the study period.Although not a primary focus, 3 measures of negative associations of ADHD were selected to reflect adverse consequences identified in the adult ADHD literature. First, given prior reports of increased frequency of physical health problems,We estimated annual prevalence rates for diagnosis of ADHD in adults and children by race/ethnicity for each year in the study period (2007-2016). The Cochran-Armitage trend test was performed to demonstrate changes of annual prevalence rates over time by race/ethnicity during the study period.21 We also included pervasive developmental disorders, eating disorders, and psychotic disorders, which have also been associated with ADHD.24 Models containing adjustment for psychiatric diagnoses were assessed for multicollinearity; all variance inflation factors were less than 3.5, indicating that multicollinearity was not a concern. Finally, we examined associations of ADHD diagnosis with negative associations, including frequent ED use, greater health care utilization, and STI diagnosis, using logistic regression with prevalent ADHD diagnosis as the independent variable.Univariate and multivariable logistic regression analyses were conducted to estimate odds ratios (ORs) for prevalent ADHD diagnosis by demographic factors, including sex, race/ethnicity, age, area-based median household income, area-based median education level, marital status, employment status, and health care utilization. Multivariable logistic regression models were used to assess the association of other psychiatric diagnoses, occurring at any time during KPNC enrollment, with prevalent ADHD diagnosis. These included depressive disorder, bipolar disorder, substance use disorder, and personality disorder, which are among the most frequent comorbidities in adults with ADHD.ICD diagnostic codes were required to be the first on record since enrollment. Members with less than 2 years of continuous enrollment before their index ADHD diagnosis were excluded from incidence calculation. Univariate and multivariable Cox proportional hazard regression analyses were conducted to estimate hazard ratios for developing incident ADHD according to the demographic factors listed earlier as well as other psychiatric diagnoses during KPNC enrollment.For supplemental analyses, we estimated annual incidence (cases per 10 000 person-years) for diagnosis of ADHD by race/ethnicity for each year in the study period (2007-2016). The Cochran-Armitage trend test was performed to demonstrate changes of annual incidence rates over time by race/ethnicity during the study period. To calculate incidence rate, the P < .05 was considered statistically significant, and all tests were 2-tailed. A total of 1 609 723 participants (30.47%) were missing information on census tract income and education, 1 625 722 (30.77%) were missing information on marital status, and 2 845 824 (53.87%) were missing information on employment status, all of which were handled via the missing indicator approach.Statistical analyses were performed using SAS version 9.3 (SAS Institute). Analysis was performed from January 2017 through September 2019. To evaluate the extent to which the trends observed were specific to adults and to facilitate comparison with other samples, we examined prevalence in children aged 5 to 11 years treated at KPNC during the same period . Among tP < .001; patients aged >65 years: OR, 0.094; 95% CI, 0.088-0.101; P < .001); lower among women than men ; lower among members of all nonwhite racial/ethnic groups compared with white patients ; higher among patients who were divorced or separated compared with patients who were single ; lower among retired and unemployed persons and those with unknown employment status compared with employed individuals  but higher among students ; higher among those living in census tracts with a higher median household income compared with those living in census tracts with a median household income under $30 000 ; and higher among those living in census tracts with more residents with a college degree compared with those living in census tracts with less than 25% of residents with a college degree . These associations were generally similar in direction in the multivariable model, with variation in magnitude. However, after adjustment, being a student was negatively associated with diagnosis , and odds were slightly lower and the association was not significant for those in census tracts with higher median income levels compared with the lowest category .P < .001), bipolar disorder , depressive disorder , personality disorder  and anxiety disorder . When comorbidities were further adjusted (model 2), all associations were reduced in magnitude . Psychotic disorders  and personality disorders  were associated with lower odds of diagnosis of ADHD, while pervasive development disorders were not associated with ADHD diagnosis  (P = .31) .P < .001; health care utilization: OR, 1.812; 95% CI, 1.770-1.854; P < .001; STI diagnosis: 1.766; 95% CI, 1.715-1.818; P < .001). After additional adjustment for psychiatric comorbidities, all 3 associations were still statistically significant but reduced in magnitude. Those with ADHD still exhibited greater health care utilization  and higher odds of STI diagnosis  but had lower odds of ED visits .The number of incident cases of ADHD and person-years of observation among the 5 282 877 adult KPNC members identified from January 1, 2007, through December 31, 2016, according to demographic characteristics and negative outcomes, appear in eTable 1 in the P < .001; unemployed persons: adjusted OR, 1.323; 95% CI, 1.280-1.368; P < .001).Using incident cases of ADHD diagnosis, eTable 2, eTable 3, and eTable 4 in the 25 This global increase in rates of ADHD cannot be attributed to country-specific insurance coverage or health care service systems. Rather, it could reflect increasing recognition of ADHD in adults by physicians and other clinicians as well as growing public awareness of ADHD during the decade under study. The lack of increase in ADHD in youth in our sample is consistent with results from a 2014 meta-analysis.26 Our data cannot address whether the trends in our study reflect valid diagnoses, increased treatment seeking for ADHD among adults, and/or increased recognition by clinicians in the KPNC system. There are many challenges to diagnosing ADHD in adults compared with the well-established definitions and assessments in youth.The increase in rates of ADHD in adults in our sample confirms the results of several other large studies of both community and primary care samples in US and Scandinavian registries.13 and with estimates of clinician diagnosis in the National Comorbidity Survey Replication.6 Similar findings show lower rates of mood disorders in racial/ethnic minority adults in several US community surveys.27White adults in this study consistently had the highest rates of ADHD throughout the study period, while Asian and NHPI adults had the lowest rates. This pattern was especially apparent for adult ADHD prevalence  and is c28 The pattern we observed in adults mimics our findings in children aged 5 to 11 years in KPNC as well as those of a prior study of children of the same age enrolled in Kaiser Permanente of Southern California,29 which reported that ADHD prevalence in Asian and Pacific Islander patients  was low compared with white patients . However, the lower rates of ADHD in black adults in our sample were not evident in black youth, in whom ADHD prevalence approached that of white individuals by the end of the study period.A possibility is that the greater prevalence of ADHD in white adults could be a true finding.30 Racial/ethnic background is known to play an important role in opinions on mental health services, health care utilization,31 and physician preferences.32 In addition, rates of diagnosis-seeking to obtain stimulant medication for nonmedical use may be more common among white vs nonwhite patients.33 Ethnic disparities could also be caused by differences in detection or attribution of ADHD symptoms in racial/ethnic minorities, although evidence for this type of bias is mixed.36 Finally, cultural influences on the manifestation or expression of ADHD could lead to racial/ethnic variation in rates.37Racial/ethnic differences could also reflect differential rates of treatment seeking or access to care. Because this study was conducted using KPNC data, differences in treatment access related to insurance status should be obviated, although other enabling resources may be unequally distributed.38 Our findings of increasing risk of ADHD diagnosis in those living in census tracts with higher median levels of education and of the highest risk of ADHD diagnosis in those identified as students may reflect that some individuals are seeking diagnosis and treatment for purposes of cognitive enhancement.Pharmacological cognitive enhancement with prescription and illegal stimulants among individuals not diagnosed with ADHD has been noted to be increasing.5 17.7% of adults with ADHD also met criteria for 3 or more other classes of mental disorders. This highlights the importance of ADHD as a multisystem disturbance that requires comprehensive assessment, irrespective of the primary condition that led to treatment entry. Treatment of ADHD in the context of comorbid conditions also requires further consideration. Use of stimulant medications without recognition of comorbid bipolar disorder or anxiety could lead to their exacerbation. Further, our finding of increased STI diagnosis among those with ADHD, even after adjustment for comorbidities, confirmed the findings of a 2018 population-based study in Taiwan20 and has clear preventive implications.Our results regarding comorbidity with ADHD across all diagnostic categories were consistent with patterns of comorbidity in large community-based samples. In the World Mental Health Surveys,A major challenge in the diagnosis of ADHD in adults is that the assessment typically relies on retrospective informant self-report. Additionally, when assessed in youth, ADHD is often the primary condition, whereas in adults, comorbid illnesses can obfuscate the attribution of symptoms to ADHD. Moreover, consequences of ADHD  can also complicate the clinical picture. This highlights the need for comprehensive assessment of adults with ADHD that focuses on the overlap of its core features with those of other conditions as well as a detailed history of the evolution and consequences of ADHD. Another distinction between adult and childhood ADHD lies in the pathways to identification. Whereas adults may recognize their own symptoms and seek treatment, youth are more likely to undergo evaluation because of recognition by a parent or teacher. Adult vs child ADHD diagnoses also differ in symptom thresholds (5 vs 6) that might affect diagnostic sensitivity and specificity in delineating ADHD from other forms of illness.16 However, the consistency of our findings with those from other regions, countries, and health care systems increased confidence in their generalizability. As noted earlier, because this is a study of administrative incidence and prevalence, we were unable to distinguish true differences in disorder rates from differences in rates of treatment. Population-based longitudinal studies of ADHD in adults would be helpful in addressing this issue.While the scale of the KPNC sample used in the present work is unprecedented, a key limitation is that it is derived from a single health care system in a specific US region. Of note, prior comparisons of residents of Northern California who participate in the KPNC system with those who do not found them highly comparable, although a lower percentage of non-Hispanic white individuals and very low-income participants were present in the KPNC system.Despite these limitations, we confirmed increasing rates of ADHD diagnosis among adults over a 10-year period, albeit with substantially lower rates of detection among the major racial/ethnic subgroups in our sample. Irrespective of the explanations for racial/ethnic differences in ADHD diagnoses, our findings suggest 2 important future efforts to bridge gaps in recognition, diagnosis, and treatment of ADHD in racial/ethnic subgroups. First, there should be an increased focus on careful, unbiased, structured screening and documentation of symptoms across development, especially as the field attempts to further delineate the temporal precedence of ADHD, patterns of comorbidity, and its consequences. Second, greater consideration must be placed on cultural influences on health care seeking and delivery, along with an increased understanding of the various social, psychological, and biological differences among races/ethnicities as well as culturally sensitive approaches to identify and treat ADHD in the total population.


PPARGC1A) are considered biomarkers for mitochondrial dysfunction. We compared the mtDNA copy number and methylation ratio of the D-loop region and PPARGC1Abetween ADHD patients and controls and also among ADHD subtypes. The present study included 70 subjects with ADHD and 70 age- and gender-matched healthy controls (HCs). We measured the relative mtDNA copy number in peripheral blood cells using quantitative polymerase chain reaction (qPCR), and the methylation ratio was measured using methylation-specific PCR (MSP) after bisulfite conversion. The relative mtDNA copy number was significantly higher in ADHD patients than in HCs (p = 0.028). The mtDNA methylation ratio of PPARGC1A was decreased in ADHD patients compared with HCs (p = 0.008). After adjusting for IQ level, only the mtDNA copy number differed between the ADHD and HCs (p = 0.01). There was a significant difference in the methylation ratio of PPARGC1Aamong ADHD subtypes. These results suggest the possible involvement of mitochondrial dysfunction in the pathophysiology of ADHD. Further large cohort studies investigating the correlation between clinical markers and biomarkers of mitochondrial dysfunction are warranted.The involvement of mitochondrial dysfunction in the pathophysiology of attention-deficit hyperactivity disorder (ADHD) has been suggested in several reports. Mitochondrial DNA (mtDNA) copy number as well as methylation of the D-loop region and peroxisome-proliferator-activated receptor γ co-activator-1α ( Attention-deficit hyperactivity disorder (ADHD) is a highly prevalent and persistent neurodevelopmental disorder characterized by developmentally inappropriate symptoms of inattention, hyperactivity, and/or impulsivity . ADHD haReportedly, mitochondrial dysfunction is involved in the pathogenesis of various psychiatric disorders –7. MitocSeveral recent studies showed that mitochondrial dysfunction underlies ADHD pathogenesis. In one previous study, lower mitochondrial respiration, lower ATPase 6/8 transcripts levels, reduced mitochondrial complex V activity, loss of mitochondrial membrane potential, and elevated oxidative stress in ADHD cybrids were reported . AnotherMitochondria contain their own genome, i.e., the mitochondrial DNA (mtDNA), which encodes essential subunits of the respiratory chain wherein electrons are combined with oxygen to allow the flow of energy through mitochondria . MtDNA iPPARGC1A) is a co-transcriptional regulation factor involved in the induction of mitochondrial biogenesis. It activates several transcription factors like the nuclear respiratory factor 1 and nuclear respiratory factor 2, which in turn activate mitochondrial transcription factor A  is a non-coding region that acts as a promoter of both the heavy and light strands of mtDNA and contains essential transcription and replication elements . The D-lfactor A . The latfactor A . The metPPARGC1A were compared between ADHD subjects and healthy controls (HCs). We used an age- and gender-matched sample to control for biases caused by age and gender. We hypothesized that 1) the mtDNA copy number would be increased and 2) the methylation ratios of the D-loop region and PPARGC1A would be decreased in the ADHD group, leading to increased gene expression to compensate for mitrochondrial dysfunction.In this study, the mtDNA copy number and methylation ratios of the D-loop region and Kim et al.  providesDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria using the Korean Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version (K-SADS-PL)  , 28. ExcSADS-PL) .We used the parent-report Korean version of the ADHD Rating Scale-IV (ADHD-RS) to assess the severity of ADHD symptoms . The ADHWritten informed consent was obtained from legal guardians and adolescent participants; child participants provided verbal consent after thorough explanation of the study. All study protocols were reviewed by the Institutional Review Board of Seoul National University Hospital, Seoul, Korea.−∆∆Ct (∆Ct = CtmtDNA CYTB − CtPK) according to a previous report , and the single-copy nuclear pyruvate kinase (PK) gene, respectively. The relative amounts of mtDNA and nuclear DNA were measured using quantitative polymerase chain reaction (qPCR) with the primers reported by Yoo et al. . The pris report .PPARGC1A promoter and D-loop region of mitochondria. The methylated or unmethylated DNA was quantified using primers of the PPARGC1A promoter and D-loop regions, as described by Sookoian et al. .Genomic DNA (200–500 ng) was prepared for bisulfite conversion according to the manufacturer’s instructions (EpiJET Bisulfite conversion kit). The technique was based on bisulfite treatment of genomic DNA, which converts all unmethylated cytosines to uracils, whereas methylated cytosines remain as cytosines. The bisulfite-converted DNA was used as the template for methylation-specific polymerase chain reaction (MSP) to determine the DNA methylation state of n et al.  and Zhenn et al. , respectn et al. , 34. Thet-tests for continuous variables and chi-square or Fisher’s exact tests for categorical variables were used for comparison of the demographic and clinical characteristics between the ADHD and HC groups.Independent PPARGC1A gene promoter, and the methylation ratio of the D-loop region between the ADHD and HC groups was performed using Mann–Whitney U tests and also among ADHD subtypes using Kruskal–Wallis tests because the variables did not follow a normal distribution. As there was a significant difference in IQ score between the ADHD and HC groups, we applied ranked ANCOVA to compare the mtDNA copy number, the methylation ratio of PPARGC1A gene promoter, and the methylation ratio of the D-loop region between the two groups. Linear regression analyses were conducted to investigate the association between mitochondrial biomarkers and ADHD-RS variables, with IQ as a covariate. All statistical analyses were performed using SPSS  and Prism 7 software . Statistical significance was set at a probability level of p < 0.05.Comparison of the mtDNA copy number, the methylation ratio of p < 0.001), but these were compensated for in the analyses by our age- and gender-matched sample. The demographic and clinical characteristics of the age- and gender-matched ADHD and HC groups are presented in p = 0.028; PPARGC1A promoter region , but there was no significant difference in the DNA methylation ratio of the PPARGC1A promoter region and the D-loop region.The mtDNA copy number in the blood samples was significantly increased in the ADHD group compared with the HC group . There was a significant difference in the methylation ratio of the PPARGC1A promoter region among ADHD subtypes . These results remained significant when excluding the not-otherwise specified subtype (p = 0.019). No significant associations were observed between mitochondrial biomarkers and variables of ADHD-RS . In several reports, the mtDNA copy number was increased in the peripheral blood of ASD patients . Bioener2O2), which suppresses striatal dopamine release  funded by the Ministry of Science, ICT, and Future Planning (NRF-2015R1A2A2A01004501 to J-WK); by the Promising-Pioneering Researcher Program through Seoul National University (SNU) in 2015 to J-WK; by a National Research Foundation of Korea (NRF) grant funded by the Korean government : and by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean Government (MSIT) (2019M3E5D1A01069345).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.


Internet addiction (IA) has emerged as a public health concern, particularly among adolescents and young adults. However, few studies have been conducted in medical students. This multi-center study aimed to investigate the prevalence of IA in Chinese medical students, to examine the associations of big five personality traits with IA in the population, and to explore the possible mediating role of attention-deficit/hyperactivity disorder (ADHD) symptoms in the relationship.Self-reported questionnaires, including Internet Addiction Test (IAT), Big Five Inventory (BFI), Adult ADHD Self-Report Scale-V1.1 (ASRS-V1.1) Screener, and socio-demographic section were distributed to clinical students at 3 medical schools in China. A total of 1264 students became the final subjects.The overall prevalence of IA among Chinese medical students was 44.7% (IAT > 30), and 9.2% of the students demonstrated moderate or severe IA (IAT ≥ 50). After adjustment for covariates, while conscientiousness and agreeableness were negatively associated with IA, neuroticism was positively associated with it. ADHD symptoms mediated the associations of conscientiousness, agreeableness and neuroticism with IA.The prevalence of IA among Chinese medical students is high. Both personality traits and ADHD symptoms should be considered when tailored intervention strategies are designed to prevent and reduce IA in medical students. The past two decades has witnessed a tremendous growth of global Internet users, with the figure increasing substantially from 0.4 billion in 2000 to 4.2 billion in 2018, and half of its current users are located in Asia , charactIA has emerged as an important issue in the fields of public health and psychiatry. Given the psychological and developmental characteristics, university students are particularly susceptible to IA . Recent Personality traits can predict one’s behaviors, and it has been consistently found that they are associated with IA in different populations and cultures , 19, 20.Attention-deficit/hyperactivity disorder (ADHD), traditionally considered a childhood disorder, can persist into adulthood for approximately two-thirds of affected children and adolescents . Two corIn terms of the relations between big five personality traits and ADHD symptoms, the results are mixed. Using different assessment tools for Big Five and ADHD symptoms, Nigg et al. demonstrated that ADHD symptoms were significantly associated with low conscientiousness and agreeableness, as well as high neuroticism , which iThough the associations of ADHD symptoms with personality traits and IA have been examined in previous studies, the possible mediating role of the symptoms in the relation between the two variables has yet been explored. According to the vulnerability model regarding the relations between personality and psychopathology, certain personality traits can predispose individuals to certain kinds of psychopathology, including ADHD symptoms . In addiFrom late September to mid-November in 2017, this multi-center cross-sectional study was carried out at three medical schools in different regions of China, including China Medical University, Guizhou Medical University, and Xiangya School of Medicine. Based on academic year, whole classes of clinical students were randomly chosen from each institution, and the students were invited to participate in the survey on a voluntary basis. A total number of 1420 questionnaires were distributed and 1312 were returned. After excluding 48 invalid questionnaires, 1264 students (effective response rate: 89.01%) became the final subjects. The study was approved by the Institutional Review Board of China Medical University, and written informed consents were obtained from the participants according to the Declaration of Helsinki.The 20-item Internet Addiction Test (IAT) was used to evaluate IA in the students . The IATPersonality traits were measured with the 44-item Big Five Inventory (BFI) , which cAdult ADHD Self-Report Scale-V1.1 (ASRS-V1.1) was developed based on the DSM-IV Criterion A symptoms of ADHD . Its 6-iDemographic information regarding age, gender, academic year, and hometowns were obtained in the study. Hometowns were dichotomized into urban area and non-urban area.p <  0.05. Descriptive statistics of demographic and psychological variables were indicated with mean, standard deviation (SD), number (N) and percentage (%) as appropriate. T-tests and one-way ANOVA were used to compare differences of IA in categorical groups. Pearson’s correlation was used to examine correlations between the continuous variables. Hierarchical regression analysis was performed to explore the effects of groups of independent variables on IA. In step 1, the demographic variables were entered; in step 2, big five personality traits were entered; in step 3, ADHD symptoms were added. Standardized estimate (β), F, R2 and R2-changes (△R2) for each step were provided. Asymptotic and resampling strategies, based on 5000 bootstrap samples, were used to examine the mediating role of ADHD symptoms on the associations of personality traits with IA [a * b product was calculated to evaluate the mediation effect. A path analysis was also performed using Amos 23.0 to further validate the mediation model. All continuous variables were standardized to avoid multicollinearity before the regression analyses were performed [All analyses were performed using SPSS 13.0, and the significance level of statistical tests was set at  with IA . The biaerformed .p = 0.004), academic year (p <  0.001) and hometowns (p = 0.046).The demographic characteristics of the medical students and the distribution of IA in categorical variables are shown in Table The means, standard deviations and the correlations of all the continuous variables are revealed in Table β = − 0.318, p < 0.01) and agreeableness  were negatively associated with IA, whereas neuroticism  was positively associated with it. The effect of ADHD symptoms on IA was significantly positive , explaining an additional 8.0% of the variance.The results of the hierarchical regression of IA are presented in Table a * b products), and 95% CI for the products are presented in Table a * b = − 0.085, 95% CI: − 0.110, − 0.066), agreeableness  and neuroticism  with IA.Path coefficients, effect sizes of the mediator . The results of the path analysis were shown in Fig. To further validate the meditational model, a path analysis was performed. Examination of the goodness of fit indicated that the model was fairly adequate (χTo the best of our knowledge, this large multi-center study is the first one to examine the associations between big five personality traits and IA in medical students, and to explore the mediating effect of ADHD symptoms on the associations. The study showed that the overall prevalence of IA among Chinese medical students was 44.7%, which was higher than 32.2% in medical students worldwide assessed by the IAT. However, caution should be taken when the prevalence is interpreted and compared since out of dozens of instruments for assessing IA, none has emerged as the diagnostic gold standard , 39, andAfter adjustment for demographic factors, three personality traits significantly predicted IA in the students. Based on the absolute value of standardized β, conscientiousness, neuroticism, and agreeableness contributed to the variance in IA. Among the three dimensions, conscientiousness was the strongest predictor, which was correspondent with the result of the meta-analysis of the relations between personality traits and IA . ConscieThe positive association between neuroticism and IA is consistent with the results of many prior studies , 24, 25.Agreeableness refers to individual differences in people’s interest in the needs and well-being of others, and is characterized by social adaptability and emotional support . The negPersonality traits were not only directly associated with IA, but also indirectly associated with it through ADHD symptoms. ADHD symptoms mediated the associations of conscientiousness, agreeableness and neuroticism with IA in the students. Higher scores on conscientiousness and agreeableness were related to lower levels of ADHD symptoms, which in turn were related to lower levels of IA. In contrast, higher scores on neuroticism were associated with higher levels of ADHD symptoms, which were associated with higher levels of IA. While the robust associations of ADHD with personality traits of conscientiousness, agreeableness and neuroticism, as well as IA have been confirmed by prior meta-analyses , 34, thiThe implication of the mediation effects is that intervention strategies for IA may consider treatment of ADHD symptoms. Psychosocial treatment is an effective treatment option for adults with ADHD, especially when medication alone fails to work or its side effects are a concern. Cognitive-behavioral therapy, often incorporating modules regarding distractibility, organizational skills and cognitive restructuring, can be tailored to successfully treat ADHD –67. GiveSeveral limitations of the study should be acknowledged. First, due to the cross-sectional nature, causality of the involved constructs cannot be determined based on the available data and analysis, and the findings should be confirmed by prospective cohort studies in the future. Second, all data were obtained through self-reported questionnaires, which might introduce response bias. Third, despite the multi-center design, before generalizing the results, more studies should be carried out in other nations where different cultures and medical education systems exist.This study revealed that the prevalence of IA among Chinese medical students is high, which warrants more attention from all parties involved. Three dimensions of big five personality traits significantly predict IA in the students. While neuroticism is a risk factor for IA, conscientiousness and agreeableness function as protective factors. ADHD symptoms mediate the associations of the three personality traits with IA. Thus, both personality traits and ADHD symptoms should be taken into account when tailored intervention strategies are designed to prevent and reduce IA in medical students.


Patients with attention deficit/hyperactivity disorder (ADHD) often experience comorbid conditions, such as autism spectrum disorder (ASD) and Tourette syndrome (TS). Although pharmacotherapies are effective for treating ADHD, they are likely to elicit a variety of adverse effects. It is, thus, important to select an effective and well-tolerated pharmacotherapeutic treatment for patients with ADHD/ASD comorbid with TS.We report the case of a 10-year-old boy with ADHD/ASD comorbid with TS who was treated with guanfacine (GUAN). He experienced several side effects of atomoxetine (ATX) and methylphenidate (MPH) before being treated with GUAN. In the presented case, symptoms of ADHD as well as tic symptoms were improved by treatment with GUAN.GUAN might be effective and well tolerated in the treatment of patients with ADHD/ASD comorbid with TS who experience side effects of ATX and MPH. Attention deficit/hyperactivity disorder (ADHD), which affects 5%–10% of school-aged children . RecentlTS, on the other hand, is characterized by the presence of multiple involuntary motor and vocal tics. TS is treated with pharmacological medications such as D2-DA receptor antagonists combined with psychological behavior therapy . Importa2A-adrenergic receptors in the PFC to enhance noradrenaline neurotransmission [Guanfacine (GUAN) was approved for children and adolescents (6–17 years) in Japan in May 2017. Orally administered GUAN is rapidly and completely absorbed, with maximum plasma concentrations occurring 1–4 h after administration . It diresmission , therebysmission . A benefsmission .To the best of our knowledge, this is the first case report that assesses the use of GUAN in the treatment of a patient with ADHD/ASD comorbid with TS. This case corroborates the effectiveness of GUAN as a viable alternative to other pharmacological treatments for patients with ADHD/ASD comorbid with TS.The symptoms of the current case and the severity of ADHD were assessed using the Japanese version of the ADHD Rating Scale IV (ADHD-RS-IV-J) of the ADHD-RS-IV “home version”, which is an 18-item scale that is reliable and easy to administer. In addition, the tic severity of the current case was assessed using the Yale Global Tic Severity Scale (YGTSS), in which a higher YGTSS score is associated with higher tic symptom severity. This scale yields three summary scores: total motor (0–25), total phonic (0–25), and total tic (sum of motor and phonic) scores. The YGTSS also contains an impairment scale (0–50), which evaluates the global level of functional impairment arising from tics.The 10-year-old boy described here  had been diagnosed with a developmental delay in head control, speech, and language by a paediatrician when he was 1 year and 6 months old. When he entered kindergarten, he often played by himself and did not make friends because of his communication problems. After entering the local elementary school, at the age of 6, he began to show hyperactivity and impulsivity. In addition, he displayed symptoms of motor and vocal tics. He was assessed at a local clinic, and diagnosed with ADHD/ASD comorbid with TS. Although he initially continued to take risperidone (0.5 mg/day), side effects such as headache and anxiety led him to discontinue the treatment. When he was 9 years old, worsened impulsivity led him to behave violently toward his mother. He, therefore, began treatment, at a local clinic, with atomoxetine (ATX) (30 mg/day). However, he discontinued the medication as he experienced worsening irritability. Although he was prescribed MPH (18 mg/day) after discontinuing the treatment with ATX, he also discontinued taking MPH, because his motor and vocal tic symptoms were exacerbated. As these symptoms continued, he was referred to our hospital at 10 years of age, with an ADHD-RS-IV-J score of 23 and a YGTSS score of 29.According to his father, he had only few friends because he had so little interest in making friends in school. The teachers often reported problems to his parents, such as when he showed physical aggression toward his friends or ran away from school during the lesson. He often got angry when the timing of activities deviated from his usual schedule. He was, therefore, diagnosed with ADHD/ASD/TS according to the criteria specified in the DSM-5.The patient was continuously prescribed GUAN at a dose starting at 1 mg/day and increasing to 3 mg/day. However, the 3-mg dose led to drowsiness , and was, therefore, reduced again to 2 mg/day. At the decreased dose, he continued to take GUAN without side effects , while there was no clear difference in effect between the 2-mg/day and the 3-mg/day doses. Importantly, his ADHD-related symptoms, such as irritability, hyperactivity, and inattention, as well as his tic symptoms, gradually improved. On the other hand, GUAN had no effect on ASD symptoms in this case. The patient was able to continue taking GUAN for 6 more months   and sedation (13.3%) , as the  effects , 38. TheNo previous study has shown that GUAN influences ASD symptoms, and our case likewise showed no effect on ASD symptoms. GUAN might, thus, be an alternative treatment for some patients who experience side effects of ATX and MPH, without exacerbating other psychiatric symptoms.The main limitation of our study is that it involves only one case, and we should, therefore, be careful when drawing conclusions. Future studies are, therefore, needed to continuously assess the effectiveness of GUAN in treating patients with ADHD comorbid with ASD and TS.This case indicates that GUAN might be an efficacious and well-tolerated treatment for ADHD and tic symptoms in patients with ADHD/ASD comorbid with TS, because pharmacological medication tends to cause different side effects in patients with ADHD comorbid with ASD than in those with only ADHD or ASD. Further studies with larger sample sizes are needed to validate the apparent efficacy, safety, and tolerability of medical treatment with GUAN.


The neural networks that constitute corticostriatothalamocortical circuits between prefrontal cortex and subcortical structure provide a heuristic framework for bridging gaps between neurocircuitry and executive dysfunction in attention deficit hyperactivity disorder (ADHD). “Cool” and “Hot” executive functional theory and the models of dual pathway are supposed to be applied within the neuropsychology of ADHD. The theoretical model elaborated response inhibition and delayed gratification in ADHD. We aimed to review and summarize the literature about the circuits on ADHD and ADHD-related comorbidities, as well as the effects of neurocircuitry on the executive dysfunction in ADHD. Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood and adolescence with an overall prevalence of 6.26% in China  and 5.2%The heritability of ADHD was calculated to be approximately 0.76 . Today, The imaging genetics will provide much greater power to identify the risky genes than disease status alone and it will provide a more precise understanding of ADHD’s potential of how the brain variations shaped by the genes. Many neuroscience studies have integrated structural and functional neuroimaging with genetic risk during the past decades. The advanced thoughts built the framework of imaging genetics which is to find associations of neuroimaging as endophenotypes with DNA variants as risky genes, and then use hypothesis-free whole-brain voxel-wise genome-wide to associate these studies . Those fThis review discusses the role of abnormal connections in each corticostriatothalamocortical (CSTC) circuit, which may be responsible for targeted executive dysfunction at the neuroscience level, respectively.The etiology of ADHD remains unclear; it is mainly considered that the disease is caused by inappropriate connection of neural network that may be associated with many different regions. The comorbidity with ADHD implies a single or multiple regional dysfunctions affecting integrated connections between regions. Because of children and adolescents’ cerebral function of differentiation and contingency involved in the neural network, especially when nervous system has been damaged, bypass can be rebuilt to compensate the damaged function called neuroplastic changes . PerceptNeuropsychological studies can be less invasive and more informative on the functioning of specific neurocircuitries involved in ADHD and have more advantages than any other studies carried out by using assessment scales or quantitative tests . NeuropsThe neuropsychological model is set up to investigate the etiology of ADHD, its related comorbidities, and pathological mechanism as well, and to guide the clinical diagnosis, treatment and rehabilitation. Regarding the complicated connotation and advanced cognitive ability, the explanation of EF model is more efficient than any other neuropsychological models. The theory of ADHD from The above definition classifies all domains of EF of ADHD into abstract thinking, which is currently known as “Cool” EF in the cognitive and behavioral level. However, such classification unilaterally ignores the changes after the involvement of emotional response. With the development of neuropsychology, decision making encountered with emotional involvement has been defined as “Hot” EF. The “Hot” EF includes motivation and reward, emotional and cognitive process, and affective decision-making process. For example, delay gratification is characterized by emotional trait, which complements the insufficiency of the classification of “Cool” EF. Based on a large number deficits in the EF of ADHD, the impaired response inhibition and delay gratification is regarded to be core problems leading to a wide range of impairments .Thus, the two major domains – abstract thinking (Cool) and emotional trait (Hot) – trigger the mechanism of onset of ADHD .Brain mechanism underlies these different functions shown in Figure Special neuropsychological tasks should be designed to meet the needs of different research purposes. The response inhibition is the core element of the “Cool” EF that refers to inhibiting the reaction of irrelevant stimulus when seeking a cognitive representation of target stimulation . The resIn the study of the “Hot” EF, the delayed gratification is a classic paradigm of mental phenomenon. The delayed gratification refers to the tendency that subjects delay short-term satisfaction spontaneously so as to obtain long-term benefits, which demands the ability of self-regulation and self-control . For exaThe observation of behavioral dysfunctions shed the light on the neuroimaging researches.Neuroimaging study, chosen to be endophenotypes between genetic inheritance and human behavior, can obtain data of disease characteristics stably and provide indirect evidence of EF association study noninvasively. According to Diagnostic and Statistical Manual of Mental Disorders (DSM-5), ADHD has been classified as a kind of neurodevelopmental disease occurs before age of 12, thus, we consider that the pathogenesis of ADHD is related with neurodevelopmental retardation. The cortex, as the upmost center of executive control system, not only needs to adjust complex cognition and emotion, but also integrates the whole neural networks rather than a single abnormal disconnection. Neuroimaging of ADHD has gone through three stages roughly over time: hypothesis of prefrontal hypofunction, hypothesis of corticostriatal pathway hypofunction and hypothesis of CSTC circuits dysfunction .Prefrontal cortex, as the most advanced part of cerebrum, has assembled a large number of related studies in ADHD including response inhibition and sustained attention locating within the DLPFC , affectiPrefrontal dysfunction causes clinical phenotypes including hyperactivity, inattention, emotional instability and lack of planned behavior . The hypAlong with further researches, the hypothesis is gradually accepted that the onset of ADHD is associated with prefrontal cortex and major striatal subregions connectivity abnormalities . The froThe malfunction of the prefrontal cortex corresponds with each substructure in striatum shown in Figure Nerve signals are projected from prefrontal cortex into striatum, and then reach thalamus before return to the cortex. In detail, thalamus produces regional interaction with area-oriented cortex. The signals of CSTC circuits that pass through the striatum are able to be synapse-linked to the special part of the striatal neurons from striatum to thalamus when getting a feedback simultaneously before finally return to the initial pyramidal cells . A cogniPrefrontal hypoactivity, influencing the DLPFC, ACC and related regions including striatum and thalamus, plays the role of a villain in the EF of ADHD . Each voThe interdiscipline of the neuroimaging and neuropsychology attracts researchers’ attention to the point that ADHD, TS, ODD, and OCD may possess the similar biological mechanism. As mentioned above, five abnormal CSTC circuits are apparently involved in ADHD, including two in ODD (the divided attention and impulsivity/compulsivity circuits; Here are a few examples of comorbidity. Whether ADHD is with comorbid TS or not, the decrease of neural volumes and connections in the CSTC circuits are quite consistent with ADHD-related symptoms . The EF The review that has been emphatically described above is focusing on the interdisciplinary interactions in ADHD, and those theories are also available in ADHD-related comorbidities. Could those studies of the EF theories help psychiatrists to better distinguish clusters of symptoms among different mental disorders? If open-minded concept is freed out of those fixed classified diagnostic criteria, many interesting phenomena are supposed to be found according to the independent symptoms.The neurocircuitries that constitute the CSTC circuit provide a framework for bridging gaps between neuroimaging and EF in ADHD , but it It is believed that more and more evidence-based medicines would be found in ADHD and its related comorbidities with the deepening of the scientific researches and interdiscipline between neuroimaging and neuropsychology after being enlightened by such theories. Further researches are recommended to be carried out on the heritability, stability, specificity and familial genetic overlap of the aforementioned neuropsychological traits. The verification and identification of neuropsychological traits may offer a previous contribution to molecular genetic studies, pharmacogenomics, and clinical management of ADHD patients.However, systematic errors can’t be avoided in this kind of review even with careful searching strategy. We did not evaluate the quality of these cited references while being presented their results as many qualitative descriptions. These reviewed papers, to some extent, were demonstrated depending on the authors’ viewpoint of ADHD. Furthermore, we noted that vast majority of neuropsychological data were measured by comparing to statistical significance between disease groups and typical development groups in the purpose of their researches, and then a relevant conclusion was drawn in those ways but neglecting the comparison between diseases. Those limitations might make the conclusions ambiguous.XJ wrote the paper. LL and HJ contributed to the overall design of the article structure. YZ wrote the protocol, managed study supervision and critical revision of the manuscript for important intellectual content.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.


Observational studies suggest childhood externalizing disorders are associated with increased smoking and earlier initiation. However, causality cannot be inferred from observational data alone. The current study uses two-sample MR to examine the causal relationship between externalizing behaviors and tobacco use.Single nucleotide polymorphisms (SNPs) associated with aggression were obtained from the Early Life Epidemiology Consortium (mean age 8), ADHD from the Integrative Psychiatric Research and Psychiatric Genomics Consortiums (age range 6–18), and tobacco initiation and age of onset from the Tobacco and Genetics Consortium. SNPs were combined using the inverse variance weighted approach, weighted median approach, and MR-Egger regression.There was no clear evidence of an effect of aggression on tobacco initiation or age of onset for childhood aggression  or adolescent aggression ]. However, there was some evidence of an association of ADHD on tobacco initiation , although no clear evidence of an effect of ADHD on age of onset .Our results provide some evidence that genetic risk of childhood ADHD is causally related to increased risk of tobacco initiation; however, the causal estimate is relatively small. We found no clear evidence that genetic risk of childhood aggression is causally related to the risk of tobacco initiation or age of onset. ExternaExternalizing disorders are associated with deficits in reward function – reduced sensitivity to favorable stimuli and increased reward sensitivity. . For exaAdditionally, externalizing disorders are characterized by impulsive behavior . These individuals typically prefer immediate rewards (over possible larger rewards in the future) . TherefoTobacco may also be used for self-medication in individuals with ADHD to alleviate ADHD symptoms through negative reinforcement . StudiesHowever, the causal nature of this relationship and the direction of causality remain unclear. Evidence from longitudinal studies suggests that externalizing behaviors in children are associated with subsequent early onset tobacco use , and whi22.1−5) for aggression. The GWAS further identified top SNPs stratified by age group, with five SNPs approaching genome-wide significance for early childhood , and six SNPs for middle childhood/early adolescence  (see Supplementary Table S1).For our externalizing behaviors exposure, we used summary data from the Early Life Epidemiology Consortium (EAGLE) consortium GWAS of aggressive behavior on a sample of 18,988 individuals. Aggression was measured using continuous study-specific scales . Six SNP−8) (see Supplementary Table S2).For our ADHD exposure, we used summary data from the Initiative for Integrative Psychiatric Research (iPSYCH) and Psychiatric Genomics Consortium (PGC) GWAS of ADHD on 55,354 individuals (ages 6–19) . ADHD wa2.2For our tobacco initiation outcome, we used summary data from the Tobacco and Genetics Consortium (TAG) GWAS of smoking behavior . Tobacco2.3http://snipa.helmholtz-muenchen.de/snipa3/) with an r2 threshold of ≥0.9. SNP-exposure and SNP-outcome associations were combined using an inverse-variance weighted approach (IVW), weighted median approach, and MR-Egger regression. Here, we use multiple methods, each with differing underlying assumptions regarding instrument validity, to triangulate our results . Where original SNPs were unavailable, proxy SNPs were identified using SNiPA . While the MR-Egger analysis suggested there is some evidence of an effect on initiation, the effect estimates were inconsistent with those from the IVW and weighted median analyses . These findings were consistent when restricted to early childhood and late adolescence , and low heterogeneity (I2  = 29%). Although MR-Egger analysis indicated that there was some evidence of pleiotropy , the bias-adjusted effect estimate remained consistent with that estimated using the IVW approach and suggested some weak evidence of a causal effect . There was no clear evidence of an effect from the genetic risk of ADHD to the age of onset (see There was weak evidence of an association from the genetic risk of ADHD to tobacco initiation (OR3.3https://sb452.shinyapps.io/power/)  . For the4Our results provide some evidence that genetic risk of childhood ADHD is causally related to increased risk of tobacco initiation; however, the causal estimate is relatively small. We found no clear evidence that genetic risk of childhood aggression is causally related to the risk of tobacco initiation or age of onset. Therefore, the observational evidence relating to these associations  may not Our findings with respect to genetic risk of ADHD and tobacco use initiation correspond with observational evidence , and theWithin individuals with ADHD, a hypoactive striatal dopaminergic system produces increased dopamine transporter within corticostriatal circuits. This subsequently decreases dopamine tone and activation of presynaptic autoreceptors, resulting in exaggerated dopamine response to salient stimuli. As nicotine stimulates a response in the striatum of smokers, nicotine-stimulated phasic dopamine releases may be more rewarding for individuals with ADHD . TherefoThese findings may help identify individuals particularly vulnerable to tobacco use behaviors, and therefore provide interventions from an early age. For example, previous evidence indicates that strong familial bonds and open communication within families and schools may serve as a protective factor, or help to delay adolescent substance initiation .There are a number of important strengths to this study. The use of Mendelian randomization analysis strengthens causal inference and removes the possibility of reverse causation, confounding, and bias , 2016a. Overall our results provided some evidence that there may be a causal association of genetic risk of ADHD on tobacco initiation, these results are in line with previous longitudinal and neurobiological evidence. However, there was no association between early aggressive behavior on tobacco initiation, suggesting these observed associations may be a result of additional variables. Our results suggest that prevention efforts should target these risk groups, and explore whether interventions to reduce these behaviors influence subsequent tobacco use initiation. By identifying at-risk individuals, prevention behaviors such as strengthening familial bonds, open communication within families and schools, and early intervention education may help delay or prevent adolescent substance use initiation. .None declared.All authors designed the study. MEF conducted the analysis and drafted the manuscript with input from MRM and HS. All authors approved the final version of the manuscript for submission.No conflict declared.


In this study, the effect of xylanase addition to a diet with an increasing content of modern hybrid rye was evaluated. In the first feeding phase (from 1 to 21 days of age), even a low dietary level of rye (5%) decreased the body weight gain of birds. However, results obtained in older birds indicated that modern hybrid rye can be used in up to 20% dietary level in broiler diets from 22 to 42 days of age, especially when the diet is supplemented with xylanase. p < 0.05); there was no effect on feed intake and feed conversion ratio. In older chickens , none of the dietary levels of rye (5–20%) affected growth performance indices. Similarly, no significant effect of increasing dietary level of rye was found for the entire rearing period (1–42 days of age). Diet supplementation with xylanase improved body weight gain and feed conversion ratio in chickens from 1 to 21 days of age. No positive effect of enzyme was found in older birds. No significant effects of the experimental factors used were noticed on the results of slaughter analysis, i.e., the carcass yield, breast meat yield, abdominal fat, and relative weight of the liver and gizzard. A high dietary concentration of rye (20%) increased the viscosity of small intestine content (p < 0.05); however, diet supplementation with xylanase significantly alleviated this effect. The findings of this experiment indicated that modern hybrid rye grain may be used at a 20% dietary level in broiler diets during the second feeding phase, i.e., from 22 to 42 days of age, without any detrimental influence on growth performance indices, while enzyme (xylanase) positively affected body weight gain and feed conversion ratio in younger chicks (1–21 days of age). In this paper, we present a study on the evaluation of the effect of xylanase addition to a diet with an increasing content of modern hybrid rye (Brasetto variety) on the performance indices and viscosity of small intestine content in broiler chickens. A total of 560 1-day-old male Ross 308 chickens were randomly assigned to 1 of 10 treatments, each comprising 7 replicate cages, with 8 male birds per cage. A 5 × 2 factorial arrangement was employed, with five dietary levels of ground rye . All the diets were either unsupplemented or supplemented with xylanase . In the starter rearing period (1–21 days of age), the inclusion of rye (without xylanase supplementation) to the diet, even at the lowest dietary level (5%), negatively affected body weight gain ( The use of rye grain as a component of diets for poultry in conditions of intensive production is very limited. The reason for its reputation for being unsuitable for broiler chicken diets is its high concentration of nonstarch polysaccharides (NSP), mainly structural, highly branched arabinoxylans (AX), in the endosperm cell wall, which create viscous water solutions ,2. A subIn recent years, several new hybrid rye varieties tending to have significantly reduced content of anti-nutritive substances, especially AX, have been developed ,15,16 an3/1 kg of BWG/1 h, and concentration of CO2 and NH3 were maintained below 2000 and 20 ppm, respectively. The chicks were weighed with BD3T electronic scales with an accuracy of 0.1 g , and randomly assigned to 1 of 10 treatments, each comprising 7 replicate cages, with 8 birds per cage . From 1 to 42 d of age, all the chickens were provided with water and feed ad libitum. A total of 560, 1-d-old, male Ross 308 chickens were used. These were obtained from a commercial hatchery and had an average initial weight of 41 g. The birds were housed in wire-floored cages, in an environmentally controlled room in the poultry house at the Experimental Station of the National Research Institute of Animal Production in Balice, Poland. During the study, the temperature in the experimental facility was maintained from 32 °C at 1 d of age to 21 °C at 21 d of age and later, relative humidity cycled from 50 to 60%, air exchange was 1 mAll the birds were reared up to 42 d of age and fed with crumbled starter (1 to 21 d) and pelleted grower–finisher (22 to 42 d) isonitrogenous and isoenergetic diets, which were formulated to meet or exceed the nutrient requirements of broilers  Table 1. Rye gra220Fiber Analyser  with heat-stable amylase and expressed inclusive of residual ash. The amino acid composition was determined by liquid chromatography (LC) using a AAA 400 amino acid analyzer  operating with an ion exchange column and post-column derivatization with ninhydrin.The nutrient content of the diets was calculated from the chemical composition of raw feedstuffs, and metabolizable energy value, in line with equations from the European Tables . Air-driNSP content with its fractionation to soluble (S-NSP) and insoluble (I-NSP) fractions was determined using gas chromatography (GC) as previously described by Englyst and Cummings . In thisUronic acids (UA) were analyzed with the colorimetric method of Scott , using 3The viscosity of water extracts was estimated with the modified method of Boros et al. . The amoThe chickens’ body weight was recorded at 1, 21, and 42 d of age; feed intake was recorded for 1–21- (starter diet) and 22-42-day (grower–finisher diet) periods, and mortality was registered daily. At 1 and 21 days of age, birds were weighed with BD3T electronic scales with an accuracy of 0.1 g , whereas at 42 days with Tru-Test AG-500 electronic scales with an accuracy of 5 g . The body weight gain (BWG) and feed conversion ratio (FCR) were calculated for the starter period (1–21 d), the finisher phase (22–42 d), and the entire feeding period (1–42 d of age). The mortality rate was recorded daily, and the weights of all mortalities were registered to correct the FCR. At the end of the experiment, and after 12 h of starvation, all of the chickens were individually weighed and 7 representative birds (one bird per each replicate cage) with live body weights close to the group average were chosen from each group, marked with number signs, and decapitated after electrical stunning . Chickens were plucked, the intestines and crop were removed, and carcasses stored overnight at 4 °C. The mass of the cooled carcass with edible giblets  was estimated and carcass yield calculated. The breast muscles , abdominal fat, livers, and gizzards were excised and weighed. The breast muscle and abdominal fat contents were expressed as a percentage of the cold carcass. The weights of the liver and gizzard were expressed as percentages of live weight . g for 10 min. Viscosity was measured on 0.5 mL of the supernatant using a cone and plate Brookfield viscometer  at 40 °C.Moreover, in selected treatments  for 7 non-fasting birds per treatment, the whole intestines were removed and total intestinal digesta from jejunum and ileum were collected for viscosity measurements. Fresh digesta were centrifuged at 10,000 × p ≤ 0.05.The data were analyzed using STATISTICA 12  software for a two-way analysis of variance (ANOVA) to determine the main effects of dietary treatments, such as dietary rye levels and xylanase supplementation, and their interactions. Duncan’s multiple range post hoc test was used to determine the differences between the treatments, and the effects were considered to be significant at a probability level of The chemical composition of rye grain (Brasetto variety) used in our study included: 89.1% DM, 9.23% CP, 0.81% CF, 1.46% of crude fibre, and 1.51% of crude ash and apparent metabolizable energy—10.97 MJ/kg. The content of essential amino acids in the used rye variety was 1.19 g/kg for methionine (Met), 2.97 for lysine (Lys), 2.63 for threonine (Thr), 3.79 for valine , and 2.50 for isoleucine (Ile). High soluble NSP content in rye grain resulted in its increased content in rye-containing diets and the high viscosity of water extracts . Inclusion of ground rye, at all used dietary concentrations, except the level of 15%, significantly reduced BWG, without affecting feed intake (FI) and FCR in the starter rearing period . No negaStatistical analysis showed that the second experimental factor, i.e., dietary supplementation with xylanase, had a positive influence on BWG and FCR during the starter rearing period . In oldep > 0.05). Thus, the carcass yield, breast meat yield, abdominal fat pad, and relative weight of the liver and gizzard were not affected by ground rye dietary level or enzyme addition to the diet . The significant interactions between experimental factors for viscosity values (the effect of xylanase on the jejunum and ileum content was much more pronounced in broilers fed rye-containing diet) were found  used in this experiment was characterized by a relatively high concentration of both total and soluble NSP. Lower amounts of NSP in rye grain were found in harvest years 1997  and 2010Analysis of the chemical composition of rye grain used in our experiment showed a relatively high content of NSP; however, the good growth performance of older chickens (22–42 days of age) fed the experimental diets indicated that hybrid rye can be used effectively as alternative feed material for broilers. Inclusion of rye grain, except the level of 15%, to the diet negatively affected growth performance only in younger broilers during the starter feeding phase (1–21 days of age), which might be connected with the high content of arabinoxylans in this rye; thus, a higher intestinal viscosity and greater susceptibility to its negative influence than was the case with older chickens was observed. According to Smulikowska et al. , in addiIn the current study, xylanase addition significantly improved body weight and feed conversion ratios in younger age chickens, i.e., aged from 1 to 21 days, probably by improvements in nutrient use, which in younger chickens was affected to a greater extent by dietary inclusion of rye. Similar findings were obtained by Santos et al. , who conAlthough the viscosity values obtained in our experiment were generally relatively low compared to results of other experiments , the visWe observed that supplementation of a diet containing 20% of rye with xylanase had a positive effect on intestinal physiology and decreased digesta viscosity. Similarly, Dänicke et al.  found thThe results of this experiment showed that hybrid rye (Brasetto variety) can be incorporated in up to 20% of the diet without any detrimental effects on the growth performance of broilers from 22 days of age. However, inclusion of hybrid rye to the diets of younger chickens, aged 1–21 days, may reduce body weight gains and worsen feed conversion ratios. The positive effect of enzyme (xylanase) addition to diets containing rye was reflected in a decrease in the viscosity of small intestine contents.


In Attention Deficit Hyperactivity disorder (ADHD), fMRI studies show asymmetric alterations: widespread hypoactivation in anterior cortical areas and hyperactivation in some posterior regions, and the latter is considered to be related to compensatory processes. In Posner’s attentional networks, an important role is attributed to functional interhemispheric asymmetries. The psychophysiological Attention Network Test (ANT), which measures the efficiency of the alerting, orienting, and executive networks, seems particularly informative for ADHD. Potentials related to ANT stimuli (ANT-RPs) have revealed reduced cognitive potential P3 in ADHD. However, there are no studies associated with asymmetry of ANT-RPs. In the present study, conducted with 20 typically developing boys and 19 boys with ADHD, aged 11–13 years, the efficiency of the three Posner’s networks regarding performance and amplitude asymmetries in ANT-RPs was evaluated according to the arithmetic difference of these parameters between different cue and target presentation conditions. The results were correlated to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) scores. Regarding accuracy and intraindividual variation in reaction time, ADHD subjects showed lower efficiency of executive and alerting network, and this effect was correlated with DSM. Regarding alerting network, ANT-RPs in ADHD did not have the right-side amplitude prevalence in the temporal regions, which was observed in controls. In all ANT conditions, significantly higher asymmetries were observed in ADHD than in controls in the occipital regions 40–200 ms after target onset. Their amplitude in ADHD subjects was inversely proportional to DSM scores of inattentiveness and directly proportional to accuracy and efficiency of the executive network. The results suggest impaired alerting and executive networks in ADHD and compensatory occipital mechanisms. Attention Deficit Hyperactivity disorder (ADHD) is one of the most prevalent cognitive disorders, occurring in approximately 5% of children , and is In the psychophysiological model for estimating attention known as Posner’s attentional networks ,11, the The functional independence of Posner’s attentional networks was emphasized by their relation to different neurotransmitter systems , 11, 18.In Posner’s attention model, an important role is attributed to the functional asymmetries of the brain, and the alerting network is supposed to be related to the right hemisphere . HoweverThere are no studies in literature on the functional or morphological interhemispheric asymmetry considering Posner's attentional networks measured by ANT. The methodological problem was resolved by combining ANT and the recording of brain event-related potentials (ERPs) evoked by ANT stimuli, i.e., ANT-related potentials (ANT-RPs) –33. The In the present ADHD study, we used ANT to search for: (1) evidence of impaired efficiency of the alerting network of performance characteristics and their correlation with Diagnostic and Statistical Manual of Mental Disorders (DSM) scores; (2) putative alterations in functional asymmetry; and (3) assumed compensatory processes related to Posner’s networks  as reflected in performance parameters and interhemispheric differences in ANT-RP amplitude and their correlation with DSM scores.This study was approved by the Ethics Committee of the Fernandes Figueira National Institute (CAAE 08340212.5.0000.5269). All participants gave their oral assent in the presence of their caregivers, who provided written informed consent after a complete description of the study.Sixty boys aged 10–13 years were recruited, classified, and included in the sample according to the DSM-IV-TR (DSM Text Revision) : 35 witha priori.Each caregiver was asked to consider DSM-IV-TR criteria for ADHD, one by one, and was instructed to indicate carefully which criteria were notable characteristics of their dependents. Criteria about which caregivers had doubts, showed hesitation, or to which they attributed little emphasis in describing the behavior of the child were not counted. Throughout the clinical interview, we inserted variables which were irrelevant for the diagnosis but could potentially create observation biases (confounding variables), namely: years of study, number of hours on the computer or playing video games per week (1 = less than 2h/week(w); 2 = 2-4h/w; 3 = 5-8h/w; 4 = 8-15h/w; 5 = more than 15 h/w; which could help develop non-specific ability for RT tests), monthly family income, and hours of sleep the previous night. Age was also considered a potential confounding variable. The confounders were decided ANT is a combination of tests to assess performance in terms of RT, IVRT, and response accuracy (AC), regarding (1) modulation of alertness state under the effect of a Neutral cue (NtCue) compared to absence of cue (NoCue), when the context is under the effect of NtCue just as a warning stimulus that indicates the imminence of target onset; (2) dynamics of attention orientation by assessing the influence of a Spatial cue (SpCue) on NtCue; and finally, (3) the ability to detect and resolve conflicts by assessing the interference of incongruent target distractors on performance parameters compared to congruent target distractors.We used an ANT version adapted to children , 32, 37,A total of 24 trials were shown randomly  in each one of the nine blocks that comprised the ANT test. The first block was designed for training the subject, and this performance was not counted. Thus, each subject performed a total of 64 trials for each cueing condition and 96 trials for each target condition. The trials were separated from each other by a random gap between 1 and 2 seconds. Each trial was completed once the subject responded to the target signal or after 2 seconds if the subject did not respond. By the end of each block, the participant was given a performance feedback (mean reaction time and number of hits) with motivational sentences indicating improved performance (if any). The subjects started the new block pressing the space bar on the computer keyboard. Accuracy (rate of correct responses), reaction time  and its standard deviation, and termed intraindividual variation (IV) were recorded.During the ANT performance, the subjects' EEG were acquired using a Nihon Kohden NK1200 EEG System at 20 scalp points according to the International 10/20 System, with linked biauricular reference (A1+A2) at a sampling rate of 1000 Hz and resolution of 16 bits, with low-pass, high-pass, and notch filters at 100, 0.5, and 60 Hz, respectively, under impedances below 10 kΩ. Low frequency movement artifacts were suppressed by high-pass filtering. Muscular artifacts of high amplitude and frequency were removed manually from ongoing EEG signal during post-recording visual inspection. We also used a statistical filter developed in our laboratory to mitigate blinks .We determined ANT behavioral variables such as (1) AC—correct responses/total responses, (2) RT, and (3) IVRT. These variables were determined for each ANT condition and for all conditions indistinctively (AllCd). Each variable was analyzed in the set of AllCd to obtain an “overall mean value” of behavioral measures without considering specific attentional dimensions. Speed-accuracy tradeoff was estimated by multiplying AC by RT for all conditions. Subjects with values lower than the mean group value minus two standard deviations were removed from the sample.The efficiency of the alerting, orienting, and executive (conflict resolution) attentional networks related to behavior and neural functioning were calculated as the difference between behavioral scores  or ANT-RP parameters of the corresponding conditions: [NoCue minus NtCue], [NtCue minus SpCue], and [‘incongruent target distractors’ minus ‘congruent target distractors’] , 32.EEG signals were resampled at 600 Hz using a polyphase anti-aliasing filter to reduce computational load. We calculated ANT-RPs for each cueing and target conditions, as well as their grand average for AllCd. The signals analyzed lay within the range encompassing 1550ms before to 1000 ms after target onset, thus including all ANT-RPs. In addition, we calculated the difference in ANT-RPs between hemispheres, subtracting the signals from homologous channels (right minus left) related to ANT-cue and target conditions. We also subtracted asymmetries (interhemispheric differences) related to different ANT conditions to determine their relation to the efficiencies of the alerting, orienting, or executive networks.Among all ANT-RPs, we extracted the peak amplitude of late ANT-RPs from Pz channels, which corresponded to P3 waves related to each cue, target, and AllCd condition  as well as ACs, RTs, IVRTs were inferred using tests for independent samples. According to the analysis of normality (Shapiro-Wilk test) and homogeneity of variance (Levene Test), we decided to use either parametric (Student t-test) or non-parametric tests (Mann-Whitney U Test), adopting α = 0.05. To evaluate whether the ADHD and TD groups are different as a whole, regarding the parietal P3 wave and the asymmetries in O2-O1 and C4-C3, we corrected p-values using the FDR method of Benjamini-Hochberg.a priori diagnosis, and we sometimes considered the groups separately. In the first case, we used Pearson's Test, calculating the coefficient of correlation ('r'). For correlations considering the groups distinctively , we used Spearman rank test to obtain their coefficient of correlation (ρ) assuming the non-normality of samples, a priori, because of the small size of the groups. We defined the effect size of correlations according to the following intervals between coefficient values: from 0.0 to 0.09—no correlation; from 0.11 to 0.30—weak correlation; from 0.31 to 0.50—moderate; > 0.50 strong correlation [To study correlations between variables, we sometimes grouped all 39 subjects without considering an To estimate significant statistical differences between hemispheres , as wellTo minimize type-I errors, we adjusted p-values using the positive False Discovery Rate (FDR) correction method . We grapTIn the Among confounding and descriptor variables , only esThe two groups, children with ADHD and controls, were statistically different regarding AC  and IVRT  of AllCD , but notIn the group with all 39 subjects, a strong correlation was observed between the total DSM score and the efficiencies of the alerting and executive networks , and a moderate correlation was observed with the efficiency of the orienting network (r = 0.48) concerning IVRT . CriteriThus, the ADHD subjects showed lower efficiencies of the executive and alerting networksregarding AC and IVRT, and this effect was correlated with DSM.Wave morphology in the ANT-RPs for AllCd was nearly the same among groups although it significantly changed between channels  Due to tThe maximum amplitudes of late Target RPs, which correspond to P3, observed in the Pz parietal channel in all conditions as well as in AllCd, were higher in the control group than in the ADHD group  . No signIn ANT-RPs of AllCd, we found significant interhemispheric differences only in the temporal areas  of both groups  and incongruent target distractors  in C4-C3, in the window from 45 to 290 ms, showing a higher right-side amplitude prevalence of negative signal in the central region in ADHD compared to the controls  and the efficiency of the executive network over AC , and moderate positive correlation with the efficiency of the alerting network over AC  . This meIn general, the rightward occipital asymmetry in ADHD subjects proved to be inversely proportional to DSM scores of inattention and directly proportional to executive accuracy and efficiency.The number of left- and right-handed subjects did not correlate with any of the asymmetries studied.Behavioral and neurophysiological ANT findings related to ADHD in the present study are in accordance with previous publications ,31, 32. Unlike the above-mentioned studies, we homogenized our samples by gender and age, and consequently, we worked with relatively homogeneous EEG patterns, as it is only from the age of 11 that the EEG may be considered homogeneous in terms of development . We therIn the present study, we found strong and moderate correlations between behavioral/biological dimensions and DSM. In a concomitant study, we reclassified these subjects based on a multivariate analysis of a dataset resulting from ANT application. We observed a “substantial level of agreement” between DSM and the phenomenological dimensions of ANT : kappa index = 0.72 , and theAccording to the results obtained, the ADHD group showed lower efficiencies of the alerting and executive networks regarding IVRT and AC. Previous studies corroborate these findings, as patients with ADHD show lower AC and higher IVRT , 31, 32 According to previous findings –17, orieIn the ANT paradigm that was used here , 32, 37,Observing the P3 wave in ADHD, we obtained results that generally replicate literature , especiaWhen analyzing asymmetries in ANT-RPs of AllCd, significant interhemispheric differences were observed in the ADHD group only in the mid- and anterior temporal areas, where they showed a right-side prevalence. In the control group, this prevalence in the same areas presented a higher level of significance and time duration and it was also observed in the posterior temporal region. When we considered asymmetries for different cue and target conditions in terms of attentional networks calculated according to Fan et al. , resultsEvidence found after the publication by Posner and Petersen  has reviIn ADHD, irrelevant information seem to overwhelm brain activity, leading to impaired regulation of voluntary attentional spotlight according to task demand , suggestPossible compensatory mechanisms in ADHD were evident in this study due to a higher negativity in the right occipital region than in the left, evoked in the first 200 ms of target processing. It is well known that the visual processing that subsides perception is modulated by top-down attention . Early EWe emphasized the compensatory nature of this asymmetry with right-side prevalence when we observed that its magnitude is inversely proportional to the inattention score and directly proportional to the accuracy of ANT responses. Asymmetry magnitude is also directly proportional to the efficiency of the executive network, and inversely proportional to the efficiency of the alerting network, both related to accuracy. This finding suggests that despite the top-down attention impairment related to alerting network, a bottom-up compensatory mechanism, probably located in early visual system, supplied visual information to improve conflict resolution between target and distractors and to provide an adequate behavioral response.Studies have suggested that posterior regions seem to develop compensatory functional mechanisms for the low performance of prefrontal executive processes, which participate in sustained attention control , 9. SomeAs studies have reported, attention is modulated by the interplay between dopaminergic and noradrenergic systems in the prefrontal cortex, and it seems that these neurotransmitters perform different roles in attention-dependent behavioral performance in ADHD: the number of hits and the IVRT are maximized by atomoxetine and methylphenidate, respectively , 70. ThuIn this context, we have proposed that impairment of the alerting network could primarily affect target perception causing lower accuracy (lower hit rates). On the other hand, bottom-up asymmetrical compensatory processes at an early stage of visual perception, which are known to be reflected in visual P1-N2 potentials, could improve ANT hit rates, and consequently, the performance of the executive network, especially concerning accuracy.Unlike occipital asymmetry, asymmetry with right-side prevalence detected in the central region C4-C3) within the 45–290 ms window after target onset showed to be significantly higher in ADHD only compared to AllCd and regarding the ‘incongruent target distractor’ condition. We demonstrated that IVRT is higher in ADHD in conflict conditions, revealed by the lower efficiency of the executive network related to motor control. Studies show that ADHD subjects usually have higher IVRT . Our beh-C3 withiBased on the findings discussed here, we defend that the efficiency of the alerting network affects clinical characteristics related to inattention in ADHD, and this inefficiency could compromise visual cognition, resulting in a poorer executive performance, which was observed regarding both AC and IVRT. The likely compensatory mechanisms evidenced in the occipital region of individuals with ADHD would be quite effective to optimize AC and performance in conflict resolution with lower efficiency of the alerting network, suggesting an impaired primordial alerting function, which induces a collateral adaptive process. While IRVT depends on the modulatory control of motricity , the numOccipital and central asymmetries would be relatively independent phenomena from the clinical condition and from primordial ADHD mechanisms. Central asymmetry showed to be dimensional , perhaps related to the performance of executive control over behavior, while coexisting occipital asymmetry showed to be a more specific condition related to ADHD phenomenology. This complex model supports the two-dimensional ADHD clinical phenomenology.The variability of ADHD clinical phenomenology, defined by at least three consistent subtypes , leads us to speculate about the coexistence of different neural processes, which would be specific to each subtype, with mechanisms common to all of them. Perhaps the ADHD subtypes correlate with alerting and executive networks in different ways. We shall establish these correlations in further studies with larger samples of ADHD subjects.S1 DatasetSee dedails in (MAT)Click here for additional data file.S2 DatasetTables with ANT performances, DSM and WISC scores, confounding variables, and peak and mean amplitudes for P3 and asymmetries respectively. Description of the data structure in (XLS)Click here for additional data file.S1 FigDetail from (TIF)Click here for additional data file.S1 TableTotal, inattention—Inn, and hyperactivity+impulsivity–Imp+hyp scores. Pearson’s correlation test (r) for all subjects.(XLS)Click here for additional data file.S2 TableO2 –O1  for each ANT condition correlated to Accuracy scores, and also efficiencies of the alerting and executive networks . For each group: Spearman’s test; and for all subjects: Pearson’s test.(XLS)Click here for additional data file.