The aim of the present study was to investigate the possible association between attention-deficit hyperactivity disorder (ADHD) and non-suicidal self-injury (NSSI) with special focus on the role of comorbidities and gender in a clinical sample of adolescents with both a dimensional and a categorical approach to psychopathology.Using a structured interview, the Mini International Neuropsychiatric Interview Kid and a self-rated questionnaire, the Deliberate Self-Harm Inventory, the authors examined 202 inpatient adolescents (aged: 13–18 years) in the Vadaskert Child and Adolescent Psychiatric Hospital and Outpatient Clinic, Budapest, Hungary. Descriptive statistics, Mann–Whitney U test, chi-square test and mediator model were used.n = 10 (28.60%), girls: n = 25 (71.40%) ((χ2(1) = 10.643 p < .001 ϕ = .452). Multiple mediation analyses resulted in a moderated mediation model in which the relationship between symptoms of ADHD and the prevalence of current NSSI was fully mediated by the symptoms of comorbid conditions in both sex. Significant mediators were the symptoms of affective and psychotic disorders and suicidality in both sexes and the symptoms of alcohol abuse/dependence disorders in girls.Fifty-two adolescents met full criteria for ADHD and a further 77 showed symptoms of ADHD at the subthreshold level. From the 52 adolescents diagnosed with ADHD, 35 (67.30%) had NSSI, of whom there were significantly more girls than boys, boys: ADHD symptoms are associated with an increased risk of NSSI in adolescents, especially in the case of girls. Our findings suggest that clinicians should routinely screen for the symptoms of ADHD and comorbidity, with a special focus on the symptoms of affective disorders and alcohol abuse/dependence psychotic symptoms to prevent NSSI. Attention-deficit hyperactivity disorder (ADHD) –the main symptoms of which are inattention, hyperactivity and impulsivity  – is one of the most common psychiatric disorders, with a prevalence of 4-6% in children and adolescents –9. MoreoDuring the last decades, several clinicians and researchers suggested that besides categorical diagnosis of psychiatric disorders, dimensional approaches should be taken into account both in clinical work and research –20. ReceNon-suicidal self-injury (NSSI) became an individual diagnosis for the first time in the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5), under Section III. ‘Conditions for Further Study’ . The defResearchers have been recently a growing interest in a possible association between ADHD and self-injury, including NSSI – already two systematic review papers have summarized the results and found a strong association between ADHD and self-injury , 29. OneAccording to our knowledge, there is no previous study that has investigated,in both adolescent girls and boys, whether there is a direct association between their symptoms of ADHD and the prevalence of NSSI or whether comorbidity between ADHD and NSSI conditions mediate this association. Therefore, the objective of the current cross-sectional study was to investigate the prevalence of NSSI in an inpatient clinical sample of adolescent girls and boys, either with the symptoms or with a full diagnosis of ADHD. Although, the cross-sectional nature of the analyses preclude causal inferences, we planned to examine whether there is a direct association between ADHD symptoms (fulfilling or not the diagnostic threshold) and the prevalence of NSSI and how the symptoms of comorbid psychiatric conditions influence this, and whether there is a difference between girls and boys at this age.The Ethical Committee of the Medical Research Council, Hungary (ETT-TUKEB) approved the study. The parents of all adolescents included in the study, and adolescents older than 14 years provided written informed consent after the nature of the study had been explained. There was no economic or any other type of compensation provided to the participants.Adolescents, who were inpatients in the Vadaskert Child and Adolescent Psychiatric Hospital and Outpatient Clinic, Budapest, Hungary between 25.02.2015 and 09.05.2016, were included in the study. Inclusion criteria were that the adolescent had to be aged between 13 and 18 years and he/she had to be psychiatric inpatient. Exclusion criterion was mental retardation in the medical history.Psychiatric symptoms and disorders with both subthreshold and fulfilling diagnostic criteria of the classification systems were evaluated by the Hungarian version of the modified Mini International Neuropsychiatric Interview Kid (M.I.N.I. Kid) 2.0 –43). TheSelf-injuries were evaluated by the Deliberate Self-Harm Inventory (DSHI) . DSHI isThe definition of psychiatric disorders, including ADHD and all comorbid diagnoses, were based on DSM-IV . The defCurrent suicidality was defined as having any suicidal ideations and/or suicide attempt with direct desire to end one’s life currently and/or in the past month. The presence of current suicidality was noted if the child answered ‘yes’ to any of the following questions: In the past month did you: Wish you were dead?;, Want to hurt yourself?; Think about killing yourself?; Think of a way to kill yourself?; Attempt suicide? –43.NSSI was defined according to DSM-5  as a: deData were analysed using IBM SPSS Statistics 22.0. Descriptive statistics, Mann–Whitney U test, Chi-square test and mediator model were used. In our survey we used bootstrapping procedure (5000 bootstrap sample) in mediator model. Mann-Whitney U test was used in order to show the age difference between gender, and Chi-square test was used to analyze gender differences among adolescents with both ADHD and NSSI. Those M.I.N.I. Kid –43 diagnIn the case of Chi-square and Mann–Whitney U test analyses, the data of those adolescents who had a diagnosis of ADHD according to the M.I.N.I. Kid were included. The data of those adolescents who had no ADHD diagnosis but who had other diagnoses were excluded.n = 202): both those who had an ADHD diagnosis according to M.I.N.I. Kid and those who did not have an ADHD diagnosis, but had more than five ADHD symptoms (subthreshold ADHD), and also those who had fewer than five ADHD symptoms. In the mediator model, the independent variable was the amount of ADHD symptoms and the outcome variable was the number of self-harm-forms according to the DSHI [While dichotomous variables cannot be used in a mediator model and only 10 variables can be handled in the model, we added the number of symptoms of the M.I.N.I. Kid diagnoses, and these continuous variables were involved in the model. Thus, in the case of the mediator model we enrolled the whole group of adolescents  affective disorders: major depressive episode, dysthymic disorder, hypo/manic episode; b) anxiety disorders: panic disorder, agoraphobia, separation anxiety disorder, social anxiety disorder, specific phobia, PTSD, GAD; c) OCD; d) CD and ODD; e) alcohol abuse and dependence; f) psychoactive substance abuse and dependence; g) psychotic disorder; h) suicidality.The study is asserting statistical mediation with cross-sectional data.p > .05).The study population included 202 psychiatric inpatient adolescents, 99 (49%) boys and 103 (51%) girls. Mean age of the whole study population was 14.87 years (SD = 1.38), the mean age of boys was 14.8 years (SD = 1.43), while the mean age of girls was 14.94 years (SD = 1.35). There was no significant difference between the mean age of boys and girls (U = 4771.000 z = −.806 p > .05).Altogether 52 (25.7%) adolescents fulfilled the diagnosis of ADHD according to M.I.N.I. Kid, 23 (44.2%) boys and 29 (55.8%) girls. The mean age of adolescents diagnosed with ADHD was 14.75 years (SD = 1.25). The mean age of boys with ADHD was 14.95 years (SD = 1.29), and the mean age of girls was 14.58 years (SD = 1.21). There was no significant difference between the mean age of boys and girls diagnosed with ADHD (U = 290.000 z = −.832 p > .05).Additionally, there were 77 (38.1%) adolescents who had more than five ADHD symptoms – which was the threshold for subthreshold ADHD – but less than the required criteria according to the DSM-IV. The mean age of these adolescents was 14.88 years (SD = 1.53). The 77 adolescents with subthreshold ADHD included 40 boys (52%) and 37 girls (48%). The mean age of boys was 15 years (SD = 1.55), and of girls it was 14.76 years (SD = 1.52). There was no significant difference between the mean age of boys and girls with subthreshold ADHD (U = 675.500 z = −.673 2(1) = 10.643 p < .001 ϕ = .452).Of the 52 adolescents diagnosed with ADHD, 35 (67.30%) had NSSI – 10 (28.60%) boys and 25 (71.40%) girls. There were significantly more girls than boys among the adolescents ‘with both ADHD and NSSI(χn = 35).Table Figure Figure N = 202). According to this result moderated mediation model contains direct and the significant indirect effects by gender  came after ADHD symptoms and before the NSSI, moreover mediator variables may temporally occur in between the predictors and the criterion measures. Our data are based self-reported NSSI, which can be biased, i.e., it can be an underestimation, why adolescents may want to deny it. Moreover, we could not use age at which NSSI first occurred in our analyses because there were too many missing and inappropriate data among answers related to this question. Finally, as described the study population are inpatients with ADHD, which suggests that these patients belonged to the more severe end of the spectrum, and in addition the reason for hospitalization could have been comorbid diagnoses, which can be severe comorbidities as well.In conclusion, the high prevalence of NSSI, especially in the case of girls, and its overlap with suicidality among adolescents with the symptoms of ADHD, calls to the attention of clinicians the importance of screening routinely for the risk factors of NSSI and suicidality in this population, with a special focus on girls. While the symptoms of comorbid conditions of ADHD, such as affective disorders, suicidality, alcohol abuse/dependence and psychotic disorders, fully mediate the relation between the symptoms of ADHD and NSSI, the early recognition and treatment of the symptoms of ADHD and these conditions can be important in the prevention of NSSI.


Aim of this study was to determine the prevalence of attention-deficit/hyperactivity disorder (ADHD), its associated correlates and relations with clinical and behavioural problems among children and adolescents with HIV/AIDS (CA-HIV) attending five HIV clinics in central and South Western Uganda.DSM-5 referenced rating scale, the parent version (5–18 years) of the Child and Adolescent Symptom Inventory-5 (CASI-5). Using logistic regression, we estimated the prevalence of ADHD and presentations, correlates and its impact on negative clinical and behavioural factors.This study used a quantitative design that involved a random sample of 1339 children and adolescents with HIV and their caregivers. The Participants completed an extensive battery of measures including a standardized n = 81; 95%CI, 4.8–7.5%). The predominantly inattentive presentation was the most common (3.7%) whereas the combined presentation was the least prevalent (0.7%). Several correlates were associated with ADHD: socio-demographic ; caregiver ; child’s psychosocial environment ; and HIV illness parameters . ADHD was associated with poor academic performance, school disciplinary problems and early onset of sexual intercourse.The overall prevalence of ADHD was 6%  contains supplementary material, which is available to authorized users. The Joint United Nations Programme on AIDS estimates that 88% of the global 3.3 million children and adolescents living with HIV (CA-HIV) reside in Sub-Saharan Africa . Most ofIn Uganda, prevalence of HIV in the general population has stabilised around 7.4% , with hiDSM IV based psychiatric assessment tool that undertakes both a symptom count and assessment of functional impairment, the South African study used the Swanson, Nolan and Pelham rating scale [DSM IV-based psychiatric assessment tool that only assesses symptom count. To date, no study has established the prevalence of ADHD among CA-HIV in Uganda.Previous studies have found that ADHD is one of the most common psychiatric disorders among CA-HIV  , 18 condng scale , a DSM IAlthough it is widely recognized that ADHD is highly heritable , a wide The study comprised a random sample of 1339 child/adolescent-caregiver dyads from the five HIV clinics in rural (Masaka) and urban  Uganda. To be eligible for the study, CA-HIV had to be between 5 and 11 and 12–17 years of age, respectively, and caregivers had to be at least 17 years of age. Both CA-HIV and caregivers had to speak English or Luganda  and plan to reside in the study area for the subsequent 12 months. Exclusion criteria were concurrent enrollment in another study (which applied to only one site), need of immediate medical attention, and unable to understand the study’s assessment instruments.DSM-5-referenced, behaviour rating scale, the Child and Adolescent Symptom Inventory-5 (CASI-5) [DSM-5 diagnosis. The CASI-5 also provides an algorithm that we used to generate the different ADHD presentations.The assessment battery comprised standardised, locally translated psychosocial instruments , 25–35. (CASI-5) , which w(CASI-5) . CASI-5 To obtain the required sample of 268 study participants per study site, research assistants identified potential participants from the patient register. Those who met eligibility criteria were then invited to enroll into the study. This procedure was repeated each clinic day until the required sample size of each site was attained. About 2% of eligible participants were not included owing to a number of reasons including participation in another ongoing study, inability to contact the caregiver to obtain consent, or refusal to give consent by the caregiver.The study protocol was administered by trained psychiatric nurses and psychiatric clinical officers supervised by a clinical psychologist (RM) and overseen by a psychiatrist (EK). Interviews were conducted in two parts, each part lasting 30 min with a tea break in between. Psychosocial assessments used for the first time in Ugandan, which included the CASI-5 , underwep-value for potential confounders is advocated by some experts, e.g., Royston et al. [Prevalence of the three ADHD presentations  as well as any ADHD was estimated with 95% confidence intervals by age-group and gender. Clinical correlates for ADHD were determined by fitting multiple logistic regression models, using the approach recommended by Victora et al. . These vn et al. .Fig. 1CoWe then examined the association of ADHD with several functional outcomes: poor academic performance at school, poor social functioning at school (experienced problems at school), number of visits to the health unit in the past month, hospital admissions in the last month, non-adherence to HIV treatment and risky sexual behaviour  /assent (CA-HIV). Participants found to have a psychiatric disorder were provided with psycho-education and referred to their local mental health departments.Briefly, 64% of CA-HIV were between 5 and 11 years, and 36% were between 12 and 17 years  of CA-HIV met CASI-5 symptom count criteria for at least one ADHD presentation Table . For spep = 0.004), socio-economic status , caregiver psychological distress scores , and quality of child-caregiver relationship   and CD4 counts (p = 0.06) approached significance.Variables associated with ADHD-I symptom count cut-off score were increasing age , quality of child-caregiver relationship , and only assessed among adolescents, having ever been beaten   , with rates highest for those CA-HIV with no living parent compared to those who had at least one living parent .Variables associated with ADHD-C symptom scores were caregiver psychological distress , caregiver psychological distress scores , quality of child-caregiver relationship  .Variables associated with having any ADHD presentation were increasing socio-economic status . None of the ADHD presentations were associated with non-adherence to HIV treatment, number of hospital visits, or number of hospital admissions.ADHD-I presentation and having any ADHD were associated with poor academic performance  with a two- to threefold increase of having any ADHD or ADHD-I . Studies conducted elsewhere have reported a positive association between ADHD and risky sexual behaviour [Early onset of sexual intercourse (only assessed among adolescents) was marginally associated . ADHD among CA-HIV was associated with poorer academic performance, school disciplinary problems, and earlier age of onset of sexual intercourse, all of which may have important implications for clinical management, quality of life, long-term outcome and possible disease transmission. Moving forward, there is a definite need to integrate mental health services into routine HIV care to include the development of cost-effective assessment and treatment strategies that have high probability of success in challenging intervention settings.In summary, approximately 6% of CA-HIV living in Uganda met Additional file 1: Table S1.Data collection tools for the study. (DOCX 30 kb)Additional file 2: Table S2.Characteristics of study participants. (DOC 47 kb)Additional file 3: Table S3.Clinical correlates of ADHD. (DOCX 14 kb)


Attention Deficit Hyperactivity Disorder is prevalent in adulthood, resulting in serious impairment across multiple domains of living. Despite clinical guidance recommendations, the relative infancy of research on service provision for adults with ADHD, along with the evidence transfer gap, means that there is a lack of specific frameworks for service delivery. Igniting research and developing service delivery frameworks within adult ADHD is an essential step in the provision of effective services for adults with ADHD.Following the methodology used in previous related research that utilises a Participatory Action Research approach, we gathered data from clinicians and service users on the domains of living in which they wish to create change, and the steps and end point of the change process. This data was utilised, alongside data gathered from previous research and policies, to develop the domains of assessment for the ADHD Star, and the scale on which change is assessed.The resulting tool, the ADHD Star, consists of eight domains: understanding your ADHD, focus and attention, organising yourself, friends and social life, thinking and reacting, physical health, how you feel and meaningful use of time. Each domain is rated on a five-point scale, the ‘ladder of change’, ranging from ‘stuck’ to ‘choice’.The ADHD Star offers a guiding framework for the development of care pathways and subsequent service provision for adults with ADHD, based on multi-disciplinary, holistic and person-centred care. Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental condition characterised by inattention, hyperactivity and impulsivity, which present in at least two settings, interfering with functioning . The meaResearch on adult ADHD has focused on symptomatic improvement with medication , 19 and In addition to a dearth of research on service provision for adult ADHD, there are well-documented barriers to the application of any research evidence to the frontline of health care. The ‘evidence transfer gap’ has been linked to the size and complexity of the research, difficulties in developing evidence based clinical policy, ineffectual continuing education programmes and poor access to best evidence and guidelines . For ADHThe development process for the ADHD Star closely followed the established four-stage process for developing an Outcomes Star , and as Experts from Triangle Consulting Social Enterprise facilitated the workshops with clinical practitioners in adult ADHD, between June 2013 and June 2014 in Yorkshire, UK. The facilitators have developed a number of Outcome Stars based on the same methodology since 2003 and are the definitive authorities internationally. Health and allied professionals from the Service for Adults with ADHD, South West Yorkshire Partnership NHS Foundation Trust participated in the workshops. This service was established in 2009 and has a catchment area of approximately 1.2 million people in West Yorkshire. The professionals involved were three Psychiatrists, two Clinical Psychologists, two Specialist Occupational Therapists, two Specialist Nurses, one Senior Clinical Pharmacist, one Principal Social Worker, one Senior Medical Liaison Advisor from a Pharmaceutical Company and two Senior Probation Service Officers. A diverse selection of service users and carers with links to this Service also participated in the data creation. This group had excellent knowledge of adult ADHD and involved the participation of representatives from two established service user and carer Charities.During workshop 1, the facilitators delineated a focus of investigation to help formulate a hypothesis that the project would examine. The discussion was informed from previous research by the lead author .i.What are the main areas in which services and service users seek to create change?ii.What is the desired end point of the change process?iii.What model of change describes the core steps that service users take on the journey towards the end point?Three key questions were derived:i.Bringing to mind an individual who has undergone a substantial change and identifying the key areas of change.ii.The use of metaphor and drawing to get a sense of the whole or essence of the change people undergo.iii.Structured questioning exercises to draw out the change steps one by one in each outcome area; drawing out concrete information about the signs of change in great detail based on the experience of the professionals, service users and carers.Focused exercises during workshops 1 and 2 generated data on participants’ subjective experiences of ADHD. A number of different techniques were used to draw out the experience and the implicit models that professional and service users and carers held about adult ADHD including:Further data was gathered from a review of the evidence base including key policy documents, National Guidelines, and relevant published research on adult ADHD.Following each workshop, the facilitators examined the transcripts and notes created by the participants and facilitators. A method of phenomenological sense-making described by Wertz  was follThe answers to the three questions outlined in Step 1 were presented back to the professionals in the form of a printed version of the ADHD Star for feedback and testing. Through an iterative process of sharing, listening, refining and sharing again, the outcome areas, the model of change and descriptions of the steps towards change in each outcome area were honed until they truly resonated with the professionals and service user and carers.An initial draft of the ADHD Star was developed following workshop 1, and presented in workshop 2, at which point, further structured questioning generated feedback from all participants. An amended version of the ADHD Star was then piloted during a 6-month period. Fifteen adults accessing the Service for Adults with ADHD participated in the pilot through the completion of the ADHD Star with a health-care professional. This was a sample of convenience in which the Star was used as part of the Service day to day practice of care planning. They had combined type of ADHD, did not have any other comorbidity, 11 were male and 4 were female with an average age of 24 years old; professionals and service users recorded their experience through questionnaires. During the workshop 3, the results of the pilot were reviewed [including feedback and ADHD Star data] and the experience of participants was again shared. The feedback was mainly about reducing the steps of the ‘ladder of change’ from ten to five and comments about specific descriptors of change in the text. On the basis of this, further revisions were made to the ADHD Star and facilitators and participants approved the final version.first aimed to understand the aspirations and goals of service users and determine a meaningful and structured ‘journey of change’ across disorder-specific domains of need. Such an approach should define the desired outcomes of a person's life, based on the goals that they set for themselves. These goals should be individualised and consider: a decent place to live, employment and/or opportunity to contribute, education, friends and recreation outlets. Together, these outcomes will comprise the quality of one's life [The aim of the current advancement was to develop a tool to serve as a framework to guide service provision for adults with ADHD. We e's life .Second, we aimed to develop a tool that incorporated this knowledge in a way that was accessible to professionals and service users. Outcome Stars developed by Triangle Consulting Social Enterprise have already been successfully utilised in health services in the UK [n the UK –47, therThe ADHD Star addresses a gap in the current provision of services for adults with ADHD, offering a person-centred measure of progress in meaningful dimensions of change. Currently, instruments utilised with adults with ADHD in the UK healthcare system  focus onThe ADHD Star offers a basis of care delivery for adults with ADHD, which has many advantages over current practice. First, it emphasises collaboration between service users and health-care professionals. Engagement with service users can be improved through the conversation generated by the tool. The outcome of this conversation is a shared care plan guided by adult ADHD specific domains that will resonate with the individual’s needs. A predicted consequence of this person-centred care is an improvement in adherence with proposed interventions and reduction in outpatient non-attendance rates. Second, the ADHD Star ensures that several domains of potential improvement will be considered as part of the assessment, thus opening the opportunity of multidisciplinary plans to be formulated and broader, holistic interventions applied. Third, the ‘ladder of change’ not only provides the opportunity to assess the service user’s current functioning, but also identifies the next step along that journey, thus ensuring robust goal-setting. Fourth, the ADHD Star enables different healthcare professionals to offer specialist input according to their skill and training across a specific domain, strengthening professional identity and specialisation. Fifth, when reviewed accordingly, the ADHD Star can be used as a tool to enable outcome-based commissioning.There are some potential limitations to the implementation of the ADHD Star in healthcare services. Administration can take approximately two hours, which some services would deem too time-consuming. However, this time is spent in collaborative care-planning with the service-user, and will ensure meaningful goals are set and enhance commitment to agreed interventions. Therefore, we argue that ultimately, the time spent administering the ADHD Star will be saved elsewhere in failed interventions, and disengagement of service users. The ADHD Star was specifically designed to focus on meaningful outcomes for service users, and thus purposely omits ‘hard’ outcomes, i.e., symptom reduction. In isolation, the ADHD Star would neglect these outcome areas, which may be important to assess for monitoring the success of appropriate medical interventions as recommended by many authorities . Thus, wPeople with ADHD present in adulthood with impairments that have been developing for years, which are attributed to their symptom experience. As a result of this longevity, a framework is required to underpin a programme of evidence-based multidisciplinary interventions that have a clear direction and goals. We suggest that the ADHD Star offers such a framework and serves as a means to monitor outcomes for the purposes of service development. Future research should focus in investigating if the ADHD Star correlates with change on existing measures of ADHD-related impairments in quality of live or objective changes in an individual’s life such as changes in income, job status, housing, education and romantic relationship status.


This study compared the effectiveness of manualised training, executive, attention, and motor skills (TEAMS) training versus standard treatment in preschool children with attention deficit hyperactivity disorder (ADHD). We conducted a randomised parallel group, single-blinded, superiority trial. The primary outcome was ADHD symptoms and the secondary outcome was functionality. Parents and primary school teachers assessed outcomes at pretreatment, posttreatment, and at one, three, and 6 months follow-up.In total, 67 children (aged 3–6 years) were randomised. In the TEAMS group, 32 out of 33 (97%) participants completed the total 8-week program, compared with only 7 out of 26 (27%) in the control group. The repeated-model analyses showed no significant change between the two interventions for ADHD symptoms and functionality levels over time. The mean difference in ADHD symptoms between TEAMS versus standard treatment at posttreatment was 2.18 points .Trial registration Clinical Trials identifier: NCT01918436 (Retrospectively registered). Registered on 7 August 2013.The online version of this article (10.1186/s13104-018-3478-3) contains supplementary material, which is available to authorized users. Attention deficit hyperactivity disorder (ADHD) is a prevalent and chronic neuropsychiatric disorder with three core symptoms: inattention, hyperactivity, and impulsivity . NeuroimEarly childhood is a particularly vital and responsive period in brain development , 5. InteWe conducted a randomised parallel group, single-blinded, superiority trial. A comprehensive description of the trial design and rationale has been published elsewhere . The stuThe recruitment period lasted from January 1, 2012 to October 31, 2015. Eligible children were referred from four child and adolescent psychiatric clinics in Region Zealand, Denmark, to an ADHD outpatient clinic in Holbaek, Denmark, where randomisation and both interventions were carried out. The interventions lasted for 8 weeks, with follow-up assessments at 1-, 3-, and 6-months.Participants were included if they: (a) had a formal diagnosis of ADHD according to the diagnostic and statistical manual of mental disorders ; (b) werThe randomisation was conducted with the web-based tool OPEN Randomize . We usedParents and teachers rated the primary outcomes at baseline, at post-treatment, and at follow-ups. The ADHD rating scale-IV (ADHD-RS IV)  is a norm-referenced checklist, and contains 26 items that measure ADHD symptomology, including hyperactivity/impulsivity, inattention, and conduct problems , 15.The strengths and difficulties questionnaire—Denmark (SDQ-DAN) is a behavioural screening questionnaire for children between 2 and 17 years, and measures emotional, conduct, hyperactivity, and peer problems . Please The participants in the TEAMS intervention were divided into groups of two to five families, who had 8 weekly 45-min meetings with separate parent and child sessions. The parent groups mainly consisted of psychoeducation and collaborative problem solving . The chiThe control group was the conventional treatment regime for preschool ADHD patients, as outlined by the Danish national clinical guidelines . It entaThe sample size was calculated based on a type I error (α) of 5% and a type II error (β) of 20% (i.e. power of 80%), with an allocation ratio of 1:1 . We usedThe significance level was set at p < 0.05. Prior to each analysis all effect measures were inspected for normality .Descriptive statistics were generated. We used a stepwise procedure to test the effect of the intervention and the effect of time. The effect size was estimated by mean differences and confidence intervals (CI) at baseline, posttreatment, 1, 3, and 6 months using independent sample T tests. Subsequently, we performed adjusted analyses with an analysis of covariance model (ANCOVA) to incorporate covariates, pre-score , and group as a fixed-factor. We compared the difference between baseline and 8 weeks after the TEAMS intervention program, as well as the difference between the two groups. The ANCOVA model allowed us to look for differences in adjusted means (i.e. adjusted for the covariates). Finally, we measured the effects of the TEAMS intervention at different time points and between groups by using a general linear repeated measure model (GLM). In advance, model fit was assessed for each regression model.As we were unable to reach the planned sample size, we conducted a post hoc trial sequential analysis on the primary teacher-rated outcome ADHD-RS IV at posttreatment. Trial sequential analysis is a tool for quantifying the statistical reliability of data by adjusting significance levels for sparse data and repetitive testing for accumulating data –23. The Only 72 participants were eligible during the trial inclusion phase from January 1, 2012 to October 31, 2015, and five declined to attend the trial. This left us with 67 eligible participants to be randomised  participants completed the total 8-week program. 33 were assessed at 1-month follow-up, 32 at 3 month follow-up and 33 and 6 months follow-up. Seven participants (21%) from the control group completed the total 8-week program. In turn, 20 (77%) participants were lost at 1-month follow-up, 19 (73%) at 3 months follow-up, and 18 (69%) at 6 months follow-up. Because of the substantial attrition rates in the control group, the intention-to-treat principle and multiple imputations were not conducted. Age, sex, and baseline ADHD-RS-IV and SDQ-DAN scores were balanced between the groups  on the primary outcome ADHD symptoms at 8 weeks –23 Addi. The reqNo significant improvements on ADHD symptoms or functionality were seen over time in the TEAMS intervention compared with the standard treatment. There was substantial dropout in the standard treatment group, with 19 out of 26 participants (73%) withdrawing during the intervention period. This was mainly because parents in the standard treatment group wanted their children to initiate pharmacological treatment. The parents in the TEAMS group seldom raised this request.The Danish health authorities recommend non-pharmacological treatments for preschool children with ADHD . We chosThis trial has some strengths. We published a protocol beforehand, the outcome assessors were blinded to treatment allocations at baseline assessment, and we only used two outcome measures, which may have protected for multiplicity issues due to random errors , 25. PubThe required sample size of 90 participants was not reached, because there were too few referrals in the target age group during the time of enrolment. Thus, the trial is underpowered to detect a true difference (i.e. at risk of type II errors). We also experienced dropouts during the initial baseline assessment on sociodemographic factors. The large and uneven attrition rates likely confounded the results as well . We planAdditional file 1. Baseline characteristics  for the TEAMS- and control group.Additional file 2. ANCOVA model of the effect after eight weeks and between-groupsa.Additional file 3. Box plot of differences between groups over time for ADHD scores. Group 1 = TEAMS and Group 0 = Control.Additional file 4. Box plot of differences between groups over time for SDQ scores. Group 1 = TEAMS and Group 0 = Control.Additional file 5. Trial Sequential Analysis on ADHD symptoms. MRDIF = Minimal relevant difference.


Eucommia ulmoides Oliver leaf. The maximum polysaccharides yield of 12.31% was achieved by microwave extraction at 74 °C for 15 min with a solid to liquid ratio of 1:29 g/mL, which agreed with the predicted value and was 2.9-fold higher than that of the conventional heat-reflux extraction method. The dominant bioactive constituent in extracts was chlorogenic acid (1.3–1.9%), followed by geniposidic acid (1.0–1.7%). The polysaccharides from the optimized extraction had a high molecular weight and polydispersity , as compared to the fraction prepared in the absence of microwave . Glucose was the dominant sugar component (38.2–39.1%) of heterogeneous polysaccharides which belonged to a structure of β-type acidic heteropolysaccharides with a glucan group and highly branched degree. The polysaccharides showed a higher DPPH radical scavenging index (0.87–1.22) than BHT (0.41) but lower than BHA (3.56), which can act as a favorable antioxidant in functional food.Microwave-induced technique was combined with response surface methodology for optimizing the isolation of polysaccharides from  These abundant polysaccharides and bioactive components are ideal candidates for potential utilization in food and biomedical industries. Eucommia ulmoides Oliver (E. ulmoides), also called Du-Zhong in Chinese, which belongs to the Eucommiaceae family, is one of the most famous traditional woody plants growing in China for nutrition and folk medicine. Used in the treatment of hypercholesterolemia, hypertension, and fatty liver diseases, Du-zhong tea (refers to the aqueous extract of E. ulmoides leaf) has been commonly adopted and already known as a functional health food8. In addition, the existence of phenolic composition results in various beneficial health properties of E. ulmoides, which occurs in nature as a mixture of esters, ethers, or free acids9. It has been found that the bioactive constituents are rich in E. ulmoides leaf, such as polyphenolic acids, flavonoids, iridoids, and nutrients11. The main effective constituents have been demonstrated to extend the mean lifespan and protect against stress-provoked influenza viral infection12. Polysaccharides are a widespread biological macromolecule composed of the same or different monosaccharides and uronic acids that condensed by glycosidic linkages, and are essential ingredients for all living organisms13. Polysaccharides are widely found in plants, microorganisms, bacteria, fungi and seaweed, and they are closely related to many physiological behaviors of life3. Moreover, polysaccharides in both simple and complex glycoconjugated form have the potential to support a variety of functions, such as antioxidant, antivirus, immunomodulation, antidiabetes, hepatoprotection, antitumour, and antifatigue functions15. It has been found that polysaccharides isolated from Eucommia ulmoides leaf possessed an important antioxidant role with effective scavenging activities on radicals, which are suitable for the development of medical reagents16.Because of the potent nontoxic effects and therapeutic properties, the research on the biological polysaccharides and associated antioxidants from plant resources has attracted an increasing interest in the last decades with a diversified range of applications. The water-soluble polysaccharides and water extracts from Chinese traditional herb materials exhibited efficient bioactivities, including antioxidant, immunomodulation and anti-tumor, as reported by the previous studiesE. ulmoides leaf polysaccharides (EULP) and antioxidants from E. ulmoides leaves is imperative. Up to now, hot water technology is the mostly adopted method for the conventional isolation of polysaccharides and active compounds17, which is however associated with longer extraction time and lower efficiency. In the effective epuration of products from different plant materials, microwave-assisted extraction (MAE) has been widely conducted due to its accelerated mass transfer between immiscible phases facilitated by the electromagnetic radiation19. As compared to other methods, response surface methodology (RSM) allows more efficient interpretation and easier arrangement of experiments. RSM is an effective multivariate statistical method for optimizing complex experimental processes. It generates a second-degree polynomial model by regression fitting of response surface analysis to evaluate the polytomy variables and its interaction, and then determine the best level. The most important advantage of RSM is the reduced number of trials on process optimization21. Box-Behnken design (BBD), a type of RSM, is an independent, spherical, and rotatable quadratic method that consists of three interlocking 22 factorial designs with points locating on the surface of a sphere surrounding the center of the design. It has been successfully exerted to optimize various biochemical and biotechnological processes22. Therefore, RSM has been used frequently to optimize the parameters of extraction experiments25.Therefore, an efficient technique for the extraction of E. ulmoides leaf. The MAE process optimized by RSM can thus be predicted and controlled for industrial applications. A mathematical model was constructed by RSM to evaluate the effects of the three independent variables and their combinatorial interactions on the extraction yield of target products. A comparative analysis between the MAE and conventional heat-reflux extraction (CHE) methods was also conducted. The eight main types of bioactive compounds associated with E. ulmoides leaf polysaccharides in the supernatant were identified and quantified by high performance liquid chromatography (HPLC). Analysis of the chemical compositions, structures, and antioxidant capacity of EULP was carried out by ultraviolet-visible spectroscopy (UV-Vis), sugar analysis, gel permeation chromatography (GPC), and Fourier transform infrared spectroscopy (FTIR) for unraveling the possibility of adopting the antioxidant polysaccharides to functional foods.In this study, a three-level and three variables BBD was used to model and optimize the extraction parameters  of polysaccharides by the MAE process for the elucidation of the different parameters that govern the extraction and structure of polysaccharides from E. ulmoides leaves were manually harvested from the arboretum of Northwest A & F University, Yangling, China. To remove dusts and impurities deposited on the surface, the leaves were rinsed in water repeatedly and then dried in an oven at 40 °C until constant weight was attained. Subsequently, the dried samples were ground and sieved to obtain fine powder of about 400‒500 μm particle diameter size, and stored in dry and dark environment prior to use.Fresh The standard reagents, such as bioactive components and monosaccharides , were of chromatographic purity. Other chemical agents, including ethanol, sulfuric acid and phenol, were purchased from Sigma Chemical Company  and used without further purification.24. Briefly, 2.0 g of ground leaf samples were mixed with specific volume  following a chromatography analysis procedure reported in the literature26. The structural formulas of these bioactive components are illustrated in Fig. Quantitative analysis of the concentration of chlorogenic acid (CGA), geniposidic acid (GPA), geniposide (GP), rutin (RU), quercetin (QU), kaempferol (KA), aucubin (AU), and pinoresinol diglucoside (PDG) in the extractum from et al.24. The molecular weights of polysaccharides were determined by GPC following an established procedure27. A 2 mg sample of EULP was dissolved in 2 mL mixture of 0.02 M NaCl and 0.005 M sodium phosphate buffer (pH 7.5) prior to measurement. The experiments were performed at least three times. High performance anion exchange chromatography (HPAEC) was employed to determine the monomeric sugars released by the acid hydrolysis of EULP with 1 M H2SO4 for 2.5 h at 105 °C27. FTIR spectra of polysaccharides were conducted using a FTIR Microscope  equipped with a MCT detector cooled by liquid nitrogen27.Phenol-sulfuric acid method was adopted for the determination of carbohydrate content of EULP with glucose as the standard reagent following the procedure described by Gan 28. The scavenging ability was calculated by the following formula:After adding the mixture of polysaccharide solutions or control (EULP-CHE) in ethanol solution, the DPPH  radical scavenging effect was measured0 is the absorbance of water used as the control, A1 is the absorbance of the sample, A2 is the absorbance of the sample under identical conditions as A1 and with water instead of DPPH solution. IC50 was referred as the concentration of EULP with 50% inhibition. Radical scavenging index (RSI) was defined as the count backwards of IC50.where Ap < 0.05 after analyzing the variance (ANOVA) and processing with SPSS 13.0. The Design Expert software  was utilized for the regression analysis and the optimization of graphics.All the data were calculated as the mean of three replicate determinations within significance Alfaro and co-workers introduced a term known as energy density, power per mass for a given unit of time, to investigate the effect of microwave power on MAE29. It is reported that once the plant matrix was destroyed by microwave radiation, the active compounds would be released. Higher power level does not give any contribution to the investigation of interaction between microwaves and extraction solvent with the sample. Temperature and microwave power were interrelated, as high microwave power could raise the extraction temperature which has been optimized in this investigation30. The process variables, including liquid to solid ratio (10:1–30:1 mL/g), extraction temperature (40–80 °C) and time (10–30 min), were selected by the single parameter analysis. As shown in Table In the current BBD of RSM, a total of 17 runs were applied in the production of EULP to optimize the three individual parameters. The effects of three MAE conditions, including liquid to solid ratio (A), extraction temperature (B) and time length (C) on the yields of EULP  were investigated  and a low p-value (p < 0.01) of the equation. The coefficient value (R2) of the model was 0.9603, implying a sample variation of 96.03% for the yield of EULP. An excellent correlation between the independent variables was determined by the adjusted correlation coefficient (R2Adj) of the model.The analysis of variances was employed for selecting the best model matched with the operation results Table . The dom31. These findings were in consistent with the fractionation of natural polysaccharides from Zizyphus jujuba cv. Jinsixiaozao21 and Anastatica hierochuntica32. The effects of liquid to solid ratio (A) and extraction time (C), and their reciprocal correlations on EULP yield at 60 °C were depicted in Fig. p > 0.05, Table In each 3D response surface plot, the interaction of two variables was studied simultaneously, while the value of third parameter was set in its middle level, and the results are shown in Fig. E. ulmoides leaf, was acquired at 73.65 °C for 15.16 min with a liquid to solid ratio of 28.9. A verified experiment was conducted under the optimal conditions to confirm the accuracy of the model. To validate the actual operation conditions, the EULP yield of 12.31% was achieved at 74 °C for 15 min with a liquid to solid ratio of 29, which matched the predicted yield of the RSM model. These results confirmed that the response model is sufficient to reflect the good correlation between the theoretical optimization and experimental value.Under the optimized experimental conditions for the MAE process, the theoretical maximum EULP yield of 12.35%, corresponding to initial weight of dried E. ulmoides leaf ratio of 29 mL/g, extraction at 74 °C in water bath for 15 min), and a yield of 5.62% was achieved. The comparison between the CHE and MAE methods indicated that microwave irradiation can greatly improve the extraction efficiency (12.31% vs. 5.62%) and the purity of polysaccharides (89.5% vs. 84.2%). This result was consistent with the previous studies of polysaccharides extraction36. The high extraction efficiency of EULP by the MAE process can be attributed to the breaking of the cells from E. ulmoides leaves by the microwave treatment, which facilitates the dissolution of the polysaccharide fractions in the solvent33. The result demonstrated that microwave-assisted extraction of polysaccharides from E. ulmoides leaf was a time-saving, efficient and high yield method.As a control sample, EULP-CHE was extracted with the CHE method at the optimized conditions , rhamnose (5.6–17.4%), and galactose (14.1–15.2%) were present in small amounts. Xylose (2.1–10.9%) and mannose (1.7–4.5%) were observed as the minor constituents in all polysaccharides. In addition, it was found that a certain amount of uronic acid (11.1–13.3%) was presented. The first polysaccharide, designated EULP-CHE, contained L-rhamnose, L-arabinose, D-galactose, D-glucose, D-xylose, D-mannose, D-glucuronic acid, and D-galacturonic acid, in the approximate molar ratios of 9:32:20:55:19:2:14:1. The other (EULP-MAE) contained the alike monosaccharides in the approximate molar ratios of 7:4:6:14:1:2:3:1. Interestingly, it was found that the discrepancy between the contents of rhamnose, arabinose, and xylose in the two polysaccharides were significant, suggesting the differences of sugar composition in polysaccharides were ascribed to the different extraction processes. The possible interpretation was that the linkages, such as the hydrogen bonds, between the polysaccharides and the other components in the plant cell walls of E. ulmoides leaf were partially cleaved, which led to different contents of sugars. It is worth mentioning that both EULP-CHE and EULP-MAE contained a major fraction of glucose, amounting to 38.2% and 39.1%, respectively. This indicated that some β-glucans or starch were probably presented in the isolated polysaccharides and the microwave-assisted treatments may favor the release of β-glucans.The monosaccharide composition of polysaccharides after acid hydrolysis was identified and determined through sugar analysisMw) and number-average (Mn) molecular weights, and polydispersity (Mw/Mn) of the polysaccharide fractions were determined to estimate the effects of the microwave heating on the molecular structures. The molecular weight distribution of fractions was analyzed by GPC and the representative spectra are presented in Fig. Mw 38,830 g/mol, Mw/Mn 2.19). From molecular weight analysis of the polysaccharides EULP-CHE, a narrower distribution and apparent reduction of the molecular weight were observed . These discrepancies in molecular weight were probably due to the nature of the sample and the various isolation conditions used, in which the backbone chain and substituent of polysaccharides may play a very important role in manipulating the molecular weight. Furthermore, molecular weight distribution curves also illustrated the structural feature of the polysaccharides obtained by different extraction processes. It was found that EULP-MAE exhibited bimodal molecular weight distribution. This suggested that the microwave had considerable linkage-breaking effects, which ultimately led to heterogeneous molecules, as confirmed by polydispersity. However, the polysaccharide fraction EULP-CHE displayed unimodal molecular weight distribution curves. This phenomenon could be ascribed to slow mass transfer between the solvent and E. ulmoides leaf when performed with the CHE. This work proved that the MAE method is a feasible way to explore the potential application of polysaccharides-based bioactive components in the food industry.The weight-average  of uronic acids in polysaccharides, and those in the region of 1652 cm−1 are due to bound water42. A weak symmetrical stretching peak at approximately 1400–1200 cm−1 can be attributed to the presence of carboxyl groups41. The peaks in the range 1200–1000 cm−1 corresponded to the ring vibrations overlapping with stretching vibrations of the (C–O–C) glycosidic linkage vibration and (C–OH) side groups43. As can be seen in Fig. –1, which corresponded to the C–C and C–O stretching modes and the glycosidic band (C–O–C) vibration in polysaccharides44. This finding implied that a typical absorbance for xylans was presented in the polysaccharide fractions. The weak absorbance at 1238 cm−1 was due to the fraction EULP-CHE, and some acetyl groups attached to the polysaccharides were confirmed by the weak peak at 1238 cm−1. This indicated that more acetyl groups linked to the polysaccharides were degraded in the presence of microwave irradiation, thus only a portion of the acetyl groups were preserved in EULP-MAE. The absorption at 913 cm−1 was related to the β-pyranose of glucose. Another absorbance at 892 cm−1 was related to the C1 group frequency or ring frequency in the polysaccharides, which corresponded to the β-glycosidic bonds between the D-mannose units. Moreover, the band at 760 cm−1 showed a β-configuration of the sugar units. Based on the FTIR and sugar analysis of EULP-CHE and EULP-MAE, it can be assumed that these polymers belonged to a structure of β-type acidic heteropolysaccharides with a glucan group and highly branched degree.To further investigate the structural heterogeneity between the bioactive hydrophilic polysaccharides, FTIR spectra of EULP-CHE and EULP-MAE were recorded Fig. . The spe45. The scavenging effect on DPPH radical of EULP-MAE was much higher than those of EULP-CHE at the concentrations ranged from 0.1 to 2.0 mg/mL, which was closely interrelated with the phenolic content of the extractum. At the sample concentration of 2 mg/mL, EULP-MAE exhibited pronounced DPPH radical scavenging activity of 84.3%, which was significantly higher than that of EULP-CHE (65.9%). The order of radical scavenging effect of EULP to DPPH in comparison with the control  was BHA > EULP-MAE > EULP-CHE > BHT. In the present study, the increment of DPPH antioxidant effect of the polysaccharide fractions was in accordance with the increase of the average molecular weight. The IC50 values were 0.41, 0.87, 1.22 and 3.56 mg/mL for BHA, EULP-MAE, EULP-CHE, and BHT respectively. The results demonstrated that all the polysaccharide fractions had lower antioxidant capacity than BHA, but higher than BHT. In comparison with the high cost and the limited efficiency of artificial antioxidants, such as BHA and BHT, the extracted polysaccharides offered a relatively feasible source of natural antioxidant. Overall, the investigations of antioxidant effect in vitro suggested that the polysaccharides extracted by the MAE process demonstrated an improved antioxidant capacity and had promising prospects in potential applications as functional foods. It could improve aging and age-related diseases by reducing intracellular free radicals46. Owing to their safety and nontoxic properties, some of bioactive polysaccharides have also been widely used in biochemical and medical industries47.As compared to the classic commercial antioxidants, including BHA and BHT, the antioxidant activity of EULP against DPPH radical is presented in Fig. E. ulmoides leaf, the MAE technology was combined with RSM for the optimization of extraction process. On the basis of contour plots and variance analysis, the maximum polysaccharides yield of 12.31% was achieved by extraction at 74 °C for 15 min with a solid to liquid ratio of 1:29 g/mL, which was 2.9-fold higher than that of the CHE method and in good agreement with the predicted yield value (12.35%). Moreover, the extractum collected by the MAE process showed 1.7-fold higher yield of bioactive constituents as compared with the CHE process. The polysaccharides were identified to belong to the glucan family from the FTIR spectroscopy analysis. All these polysaccharides have similar compositions which were comprised of a large amount of glucose (38.2–39.1%) and a small quantity of other sugar components. The polysaccharides from optimized MAE process had a high sugar content (89.5%), together with a high molecular weight  and polydispersity (Mw/Mn 2.19), and exhibited high antioxidant activity (RSI 1.22). It was concluded that the MAE provided a promising alternative to isolate polysaccharides and bioactive components from E. ulmoides for potential application as natural antioxidants in food or biomedical industry.To improve the yield of polysaccharides from


Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are neurodevelopmental disorders characterized by social impairments. The first objective of this study was to analyze social cognition deficits of children with ADHD, high-functioning ASD (HFASD), and typical development (TD) in their performance on explicit and applied measures of theory of mind (ToM). The second objective was to investigate the relationships between executive functions and social cognition in HFASD and ADHD. One hundred and twenty-six 7- to 11-year old children, 52 with HFASD, 35 with ADHD, and 39 with TD, performed the NEPSY-II social perception subtests. Parents estimated their children's ToM skills using the Theory of Mind Inventory (ToMI). Teacher-reported data from the Behavior Rating Inventory of Executive Function (BRIEF) were also obtained. The HFASD and ADHD groups showed worse performance on the verbal ToM task than the TD group, and only the performance of the HFASD group was significantly lower than the TD group on the contextual ToM task. Parents also estimated that the HFASD group had more difficulties on the applied ToM than the ADHD and TD groups. Furthermore, there is a different executive function-theory of mind link in the HFASD and ADHD groups: behavioral regulation processes such as inhibition and emotional control are more associated with social cognition in children with ADHD, whereas metacognitive processes such as initiation and planning have a strong association with social cognition in children with HFASD. These findings have implications for understanding social perception deficits in neurodevelopmental disorders, highlighting the need for early intervention. Autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) are two disorders that stem from a disruption in the development of the brain and share the same genetic etiology, which largely explains the complexity of the impairments that characterize them  refers to the mental operations that underlie social interactions and involve interpersonal sensitivity in real social settings. It is a broad, complex, and multifaceted construct that reflects a wide variety of psychological processes, highlighting affect recognition (AR) and theory of mind (ToM). On the one hand, AR consists of identifying emotionally salient information in the environment, including verbal  and nonverbal  cues about other people's emotions , group differences in intelligence, and the diagnosis of the type of presentation of the ADHD participants. Thus, one important area for future research is the continued investigation of these two neurodevelopmental disorders. This study builds on the previous one, focusing on the analysis of similarities and differences between the implicit and explicit ToM systems and possible links between ToM and EF in children with HFASD and children with ADHD. In order to obtain reliable conclusions, critical factors have been controlled, specifically the intelligence level (IQ) and verbal ability, given the degree of overlap between IQ and EF and the relationships between verbal ability and the capacity to represent mental states Happé, .Considering the significance of these findings about similarities and differences between ASD and ADHD in the conceptualization of these two disorders, the first objective of this study is to compare the AR and ToM abilities, both explicit (laboratory tasks) and applied , in children with HFASD, ADHD, and TD, matched on chronological age, mental age, and vocabulary. Children with HFASD are expected to have worse performance on all the measures of social cognition than the children with TD. Children with ADHD are expected to show a more variable performance, depending on the type of measure, and occupy an intermediate position between the children with HFASD and the children with TD.The second objective consists of exploring in the two clinical groups, children with HFASD and children with ADHD, the interplay between AR and ToM skills and “everyday” components of EF measured by the BRIEF. Based on the limited literature examining the relationship between executive and social functioning in children with ASD and children with ADHD, we predict that the EF components that have a significant relationship with the ToM in both disorders will differ. Specifically, we expect that EF behavioral regulation index subdomains, a characteristic deficiency seen in individuals with ADHD Barkley, , will man = 52), a group with ADHD (n = 35), and a group with TD (n = 39). Mean age of children with HFASD, M = 8.59, SD = 1.38; children with ADHD, M = 9.14 SD = 1.41; children with TD, M = 8.46, SD = 1.27. The decision on the age range was motivated by developmental reasons  and due to the importance of Primary Education in the Spanish education system that coincides with this developmental period. All the participants had an overall IQ equal to or above 80, measured with the K-BIT  = 2.61, p = 0.078, total IQ, F = 0.865, p = 0.423 and semantic language level, assessed with the vocabulary subtest of the WISC-IV  = 1.03, p = 0.350. In addition, 91.42% of the HFASD group and 94.3% of the ADHD group were male.Participants in this study were 126 children from 7- to 11-years old, distributed in three groups: a group with HFASD . The clinical diagnoses of HFASD and ADHD were confirmed before applying the battery of tests selected for the present study. Specifically, to confirm the HFASD diagnosis, strict cut-off points recommended for the Social Communication Questionnaire  and two children with ADHD (5.7%) were attending school in regular classrooms full time; 29 children with HFASD (55.7%) and 33 with ADHD (94.3%) attended regular classrooms but received educational support for their specific needs in the school; and finally, 20 children with HFASD (38.5%) were placed in the Communication and Language classrooms modality.Participants with TD were all attending school in regular classrooms in the same schools where the children with ADHD and HFASD attended. They had no history of psychopathology or referral to children's mental health units (USMI), according to the information from the school records, and they did not meet the DSM 5 criteria for ADHD or HFASD on the screening carried out by SCQ before beginning the evaluation.The exclusion criteria for the children who participated in the study were evaluated through an extensive prior anamnesis carried out with the families. They included severe or genetic neurological diseases, brain lesions, psychosis, visual, auditory, motor, or sensorial deficits, and an intelligence coefficient <80. The administration of psycho-drugs was only an exclusion criterion for the TD group. By contrast, 32.7% of the children in the HFASD sample were taking antipsychotics (mainly Risperidone), and 71.4% of the children in the ADHD sample were receiving psychostimulants, generally time-released (mainly Methylphenidate).The study was approved by the Ethics Committee of the University of Valencia . It obtained the approval of the Consellería de Educación de la Generalitat Valenciana to locate children who had received a previous diagnosis of HFASD or ADHD by professionals in specialized childhood mental health services. The families were personally told about the aims of our research and asked for their informed consent. Oral permission from the children and written informed consent from their parents were obtained before beginning the evaluation, which took place in the schools in which they were enrolled.The intelligence test and the two tests from the social perception domain were administered to all the children individually by trained examiners in prepared classrooms in the different schools. The parents provided information about their children's ToM skills in daily life contexts, and the teachers-tutors filled out the questionnaire selected to assess the EF.The subtest from the social perception domain of the NEPSY-II battery  and specificity (0.9) when used to examine children with ASD, although its purpose is not to perform a differential diagnosis . The items are grouped in 8 scales: Inhibit (“Interrupts others”); Shift (“Becomes upset with new situations”); Emotional control ; Initiate (“Is not a self-starter”); Working Memory (“Has a short attention span”); Plan/Organize (does not finish long-term projects); Organization of materials (“Leaves playroom a mess”); and Monitor (“Does not check work for mistakes”).The scales make up two indexes. The Behavioral Regulation Index (BRI) is composed of the Inhibit, Shift, and Emotional Control scales, assessing the child's capacity to make cognitive changes and adjust his/her emotions and behavior through appropriate inhibitory control. The Metacognition Index (MI) is composed of the Initiate, Working Memory, Plan/Organize, Organization of materials, and Monitor scales. This index reflects the child's ability to initiate, plan, organize, self-monitor, and maintain working memory. It could be interpreted as the ability to self-manage cognitive tasks and supervise their performance. This index is related to the capacity to actively solve problems in a variety of contexts.The direct scores can be transformed into T-scores, with higher scores indicating worse EF. The questionnaire's reliability and validity have been adequately demonstrated , version 22.00 . Multivariate Analysis of Variance (MANOVA) was conducted to analyze differences between the HFASD, ADHD, and TD groups on the AF and ToM (explicit knowledge) subscales of the NEPSY-II and the ToMI inventory (applied knowledge). For the additional ANOVAs, the level of significance was set at F = 13.76, p < 0.001, η2p = 0.48]. ANOVAs showed significant differences in the NEPSY subscales: Affect recognition, F = 18.57, p < 0.001, η2p = 0.23; Verbal-ToM, F = 13.91, p < 0.001, η2p = 0.18; Contextual-ToM, F = 5.84, p = 0.004, η2p = 0.08, and Total-ToM score, F = 17.28, p < 0.001, η2p = 0.22. Statistically significant differences were also shown in the applied knowledge task (TOMI): Early-ToMI, F = 35.65, p < 0.001, η2p = 0.36; Basic-ToMI, F = 64.25, p < 0.001, η2p = 0.51; Advanced-ToMI, F = 116.04, p < 0.001, η2p = 0.65 and in the ToMI total score .The MANOVA conducted to assess the main group effect on the conceptual knowledge  and applied knowledge (ToMI) indicators was statistically significant [Wilk's Lambda (Λ) = 0.26, post-hoc analyses showed statistically significant differences between the TD group and both clinical groups on AR, Verbal-ToM, and Total-ToM (p < 0.001), with no significant differences between clinical groups. On the contextual task, the HFASD group showed significantly worse performance than the TD group (p < 0.001), and performance of the ADHD and TD groups was similar. However, there were no significant differences between clinical groups on this task. A different pattern was observed for ToM applied knowledge, where there were statistically significant differences among the three groups, HFASD, ADHD, and TD, on the three subscales of the ToMI and on the Total score (p < 0.001). The HFASD group had the lowest score, whereas the TD group had the highest, according to parent estimations. See Table Bonferroni p < 0.001), Shift (p < 0.001), Emotional control (p = 0.012), and the BRI (p < 0.001). There were also significant correlations between AR and Monitor (p = 0.016). There were no significant correlations between AR and EF in the HFASD group, as Table p = 0.009) and Total-ToM (p = 0.020), both from the NEPSY-II battery. Similarly, there were significant correlations between Initiate and Basic-ToMI (p = 0.033), Advanced-ToMI (p = 0.046), and Total-ToMI (p = 0.040). There were also significant correlations between Organization of materials and Basic-ToMI (p = 0.033), advanced-ToMI (p = 0.030), and Total-ToMI (p = 0.016), and between MI and advanced-ToMI (p = 0.043) and Total-ToMI (p = 0.026).In the ADHD group, AR significantly correlated with Inhibit (p = 0.034), Basic-ToMI (p < 0.001), and total-ToMI (p = 0.027), as well as between emotional control and Early-ToMI (p = 0.045). The same pattern was observed between the BRI and the Early-ToMI (p = 0.014), Basic-ToMI (p = 0.013), and Total-ToMI (p = 0.049). Regarding the metacognitive processes, there were statistically significant correlations between Organization of materials and Early-ToMI (p = 0.026), Basic-ToMI (p = 0.012), and Total-ToMI (p = 0.049), as well as between Monitor and Early-ToMI (p = 0.018), Basic-ToMI (p = 0.013), and Total-ToMI (p = 0.022).Correlation analyses in the ADHD group did not show significant associations between ToM tasks on the NEPSY-II and BRIEF subscales. However, there were significant negative correlations between inhibit and Early-ToMI : Parents perceived that the ASD group had more difficulty than the other two groups in understanding basic emotions, distinguishing between physical and mental, making second-order inferences, or making complex social judgments. In addition, there appeared to be a symptomatic continuity, such that the ADHD group was found in an intermediate position between TD and ASD in the practical application of ToM abilities. The results agree with the trend found in previous work (Demurie et al., When the achievement levels of children with HFASD and ADHD are compared on the two types of ToM tasks, explicit and applied, the results are not fully consistent with the work of Hutchins et al. . In the Our results suggest the existence of more severe impairments in social cognition in the HFASD group compared to the ADHD group, although both neurodevelopmental disorders involve difficulties in processing social information. Furthermore, deficits are found on the AR task, which requires perceptual skills, as the children do not have any other information apart from what is contained in the facial expressions, and on the ToM tasks, which require higher thought processes such as logical skills, pragmatic language, and the recognition that one's mind is different from the minds of others. Deficits are also shown in both structured ToM test situations and multidimensional real-life situations, which require more complex and sophisticated skills. Moreover, the worse performance of the group with HFASD on ToM abilities, compared to the group with ADHD, does not seem to be due to language limitations, considering that the two groups were matched on expressive vocabulary. HFASD difficulties may be linked to a more severe meta-representational deficit, an idea that future research will have to verify.The second objective of this study was to explore the interplay between AR and ToM abilities and “every day” EF in children with HFASD and children with ADHD to find out whether ToM deficits are related to different EF subdomains in these children. A first analysis showed that, in both groups, significant relationships were found on scales measuring the application of ToM skills in the real world. Social interactions in daily life where we must respond spontaneously to a variety of events require more EF resources than laboratory tasks performed in contexts with greater control and stimuli isolation. Hence, it is important to complement the evaluation of ToM performance tasks by measuring how children cope with real-world social interactions that can result in success or failure and have emotional consequences.As expected, the interrelationships between EF and ToM abilities presented a different profile in ASD and ADHD. In children with ADHD, Inhibit, Shift, Emotional control, and the Behavioral regulation index presented high and significant correlations with AR and Early TOMI. Inhibitory control and the Behavioral regulation index also correlated significantly with the Basic TOMI. Finally, Monitor presented correlations with AR and Early and Basic TOMI scales, underlining the ongoing control that the integration of emotional cues requires in the constantly changing social environment. The findings coincide with previous literature (Yang et al., The correlations in the ASD group show a quantitatively and qualitatively different situation. This group shows a somewhat worse profile that focuses on the EF of Initiate. A poor decisive attitude, or difficulty in thinking of alternatives to solve problems, correlated negatively with performance on the verbal ToM task and, especially, with two scales that assess the application of ToM abilities in the context of everyday life, that is, Basic and Advanced TOMI. Organization of materials was significantly associated with the Basic TOMI, whereas the Metacognitive index was associated with the Advanced TOMI. Previous studies have demonstrated a link between ToM and EF in children and adolescents with ASD, specifically on set-shifting skills (Joseph and Tager–Flusberg, Our findings add to existing knowledge about deficits of children with ADHD and HFASD in AR and understanding others' mental states, which reflects a certain symptomatological continuum where HFASD shows greater severity. However, the social impairments of these two neurodevelopmental disorders cannot be explained solely on the basis of ToM failures. According to a recent meta-analysis (Imuta et al., The present study has several methodological limitations. Sample size and the fact that most of the children in the ADHD group have a combined presentation may affect the generalizability of the results. Moreover, the low number of females and the recruitment of participants from families with middle-class income levels may not adequately represent the general population. A high percentage of children with ADHD were medicated. Another limitation is related to the ToM measures used. Although, an effort was made to integrate measures of a different nature, it would have been desirable to also incorporate measures based on direct observation protocols. In addition, the present study relied only on teachers' reports of EF, without including supplemental laboratory performance measures. Future work should combine laboratory and informant-based measures for a more in-depth investigation. In particular, the unexpected lack of significant relationships between working memory and ToM in both the HFASD and ADHD groups may be due, at least in part, to the measurement methodology used. It would have been advisable to use other memory indicators such as performance tests. Furthermore, the results of the correlation analyses have an exploratory nature, due to the many variables that intervene in the analyses. However, the application of the Bonferroni correction in this situation would involve a greater possibility of committing a Type II error and rejecting relationships that may exist. Finally, the cross-sectional design does not allow us to conclude whether the interrelationships between mental abilities and EF follow a different course in ASD and ADHD. A longitudinal research design would make it possible to test the directionality of the influence.Despite these limitations, this study provides evidence about deficits in social cognition processes in children with ASD and ADHD and the differential role of EF. It supports the importance of incorporating EF measures in the evaluation and treatment of children with these two neurodevelopmental disorders. A better understanding of the individual differences in this interdependence will lead to greater possibilities of carrying out successful interventions. Inhibition and behavioral regulation deficits need special treatment that might differ from interventions for metacognitive deficits. Above all, interventions on social problems will be more successful if they are developed from the point of view of performance, the family, and the school, and introducing multimodal components of EF and ToM, given the relationships between these skills.AM, CB, BR, IB, and CC each made substantial contributions to the conception and design of the work, to the acquisition, analysis, or interpretation of data for the work, drafting the work or revising it critically for important intellectual content, final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.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.


For the diagnosis of attention-deficit/hyperactivity disorder (ADHD), the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) proposes that adherence to six symptoms in either group (inattention and hyperactivity/impulsivity) will lead to the diagnosis of one of three presentations of the disorder. Underlying this diagnostic algorithm is the assumption that the 18 symptoms have equal relevance for the diagnosis of ADHD, all are equally severe, and all have the same power to detect the presence of the disorder in all its degrees of severity, without considering the possibility of using marker symptoms. However, several studies have suggested that ADHD symptoms differ in both their power to discriminate the presence of the disorder and the degree of severity they represent. The aim of the present study was to replicate the results of previous research by evaluating the discriminative capacity and relative severity of ADHD symptoms, as well as to extend the investigation of this topic to Spanish-speaking Latin American samples.The properties of ADHD symptoms rated by the parents of 474 Chilean children were analyzed. Symptom parameters were estimated using the graded response model.The results suggest that symptoms of ADHD differ substantially in both the accuracy with which they reflect the presence of the disorder, and their relative severity. Symptoms “easily distracted by extraneous stimuli” and “have difficulty sustaining attention in tasks” (inattention) and “is on the go, acting as if driven by motor” (hyperactivity/impulsivity) were the most informative, and those with relatively lower severity thresholds.The fact that symptoms differ substantially in the probability of being observed conditionally to the trait level suggests the need to refine the diagnostic process by weighting the severity of the symptom, and even to assess the possibility of defining ADHD marker symptoms, as has been done in other disorders. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a genetic basis, characterized by persistent symptoms of inattention (IN) and/or hyperactivity and impulsivity (HI), which are maladaptive and incoherent with regard to the child’s level of development . The preFor the diagnosis of ADHD, the DSM-5 requires the presence of at least six symptoms in either of the two groups, inattention (IN) and/or hyperactivity-impulsivity (HI), giving rise to three possible diagnoses: combined ADHD, ADHD with a predominance of attention deficit, or ADHD with a predominance of hyperactivity/impulsivity. To this diagnostic algorithm underlies the assumption that the 18 symptoms are equally relevant for the diagnosis of ADHD, all are equally severe, and all have the same reliability to detect the presence of the disorder in all its degrees of severity. Thus, any of the possible combinations of six or more symptoms will comply with the diagnostic criterion B, without considering the existence of marker symptoms, unlike other disorders such as major depression, whereby depressed mood and/or loss of interest are a necessary condition for diagnosis . HoweverThe dimensionality and internal structure of ADHD symptoms has been intensively researched in the last decades, in both the models proposed by the DSM and the International Statistical Classification of Diseases (ICD)  and alteThe studies devoted to the evaluation of individual symptom properties have been much scarcer. The majority have consisted of applications of Item Response Theory . WithoutThe aim of the present study was to replicate the results of previous studies by assessing the discriminative power and the relative severity of the symptoms of ADHD, under the hypothesis that (a) symptoms differ in the accuracy with which they reflect the presence of the disorder, and (b) symptoms are associated with different degrees of ADHD severity. To do so, we applied the graded response model  to the dThe sample was composed of 474 children, aged between six and fifteen years , of which 42% were male. The sample was obtained through the mediation of two schools from two regions of Chile, which voluntarily agreed to participate in the study. Usual parent meetings were used to discuss the objectives of the research and invite the parents to participate. Parents (89% mothers) who agreed to participate were informed about how to respond to the questionnaire, which they completed with the direct support of the main researcher or one of the project collaborators. There were no cases with missing data due to the monitoring performed during data collection. In all cases, we obtained an informed consent for using the data in the research, with an acceptance rate of 100%. All procedures performed in this study were in accordance with the ethical standards of the institutional research committees  and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.almost never (never or about once per month), seldom (about once per week), sometimes , often (about once per day), very often , and almost always (many times per day)), choosing the option that best described the frequency of their children’s usual behavior . Earlier studies with children from Chile and Spain provide support for the reliability and validity of scores for the ADHD-IN and ADHD-HI scales of the CABI  is the probability of responding to option k of item i with a latent trait level θj; k or higher in item i with a latent trait level θj; θj is the latent trait level of the person; βik isthe location parameter of the alternative k of item i; αi is the discrimination parameter of item i, and D is the constant 1.702.The GRM specifies the probability of a person being rated with a category ik or higher as opposed to being rated with a lower category when the rating scale has at least three categories, and is expressed as χ2 values of the matrix of expected and observed response frequencies to each item   .χ2 (p > 0.01) and associated RMSEA values close to zero .For the assessment of model fit, we examined the statistic M2 , its assχ2 . In the ro <.08;  are expeχ2 values associated with the expected frequencies against those values observed in both subscales were between .10 and 15.4 . Two of the 42 contrasts were greater than 10, without observing clusters of extreme LD-χ2 values that could suggest the presence of substantive sources of non-modeled systematic error. As a result, the criteria of unidimensionality and local independence can be considered adequately complied with, and estimation of the GRM models proceeded.M2 and RMSEA statistics were examined for each of the scales. The results for both the IN scale  and for the HI scale  may indicate some lack of fit. However, the low associated RMSEA values suggest that this misfit may be due to a limited amount of unmodeled error , in both sub-scales (six cases in IN and nine in HI).To assess the fit of the data to the GRM model, the ed error . Most ofαi and βik, a marginal maximum likelihood method was used, given the sufficiently large sample size. θ . For each item, six curves are drawn, each of which represents the probability, represented on the ordinate axis, of being located in each of the response categories conditionally to the trait level. Thus, in the symptom discussed, for the most likely response to be “many times a day” (highest category), the child must present a very high level of inattention (approximately 2 standard deviations or more above the mean). On the other hand, the most likely score of a child near the mean (Theta = 0) would be “once a week” (category 2).To estimate the item parameters αi and βik. Since, according to αi values from 0.01 to 0.24 are very low, from 0.25 to 0.64 are low, from 0.65 to 1.34 moderate, from 1.35 to 1.69 high, and more than 1.7 are very high, we conclude that, in absolute terms, the discrimination parameters have been very high (>1.70). In relative terms, we observe that in the IN scale the most discriminative items have been 2  and 8 . On the contrary, while maintaining a reasonable level, symptom 7  has presented substantially less discriminative power than the rest, so that its relative contribution to the test information has been lower. In the case of the HI scale, the three most discriminative symptoms were 5  2  and 7 . No symptom has been clearly less discriminative than the others.βik (θ = 1.3) and least severe .Regarding the parameters βik , the valβik , with diIn the present study, the graded response model has been applied to a sample of Chilean children rated by their parents in the 18 symptoms of ADHD proposed by the DSM-5. The results suggest that, in the general population, the symptoms present adequate psychometric properties and are configured as a semi-trait, where most of the information is located at high levels of the latent variable  of the inattention sub-scale has presented low discrimination values relative to the rest of symptoms, as well as poorer information and lower reliability at all levels of the latent trait. Our results are compatible with previous evidence of its reduced informative capacity . This fiIn summary, the differences between symptoms in severity and power of discrimination suggest the need to identify which symptoms are more relevant than others for the diagnosis of the disorder and its subtypes . RegardiFinally, for a proper interpretation of the results, it is necessary to bear in mind some of the limitations of this study, which in turn would suggest possible future research. First, sample was non-probabilistic, so the generability of results to the population is limited. Second, the psychometric properties of the items were based on parental ratings; it would have been desirable to compare them with the teachers’ scores, given that similar studies have shown certain differences in the usefulness of the symptoms by type of informant e.g., . Third, ADHD symptoms differ substantially in both the accuracy with which they reflect the presence of the disorder, and its relative severity. This suggests the need to refine the diagnostic process by weighting the severity of each symptom, and even to assess the possibility of defining ADHD marker symptoms, as has been done in other disorders. These results also suggest that ADHD would be better assessed as a spectrum of symptoms that differ in severity along a continuum, than by categorizing subjects according to a fixed threshold of endorsed symptoms.10.7717/peerj.4820/supp-1Data S1Click here for additional data file.