Methylphenidate (MPH) is the treatment of first choice for developmental ADHD. To date, no reliable method to predict how patients will respond to MPH exists and conflicting results are reported on clinical characteristics of responders. The present study aims to give a more precise characterization of the patients who will respond best to MPH to help clinicians in defining the treatment plan. Age, neuropsychological functioning , and behavioral/emotional symptoms of 48 drug-naïve children and adolescents with ADHD  were studied to assess how these different characteristics affected a single-dose MPH response. Four hierarchical linear regression models were used to explore whether age, neuropsychological measures at baseline, and behavioral/emotional symptoms could predict attention and working memory measures after a single-dose MPH administration. We found that improvement in attention and working memory was predicted by age, neuropsychological measures at baseline, and severity of ADHD symptoms. No behavioral and emotional symptoms predicted single-dose MPH response with the exception of conduct symptoms. Executive functions (EF) are cognitive processes that allow problem-solving behavior geared toward the attainment of a future goal . SeveralStudies have demonstrates that patients with ADHD improve significantly in EF when on methylphenidate (MPH), the first-choice treatment for ADHD in the developmental age ,10. In pA recent meta-analysis  suggestsThere is evidence that when MPH dosage was optimized the majority of patients with ADHD achieved a remission of symptoms and demonstrated functional improvement attaining to the level of non-ADHD peers . HoweverThere has been a growing interest in identifying predictive factors of response to pharmacological treatment in ADHD. Besides comorbid psychopathology that could worsen the MPH response, pre-treatment EF measures have been recently found as predictors of the clinical response to MPH . Age hasThe aim of the present study is to better understand what factors condition the response to MPH in children and adolescents with ADHD.In this context, we examine how different aspects of drug-naïve children and adolescents with ADHD, such as age, EF  at baseline, and behavioral/emotional symptoms impact on EF changes after a single dose of MPH administration.We hypothesize that the greater the severity of ADHD, behavioral and emotional symptoms, age of the participants, attention and working memory deficits, the worse the response will be to the MPH administration.Three hundred and two children and adolescents received a first diagnosis of ADHD at the Child and Adolescent Neuropsychiatric Unit of the Bambino Gesù Children’s Hospital in Rome in 2020. Among these patients, 110 were prescribed MPH for the first time and underwent a single MPH dose challenge. We excluded from the current study 62 patients for the following reasons: (1) they were under psychopharmacological treatment different from MPH at the time of recruitment; (2) they suffered from autistic spectrum disorder; (3) they suffered from genetic syndromes; (4) they suffered from neurological disorders; and (5) they had an IQ below 80.According to the exclusion criteria, 48 participants with the combined hyperactive/impulsive and inattentive presentation of ADHD were recruited . NeurocoAfter performing the neuropsychiatric and psychopathological assessment, each participant completed neuropsychological tasks at baseline (t0) and after MPH administration (t1). All participants and parents were informed about assessment instruments and treatment options. Written informed consent was obtained from parents. The study was conformed to Declaration of Helsinki.Psychiatric diagnoses were based on developmental history, extensive clinical examination and the Schedule for Affective Disorders and Schizophrenia for School-Aged Children Present and Lifetime Version DSM-5 , a semi-Behavioral and emotional symptoms were assessed by the child behavior checklist 6–18 (CBCL) and the Achenbach system of empirically based assessment (ASEBA) questionnaire. The CBCL parent questionnaire  is a welThe severity of ADHD symptoms was assessed by Conners’ parent rating scales long version revised (CPRS) , completThe continuous performance test II (CPT)  is compoThe N-back  is one oMPH is the first-line medication for children and adolescents with ADHD in line with the National Institute for Health and Care Excellence (NICE) and Agenzia Italiana del Farmaco (AIFA) guidelines. Before the single-dose MPH challenge, all the patients who were eligible to receive MPH treatment underwent an electrocardiogram (ECG) with the calculation of the corrected QT interval, and blood tests to exclude any other medical condition associated with ADHD or potentially mimicking ADHD symptoms . All participants underwent CPT and N-back one day before drug administration (t0) and one hour after the administration of 0.3 mg/kg of the short-acting MPH preparation Ritalin© (t1). t-tests were used to compare EF measures at t0 and at t1. To correct for multiple comparisons , Holm–Bonferroni-corrected alpha values were applied [Paired sample  applied . To determine whether MPH response was predicted by age, EF measures at t0 and behavioral and emotional measures, four different hierarchical regression analyses with 3 steps were computed. Precisely, the dependent variables were EF measures  at t1 and the predictors were age at step 1, EF measures at t0, the two DSM-IV symptoms scales of CPRS (inattentive and hyperactive-impulsive) at step 2, and the six DSM-oriented Scales of CBCL  at step 3. Moderation effects were examined using multicollinearity tests for interaction.The statistical software SPSS Version 22  was used for analyses.47 = −2.35, p = 0.023, Cohen’s d = 0.44) as reported in Concerning working memory, results on N-back demonstrated that the scores obtained by children and adolescents with ADHD at t0 were lower than scores obtained at t1  and reduced CPT RTV  at t1 compared to t0. CPT RT did not differ between t0 and t1 . As for CPT, we found that participants improved CPT accuracy (tp = 0.04), CPT accuracy (p = 0.004), and CPT RTV (p = 0.004) were still significant.After the Holm–Bonferroni correction, N-back scores  were entered at step 2, and the six DSM-oriented scales of CBCL  were entered at step 3 as predictors. Overall, the regression model accounted for 51.9% of the variance. As reported in Moreover, CPRS M accounted for 5.5% of the unique variance (with lower scores for higher N-back scores at t1) and CBCL ADHD problems accounted for 9.8% of the unique variance (with lower scores for higher N-back scores at t1). No interaction effect was found between any of the predictive variables.In the second model of forward hierarchical regression to predict CPT accuracy at t1, age was entered at step 1, CPT accuracy at t0, the two DSM-IV symptoms scales of CPRS (inattentive and hyperactive-impulsive) were entered at step 2, and six CBCL DSM-oriented scales  were entered at step 3 as predictors. Overall, the regression model accounted for 51.8% of the variance. As reported in In the third model of the forward hierarchical regression to predict CPT RT at t1, age was entered at step 1, CPT RT at t0, the two DSM-IV symptoms scales of CPRS (inattentive and hyperactive-impulsive) were entered at step 2, and the six DSM-oriented scales of CBCL  were entered at step 3 as predictors. Overall, the regression model accounted for 41% of the variance. As reported in Similarly, in the forward hierarchical regression to predict CPT RTV at t1, age was entered at step 1, CPT RTV at t0, the two DSM-IV symptoms scales of CPRS (inattentive and hyperactive-impulsive) were entered at step 2, and the six CBCL DSM-oriented scales CBCL  were entered at step 3 as predictors. Overall, the regression model accounted for 48.5% of the variance. As reported in This study aimed at a better characterization of different factors potentially associated with MPH response. Specifically, we explored whether age, EF measures at baseline, and behavioral/emotional symptoms could affect EF in a group of drug-naïve children and adolescent with ADHD after a single dose of MPH administration. We found that attention and working memory improved after a single MPH administration and that age, EF measures at baseline, the severity of ADHD symptoms, and conduct problems modulated MPH effect on EF performances. MPH is the first-choice treatment for patients with ADHD. Although its exact mechanism is unclear, it seems to increase and stabilize catecholaminergic neurotransmission in prefrontal cortices . The actNeuroimaging studies demonstrated that EF deficits were highly related to reduced activity in fronto-striatal and fronto-parietal networks of patients with ADHD . In partOur results on attention and working memory improvements after a single MPH administration supported previous findings observing that MPH significantly ameliorating attention by reducing RT ,42, and Moreover, we found that higher scores in N-back and CPT tasks at baseline favored performance in N-back and CPT after a single dose of MPH administration. Previous research in children with ADHD studied whether the performances on EF tasks before MPH administration were correlated with responses to MPH ,43,44 wiRegarding age, we found that improvement in attention and working memory after a single dose of MPH administration was predicted by age. Specifically, older children with ADHD were those who got the most benefit from a single dose of MPH administration in EF . It could be that as patients with ADHD develop, they learn to solve complex problems with increasing accuracy, reducing the variability in the performance and shortening times to information processing. Specifically, the performance of patients with ADHD in shifting attention (correct responses and errors) improved with age and children below 10 years old were less respondent to MPH .Additionally, our results demonstrated that the MPH effect on working memory (N-back) depended on the severity of ADHD symptoms. In particular, we found that the children and adolescents who demonstrated less severe symptoms of ADHD  were the ones who improved the most in N-back scores. Our findings were in line with studies that found that patients with more severe ADHD symptoms also responded less to stimulants ,48. Among emotional and behavioral symptoms that may influence the MPH response, our results demonstrated that patients with more conduct problem symptoms (CBCL conduct problems) responded more to stimulants (CPT RT). Our findings are in line with previous studies demonstrating that children with ADHD and conduct problems respond better to medication ,24,49,50However, it is difficult to compare our results with other studies, because the same CBCL scales to predict MPH response were not selected. Specifically, Ludwig and colleagues  selectedFurther studies are needed in order to establish whether and how clinical characteristics impact pharmacological treatment for ADHD.In the present study of a group of medication-naïve children and adolescents with ADHD, we investigated whether age, EF measures, and clinical characteristics before MPH administration influenced response to medication.We found that improvement in attention and working memory performance after a single administration of MPH were predicted by age, EF measures, and severity of ADHD symptoms. Moreover, we found that children and adolescents with ADHD and conduct symptoms improved EF more than patients with ADHD and other symptoms after a single dose of MPH.Early attention to these factors may help clinicians identify young patients with ADHD who are likely to gain greater benefit from MPH treatment, thereby optimizing the risk/benefit ratio in the pharmacologic treatment of ADHD.


Attention Deficit Hyperactivity Disorder (ADHD) can be associated with limited understanding of the condition and poor social skills. Some evidence favors a psychoeducational approach, but little is known about the effectiveness of psychoeducation.Systematic review and meta-analysis of studies assessing psychoeducational interventions that aim to improve social skills of young people with ADHD.Ten studies, including 943 participants, reported across 13 papers met the inclusion criteria. Although effect sizes were small, findings suggest the included interventions significantly improved social skills in young people with ADHD.Results show promise for psychoeducational behavioral interventions . However, the recommendations that can be developed from existing evidence are somewhat limited by the low quality of studies. Further rigorous trials are needed. In addition, future research should consider the long-term outcomes for these interventions, they should be iteratively co-designed and research should consider the context they intend to be delivered in. Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder affecting children and young people (CAYP) with a worldwide prevalence of around 3.4% of school age children , 9.4% ofA number of difficulties have been reported in ADHD, such as executive dysfunction , emotionSocial functioning refers to social skills, information processing and peer functioning . It is wADHD is a highly co-morbid condition, particularly with Autism Spectrum Disorder (ASD) . Indeed,Hence improving social skills in CAYP with ADHD and co-morbidities would be beneficial and psychoeducation is considered a possible intervention to achieve this.Definitions of psychoeducation are heterogeneous. Initially, psychoeducation described a behavioral concept including briefing a patient about their illness, problem solving, communication and self-assertiveness training, which included relatives . More reRecipients of psychoeducation interventions can vary and include the individual, parents, teachers or others . ObjectiA plethora of evidence demonstrates the benefits of psychoeducation on adult populations . HoweverPsychoeducation is recommended in a number of clinical guidelines for CAYP with ADHD for example, in the UK, NICE recommends psychoeducation for parents of CAYP with ADHD and for information to be provided to people with ADHD at a developmentally appropriate level, tailored to their individual needs . The CanPsychoeducation interventions that aim to benefit CAYP with ADHD can vary based on the form they take and the recipient of the intervention. For example, behavioral parent interventions are often based on social learning principles and include providing parents with strategies to reduce behavioral problems in their child and to improve parental attitudes toward parenting . The effClassroom-based interventions can include behavioral strategies for teachers and for example, promote the use of rewards to reduce problematic classroom behavior  and focuRandomized controlled trial (RCT) evidence has demonstrated that psychoeducation interventions with families of CAYP with ADHD could help to reduce ADHD symptoms . PsychoeHowever, lack of adherence to treatments can weaken the impact of both pharmacological and psychosocial interventions , thus imInterventions where CAYP with ADHD themselves are the recipients include child psychological therapy involving components such as social skills training, anger management and problem solving . EvidencSome review evidence does suggest that behavioral interventions  and sociA recent systematic review assessed psychoeducation interventions for parents and teachers of CAYP with ADHD . This reTherefore, this review aims to address the specific research question “Do psychoeducation interventions improve social skills in CAYP with ADHD?”The systematic review protocol was registered with PROSPERO (CRD42019157454) and was undertaken in accordance with the principles recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Meta-Analysis Reporting Standards (MARS) .In line with the Cochrane Handbook  the PopuDatabases were searched from 1994 to 2019. This is because the Fourth edition of the Diagnostic Statistical Manual (DSM IV)  introducThe search was conducted in the following databases in November 2019: MEDLINE, PsychINFO, The Cochrane Library, CINAHL, Web of Science (Core Collection), ProQuest, ASSIA and Scopus. Medical Subject Headings (MeSH) keywords used were child, child behavior, adolescent, young adult, adolescent health, adolescent psychiatry, students, minors, young adult, attention deficit and disruptive behavior disorders, attention deficit disorder with hyperactivity, conduct disorder, attention, hyperkinesis, patient education as topic, education, health education, teaching, schools, training support, knowledge, patient medication knowledge, behavior, adolescent behavior, behavior control, behavior therapy, child behavior, problem behavior, behavioral research, behavioral symptoms, attitude, attitude to health, social skills, social behavior, interpersonal relations, social isolation, social problems, social skills, peer group, communication, interpersonal relations, friends.Text terms used were child disorders, young people, young person, teenage, student, school age, minor, boy, girl, YP, teen, youth, young, juvenile, Juvenescent, pubescent, conduct disorders, child behavior disorders, ADHD, ADDH, ADHS, HKD, TDAH, behave, disrupt, disorder, defiant, impulsive, inattentive, inattention, psychoeducation, educate, education medical, train, teach, school, tuition, tutor, coach, guide, instruct, inform, knowledge, develop, lesson, behavior change, behavioral, conduct, disruptive, impulse control and conduct disorders, habit, prosocial, interact, social, social develop, disrupt, peer reject, communicate, empathy, peer problem, peer interact, Social dysfunction, Peer relationship, peer function, peer reject, friendship.Terms were combined using Boolean logic . MeSH are specific recognized terms used to identify journal articles and books in electronic databases. Free text terms and synonyms are specific words that the search strategy looks for in the title and abstract.The MEDLINE search strategy is available in Supplemental Appendix 1. Electronic references were downloaded to reference management software.includes information about the illness and its treatment, skills development, and patient empowerment”  . This toTitles, abstracts, and/or full text papers were screened independently by two review authors  to identify studies compliant with the inclusion criteria. Reviewers resolved disagreements through discussion. A standardized Microsoft Excel form was used to extract data. Details of the study characteristics, including location of study, participants, the intervention, comparator and results were recorded. Data extraction was carried out by reviewer LP and checked for accuracy by reviewers AW and JP.A random effects meta-analysis and narrative review was undertaken with tables and text providing supporting evidence. Revman5  was usedThe electronic literature search yielded a total of 20112 records following deduplication. Two additional citations were identified via handpicking methods. This involved reviewing reference sections of papers during the selection process. Therefore 20114 citations were screened by authors LP and JP and 19625 articles were excluded based upon information in the titles and abstracts. At this stage, 67 full texts were obtained, 54 were excluded see  and 13 on = 10) with 886 participants at follow up. This means there was a mean of 94 participants at baseline and 89 at follow up with a mean of just five participants dropping out per study.Overall, there were 943 CAYP with ADHD recruited across all included studies  and weight of each study is then provided in the following columns for the intervention and control groups. The vertical line through the forest plot gives the 95% confidence interval. On the right-hand side of each figure, there is a summary of the CRoB results.p = .004) and parent reported measures (p = .0001). The effect size is also significant but small for both parent (.39) and teacher (.32) measures.The meta -analysis found significant between group differences in favor of the intervention for improving social skills in CAYP with ADHD for both the teacher reported (Only one study reported an intervention whereby CAYP with ADHD are the only recipients of the intervention . Signifip < .01) using the SSRS however, these results were not supported by teacher rated SSRS scores (Three interventions across three articles reported RCTs whereby parents are the only recipient of the intervention . Two of S scores .p < .01) and the amount of disengagement displayed by children on playdates (p = .52)  . This mep = .52) .Two studies reported interventions across three articles that targeted both children and parents in separate groups , 2013, op < 0.05) with problematic behaviors reducing only in the intervention group. Prosocial behavior improvements in the SDQ were not observed (One study observed improved parent ratings of the SDQ (observed .p < .0001). However, teacher rated SSRS scores did not demonstrate a significant improvement in social skills (p > .1). The parent mediated SST group also demonstrated improved social skills as reported by the teacher rated SSRS from pre-treatment to post-treatment (p .001) and from pre-treatment to follow up (p < .001). Significant differences were not found between the SST and control groups (p > .1) ((p > .1) .p = .0065). The Test of Life Skills Knowledge also found significant between group differences, favoring the intervention group, for knowledge of social and organizational skills taught during the intervention (p = .0001) (A further study by = .0001) .p = .0393). They also found significant between group differences in favor of the CLAS intervention for both parent-reported (p = 0.04) and teacher reported (p = 0.02) SSIS. Differences were maintained at follow up but not then significant for teacher reported outcomes.The CLS study , 2018 fop < .001).The Incredible Years Study , 2013 foThe CRoB quality assessment summary can be found in Parent and teacher outcomes were assessed using the GRADE quality assessment and found that there was on average, a low quality of evidence. This means that any conclusions and recommendations should be viewed with caution and further high-quality research is needed. Two meta-analyses were conducted. Of the 10 included studies, eight were included in the meta-analysis.This review set out to answer the question “Do psychoeducation interventions improve social skills in CAYP with ADHD?” Following exclusions, 10 studies reported across 13 articles were included. Overall, there were 943 CAYP with ADHD recruited across all 10 included studies with 886 participants at follow up. This means there was a mean of 94 participants at baseline and 89 at follow up with a mean average of five participants dropping out per study.Encouragingly, our meta-analysis indicated small but significant improvements in social skills in CAYP with ADHD in favor of the intervention for both parent and teacher reported outcome measures. Seven of the included 10 studies involved CAYP with ADHD as recipients of the intervention . Six of One of the eight studies that included children as intervention recipients did not report significant improvements in social skills in CAYP with ADHD . This stRecent systematic review evidence  has concOur meta-analysis shows that parent reported measures were likely to demonstrate a significant improvement in social skills in CAYP with ADHD. It should be acknowledged, however, that parents were not blinded to the intervention their children were receiving. This could indicate that parents, who would have invested their time and effort into the interventions, expected or hoped to observe improvements in their child’s social skills and could therefore reflect observer bias. It should, however, be noted that due to the nature of the interventions, it is often impossible to blind participants and their families to the arm of the study allocated to the participant. The meta-analysis also demonstrated that the teacher reported measures were significant in improving social skills for CAYP with ADHD, adding weight to the parent reported measure findings.It is clear that social skills difficulties are a significant problem for CAYP with ADHD and their families. However, previous research as to the value of psychoeducation in establishing long term improvements in social functioning in CAYP with ADHD remains difficult for clinicians to interpret. The studies reported in this review involved significant time commitment from parents, teachers and clinicians.n = 15). This is why five of the 10 included studies were not included in the meta-analysis. It is important to note that the interventions included in this review do not focus solely on psychoeducation therefore results should be interpreted with caution as it is difficult to definitively state that the effectiveness of the interventions in the meta-analysis are due to the psychoeducation mechanisms provided.Although 10 studies are included in this review, they include a large number of, often non-comparable, outcome measures (Further, it would be beneficial if consistent outcome measures could be adopted across multiple trials to enable fair comparison across studies. In order to reduce bias, it may be useful to additionally adopt social skills assessments that do not involve subjective measures in order to decrease the potential for bias by the evaluators. This could involve the utilization of emerging objective measures such as the use of technology .This review does however highlight the potential for interventions for CAYP with ADHD to include a psychoeducational component that educates the child about ADHD and/or teaches them a new skill to help them cope with their ADHD related difficulties such as social skills training. This approach has been successful in other conditions such as depression in adolescents , asthma Further research is required to explore which components should comprise such interventions for CAYP with ADHD in order to make them successful.It must however be noted that research to evaluate interventions to improve social skills in CAYP with ADHD is complex. ADHD is a highly variable, comorbid condition and the individuals involved often live in complex circumstances. No single intervention will work for every child.A recent systematic review of 25 studies reported across 45 papers concluded that “there is little evidence to support or refute social skills training for children and adolescents with ADHD” . It mustIn the future, design of social skills interventions should consider both the variable personal and environmental context in which the intervention delivered . That isSocial skills training interventions for CAYP with ADHD are often based upon the assumption that CAYP with ADHD do not understand social skills and need to be taught what they are. This often happens in a clinic setting that is not representative of real life scenarios, hence the argument that social skills training will not work in such an artificial situation . HoweverIt is also important to consider that there is no way of knowing the extent to which comorbid conditions have confounded the extent to which CAYP with ADHD may respond to the interventions in this review. This is especially challenging as three of the 10 included RCTs did not report on comorbid conditions and one RCT excluded participants who had a diagnosis of any other “major developmental disorder” . This isOf the 10 included studies, only one was conducted in the UK; one in Sweden, one in Australia and seven studies in North America. Therefore, the conclusions of this review must be generalized to an international population with caution. The included studies are also limited to those provided in the English language, which can cause information bias.The evidence is limited to the broad definition of psychoeducation adopted . This waThis review is also limited to the evidence in the literature, which as previously discussed, runs the risk of not being representative of a wider population of families who live with CAYP with ADHD and have difficulty accessing such support. Much of the evidence does not consider maintenance of efficacy and ongoing support needs. Future research is advised to consider this  and to eFuture research should report significant factors that could impact upon the effectiveness of their intervention. This includes gender, the presentation and severity of participants’ ADHD, whether or not a parent has previously attended a parent group, socio-demographic factors, comorbid conditions including ASD and if the child is taking ADHD medication at any point in the study. Where possible, this information should at least be collected at baseline and at the end of the study to highlight any changes during the duration of the study. If a young person is optimized on medication, does this improve outcomes of psychoeducation and indeed other behavioral therapies?Psychoeducational interventions for CAYP have the potential to empower the individual and to maximize self-care  and offeCo-design can be a challenging approach, especially when working with a population with attention difficulties such as ADHD. However, evidence suggests that it is indeed possible . HoweverADHD is a complex, comorbid condition. Individuals with ADHD can benefit from a package of care which includes a number of interventions targeting different facets of their difficulties .The findings of this review indicate that behavioral interventions including a psychoeducation element could be valuable for improving social skills in CAYP with ADHD. The effect sizes in the present review are small but significant. Specifically, involving CAYP with ADHD interactively in the intervention shows promise and may be a reflection of CAYP with ADHD requiring support with the performance rather than the acquisition of social skills. However, the quality of the included studies is uniformly, limited so the conclusion should be generalized with caution. Blinding of the participant and their families is often impossible when delivering behavioral interventions within an RCT design. It would be beneficial if consistent outcome measures and optimal study design to reduce bias could be agreed.We recommend that future interventions to improve social skills in CAYP with ADHD should involve a psychoeducational component, clear and transparent reporting, be co-designed, and consider the personal and environmental contexts in which the intervention is to be delivered. Only then can clinicians understand which interventions will best support the complex children, young people and families they strive to support.Click here for additional data file.Supplemental material, sj-pdf-1-jad-10.1177_1087054721997553 for Psychoeducation Intervention Effectiveness to Improve Social Skills in Young People with ADHD: A Meta-Analysis by Lauren Amy Powell, Jack Parker, Anna Weighall and Valerie Harpin in Journal of Attention Disorders


Background and Objectives: Emotional dysregulation is central to the problem of the overlap between attention-deficit/hyperactivity disorder (ADHD) and cyclothymia. The aim of the study was to evaluate comorbidity rates between ADHD and cyclothymic disorder and to explore demographic and clinical differences among the groups, focusing on affective temperament and emotional dysregulation. Materials and Methods: One hundred sixty-five outpatients attending the Second Psychiatry Unit at the Santa Chiara University Hospital (Pisa) were consecutively recruited: 80 were diagnosed with ADHD, 60 with cyclothymic disorder, and 25 with both conditions. Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (TEMPS-M) and the 40-item version of Reactivity, Intensity, Polarity, and Stability questionnaire (RI-PoSt-40) were administered. Results: Cyclothymic patients were more frequently female and older with respect to the ADHD groups. Both comorbid and non-comorbid ADHD patients showed significantly lower educational attainment and more frequently had substance use disorders. Panic disorder was common in non-comorbid cyclothymic patients, who showed significantly higher rates of familial panic disorder, major depressive disorder and suicide attempts in comparison with patients only diagnosed with ADHD. Cyclothymic patients without ADHD were also characterized by fewer hyperthymic temperamental traits, higher depressive and anxious dispositions, and a greater negative emotionality. No significant differences among groups were observed for cyclothymic temperament and overall negative emotional dysregulation, but comorbid patients with both conditions scored the highest in these subscales. This group also showed significantly higher affective instability with respect to ADHD patients without cyclothymia and was less frequently diagnosed with bipolar disorder type II than patients from both the other groups. Conclusions: ADHD and cyclothymia often co-occur and show similar levels of emotional dysregulation. However, cyclothymic patients may be more prone to negative emotionality in clinical settings. Subjects with “sunny” cyclothymic features might escape the attention of clinicians unless ADHD is present. The failure to regulate emotions, namely emotional dysregulation, is a novel dimension of interest in psychiatric research, which characterizes a multitude of conditions usually observed in clinical practice. Emotional dysregulation shows heterogeneity in its nomenclature, definition, and presentation and can be broadly defined as “rapid oscillations of intense affect, with a difficulty in regulating these oscillations or their behavioural consequences” . Issues ADHD is a neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity, and impulsivity, which first appears during childhood and, in approximately half of the cases , persistAt the same time, emotional dysregulation has been long considered a distinctive constitutional trait underlying cyclothymic temperamental variants associated with bipolar affective disorders . CyclothBoth ADHD and bipolar spectrum disorders share a difficulty in modulating emotionally driven behavioral responses. Accordingly, a plausible common neurophysiological basis has been hypothesized, involving neurodevelopmental dysfunctions of amygdala and fronto-limbic circuitries ,17,18. HThe recently developed Reactivity, Intensity, Polarity, and Stability questionnaire could represent a useful self-report tool to quantify emotional dysregulation in some of its different facets both in psychiatric patients and healthy subjects . We receThe first aim of the present study was to evaluate comorbidity rates between ADHD and cyclothymic disorder in outpatients attending the Psychiatry 2 Unit at Santa Chiara University Hospital in Pisa. Second, we explored demographic and clinical differences among patients diagnosed with ADHD, cyclothymia, or both disorders. Special attention was given to affective temperamental dispositions and emotional dysregulation facets.According to a naturalistic approach, patients were consecutively enrolled between January 2018 and June 2019 at the Outpatient Service of the Psychiatry 2 Unit of Santa Chiara University Hospital . All subjects provided written informed consent for the study participation. The study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki), and the study protocol was approved by the Ethical Committee of the University of Pisa on 15 March 2018 (N. 12712_PERUGI).Adult patients (age ≥ 18 years) receiving a diagnosis of ADHD in accordance with structured Diagnostic Interview for Adult ADHD, second edition (DIVA 2.0), and/or meeting criteria A-B and D-G for cyclothymic disorder from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), were included in the study. Exclusion criterion C for cyclothymic disorder was not applied, and a lifetime history of major mood episodes, whether depressive or (hypo)manic, did not rule out the diagnosis. In contrast, patients presenting with current major depressive or (hypo)manic episodes were excluded. This approach permitted the inclusion of patients with a cyclothymic background, otherwise diagnosed with major depressive, bipolar II, or bipolar I disorder, who experience frequent mood shifts, mild to moderate symptoms, and significant distress and functional impairment. In addition, an early undetermined onset of cyclothymia (<21 years old) was considered mandatory, in accordance with Akiskal and Mallya criteria for cyclothymia , to exclSocio-demographic variables and lifetime psychiatric comorbidity according to DSM-5 criteria were assessed in a single consultation by the participating psychiatrists. Affective temperamental traits were measured by means of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (TEMPS-M) ,22, a seAll the statistical analyses were performed using IBM SPSS Statistics for Mac, Version 25.0 . Demographic and clinical variables as well as RIPoSt-40 and TEMPS-M scores were compared among the groups. Descriptive statistics ) were used to describe characteristics of the subsamples. Comparative analyses were conducted using chi-square test for categorical variables (with z-test contrasts and Bonferroni’s correction) and one-way analysis of variance (ANOVA) for continuous variables (with a posteriori contrasts according to Scheffé’s procedure). Finally, a principal component analysis (PCA) with varimax rotation was performed on TEMPS-M and RIPoSt-40 subscales. All the components with an eigenvalue greater than 1 were retained, according to Kaiser criterion , and comA sample of 165 patients was recruited: 80 of them were diagnosed with ADHD, 60 with cyclothymic disorder, and 25 with both ADHD and cyclothymic disorder. Significant differences in age, gender, and educational level were observed among these groups . Cyclothp = 0.060): in patients with cyclothymia, whether comorbid with ADHD or not, panic disorder was almost twice as prevalent as in patients only affected by ADHD (28.2% vs. 15.0%).Bipolar disorders were common among all the groups, being diagnosed in 83 of 165 patients (50.3%). No significant differences in bipolar disorder type I prevalence were found among the groups. However, bipolar disorder type II was more frequently diagnosed in non-comorbid ADHD and cyclothymia than in comorbid ADHD–cyclothymic patients. Substance use disorders were significantly more frequently observed in both the ADHD groups, which showed a prevalence approximately twice that reported in non-comorbid cyclothymic patients (63.8% vs. 28.3%). The opposite pattern was observed for panic disorder, though not significantly (p = 0.064). On the other hand, familial panic disorder was significantly more frequent in non-comorbid cyclothymic patients than in non-comorbid ADHD, while comorbid patients had an intermediate rate and did not significantly differ from both the other groups. Importantly, a similar pattern of significant differences was found for familial major depressive disorder and suicide attempts.Approximately a half of patients had a first-degree family history of bipolar disorder , without significant differences among the groups. As for the other disorders, first-degree family history showed patterns that were similar to those observed for psychiatric comorbidity. On one hand, the highest rate of familial substance use disorders was found in ADHD patients, and the lowest was found in non-comorbid cyclothymic patients. Comorbid ADHD–cyclothymic patients showed an intermediate rate. However, these differences failed to reach statistical significance  and positive components . Patients only diagnosed with cyclothymia scored significantly higher on the first component than patients with only ADHD (z-scores (mean ± SD): 0.23 ± 0.98 vs. −0.23 ± 0.96), while comorbid patients with both diagnoses did not significantly differ from the others (z-score (mean ± SD): 0.18 ± 1.04). Conversely, both comorbid and non-comorbid ADHD groups had significantly higher scores for positive affect than patients with non-comorbid cyclothymia. The highest score was found in patients with both ADHD and cyclothymia, followed, in order, by ADHD and cyclothymia (z-scores (mean ± SD): 0.34 ± 1.03; 0.20 ± 0.91; −0.40 ± 0.97).Finally, two components, explaining 63.74% of the variance, were extracted through PCA with varimax rotation performed on TEMPS-M and RIPoSt-40 subscales . CyclothIn our study, we consecutively recruited adult psychiatric outpatients diagnosed with ADHD and/or cyclothymic disorder. Importantly, a high diagnostic overlap among categories was observed. Indeed, approximately one-fourth of all the ADHD patients included in the study also presented with cyclothymic disorder . This latter rate doubles the lifetime prevalence of bipolar disorder in ADHD samples, which approximately settles to 10% according to recent estimates . A selecAmong cyclothymic patients recruited in our study, almost a third were diagnosed with ADHD . This figure outweighs the estimated prevalence of ADHD in adults with bipolar disorder, which nearly reaches 20% based on recent meta-analytic findings . HoweverThe greatest differences were observed between non-comorbid patient groups . Cyclothymic patients were more frequently female, were older, and more frequently achieved a high educational level. ADHD patients, instead, were more frequently male, were younger, and had lower educational achievements. ADHD patients with comorbid cyclothymia showed a similarly low educational attainment, which suggests a higher impact of attentional and hyperactive–impulsive dimensions, rather than affective symptoms, on academic achievements. Indeed, even if emotional impulsivity has been previously associated with educational outcomes, including high school and college graduation, in adults with ADHD , attentiSubstance use disorders were also specifically associated with ADHD, regardless of the presence of cyclothymia. Previous studies consistently supported the association between childhood ADHD and adult substance use disorders based on both prospective assessments  and retrOn the opposite, a trend toward higher comorbidity of cyclothymia with panic disorder was observed, and a first-degree family history of panic disorder, major depressive episodes, and suicide attempts were more frequently reported by cyclothymic patients. The relationship between soft bipolar disorders and panic disorder has been long established , and panOverall, the differences observed in familial history suggest a higher genetic load for conditions associated with negative affect and harm avoidance in patients with cyclothymia with respect to ADHD patients, whose pattern of comorbidity is indicative of a greater inclination toward sensation seeking. Indeed, ADHD has been repeatedly characterized by high novelty seeking , while bDifferences in affective temperamental traits and negative emotionality could also be attributed to different triggers for referral to psychiatric services. In our context, approximately one-fifth of patients diagnosed with ADHD during childhood or adolescence continue to use mental health services in adulthood , a rate Interestingly, while no significant differences among our groups were observed for cyclothymic temperament and overall negative emotional dysregulation, comorbid patients with both ADHD and cyclothymia scored the highest in these subscales. In addition, this group also showed higher affective instability with respect to ADHD patients without cyclothymia and was less frequently diagnosed with bipolar disorder type II than patients from both the other groups. This could be due to conservative attitudes toward diagnosis: since clinicians may be less prone to diagnose a patient with both ADHD and cyclothymic disorder due to overlapping symptoms of these conditions, only ADHD patients showing really severe, rapid, and frequent mood swings, which are reflected in greater affective instability scores and fail to reach duration thresholds for hypomanic episodes, may receive the diagnosis of “comorbid” cyclothymic disorder. We suggest that these patients are likely to be characterized by “dark” unstable expressions of soft bipolarity and to be diagnosed as affected by borderline personality disorder, which highly overlaps both with ADHD and bipolar disorder . Indeed,Several limitations of this study should be acknowledged. First, the clinical setting (a tertiary psychiatry unit) may have not been representative of the whole population of patients with ADHD and/or cyclothymia, but of a more complicated subpopulation, possibly showing higher rates of comorbidity and a greater severity. Second, the cross-sectional study design mostly limited the assessment of psychiatric comorbidity to retrospective accounts, which may be at risk of recall bias. In addition, the evaluation of affective temperaments and emotional dysregulation facets was based on self-report questionnaires, which may be biased by differences in social desirability, lack of insight, or malingering attempts. Finally, the criteria used to identify patients affected by cyclothymia slightly differed from DSM-5 criteria, possibly being more inclusive. As a consequence, our results should be interpreted with caution. Further longitudinal studies on epidemiological samples are needed to investigate comorbidity rates and psychopathological differences between ADHD and cyclothymia, possibly including different definitions of the latter disorder.To the best of our knowledge, this is the first study to investigate the comorbidity between ADHD and cyclothymic disorder in adult clinical samples and compare patients diagnosed with either one or both of the disorders. Based on our findings, ADHD and cyclothymic disorder often co-occur. While differences can be observed in socio-demographic variables , emotional dysregulation is a common feature in both conditions, with a slightly greater severity in patients diagnosed with both disorders. Based on psychiatric comorbidity, family history, and differences in affective temperaments and emotional dysregulation facets, cyclothymic patients were found to be significantly more prone to negative emotions, such as anxiety and depressed mood, in comparison with patients affected by ADHD, more often comorbid with substance use disorders. However, these differences could be limited to the clinical setting, where different reasons for referral are likely to bias sample selection. Patients with ADHD without emotional dysregulation and subjects with “sunny” cyclothymic temperament might be found in the community. On this assumption, we propose that the co-occurrence of conditions within the attention-deficit/hyperactivity and cyclothymic spectra can be summarized according to non-orthogonal, but also non-overlapping, intersected dimensions of deficient executive functioning and negative emotionality in adults with emotional dysregulation, both of which are likely to influence clinical attention. Alternatively, different emotional dispositions characterize patients with ADHD or cyclothymia. While positive affect could counterbalance negative emotionality in the former group, depressive and anxious tendencies may prevail in the latter.


Purpose: This study aimed to explore alterations in functional connectivity (FC) within and between default mode network (DMN), central executive network, and salience network in autism spectrum disorder (ASD) with co-occurring attention deficit hyperactivity disorder (ADHD).Method: A total of 135 individuals' date of the Autism Brain Imaging Data Exchange II was used to compare the ASD+ADHD group with the ASD group in relation to the abnormal within-network and between-network connectivity of the ASD group relative to the TD group; consequently, the correlation analysis between abnormal FC and behavior was performed.Results: The ASD+ADHD group exhibited decreased within-network connectivity in the precuneus of the ventral DMN compared with the ASD group. Among the three groups, the ASD+ADHD group showed lower connectivity, whereas the ASD group had higher connectivity than the TD group, although the effect of the separate post hoc test was not significant. Meanwhile, the ASD+ADHD group showed increased between-network connectivity between the ventral DMN and dorsal DMN and between the ventral DMN and left executive control network, compared with the ASD and TD groups.Conclusion: Dysfunction of DMN in the “triple-network model” is the core evidence for ASD with co-occurring ADHD. Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are defined by symptom-based classification. As described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), ASD exhibits abnormal behavioral symptoms of social/communication deficits and restricted and repetitive behaviors, whereas ADHD is defined by attentional and/or hyperactive/impulsive traits . The newIn recent years, the development of functional magnetic resonance imaging (fMRI), a common neuroimaging technique, has provided a promising tool for investigating cognitive dysfunction. Several resting-state fMRI (rs-fMRI) studies have demonstrated that ASD or ADHD is related to atypical patterns of functional connectivity (FC) in large-scale brain networks –9. Of thIn this study, we applied the triple-network model to investigate the specific alterations of both within-network and between-network FC of the three core neurocognitive networks in the ASD with co-occurring ADHD (ASD+ADHD group) and ASD without co-occurring ADHD (ASD group) using rs-fMRI while identifying the relationship to clinical symptoms. We used independent component analysis (ICA) to identify the brain regions of the DMN, SN, and CEN according to the Stanford Functional Imaging in Neuropsychiatric Disorders (FIND) Lab. We hypothesized that altered connectivity existed both within and between these three core brain networks and predicted that specific FCs would explain the brain-behavior relationship that contributed to explaining the phenotypes of the ASD with ADHD co-occurring, thus demonstrating the diagnosis and potential therapeutic biomarkers of such people.http://fcon_1000.projects.nitrc.org/indi/abide/abide_II.html] with most subjects meeting the following criteria: first, we included individuals with a full-scale IQ and near full-brain coverage structural and rs-fMRI scan data and excluded individuals with excessive head motion characterized by a mean framewise displacement (FD) of more than 0.30 mm; next, we divided the people into two groups (ASD+ADHD and ASD) on the basis of the psychiatric comorbidity information on the ABIDE II website; and finally, from each site, we selected from the included dataset the same number of individuals matching in terms of age- and IQ-matched typical development (TD) with the other two groups. These inclusion criteria and an additional step for matching the three groups at each site resulted in a cohort of 135 individuals , with whom the three groups were matched by age, sex, and full IQ (FIQ) in the scanner , nner see . A selecThe acquisition parameters and protocol information of the MRI images are provided in http://www.icatb.sourceforge.net). The aggregate preprocessed data were written and projected into 29 independent components (ICs), the optimal number of their dimensions estimated by the minimum description length criteria tool within the GIFT software  using the InfoMax algorithm, as implemented in the Group ICA of fMRI Toolbox (GIFT) version 4.0  was used to examine specific temporal correlations in a nonparametric pairwise manner, with a maximal lagged correlation approach, and calculated lags that were correlated to each other. Thus, all nine RSNs were paired with one another among the triple-networks to obtain 36 pairwise combinations, and the coefficients were then transformed into z-scores using Fisher's z-transformation. The transformed z-scores were indexed the between-network connectivity of each network pair.The z-map of each subject-level component was indexed within-network connectivity measurements. Rs-fMRI data were band-pass–filtered (0.008–0.15 Hz) before the functional network connectivity (FNC) analysis , and thet-tests with age, site, sex, FIQ, and mean FD as covariates were used to analyze the group differences (ASD+ADHD and ASD) of within-network connectivity. The comparisons were limited to the network mask generated by composing the results of the one-sample t-test of each group     or the chi-squared test (sex) using Statistical Product and Service Solutions software (version 25.0). The statistical module in DPARSF was used to perform statistical analysis on the spatial z-map . In eachion] see . The sigtations) . We thenpost hoc test.To explore the differences in between-network connectivity, the resulting pairwise correlation coefficients were transformed to Fisher's z-values and then extracted into MANOVA while regressing out site, age, sex, FIQ, and mean FD. In addition, we further explored the differences in aberrant between-network connectivity between the ASD+ADHD and ASD groups using a n = 86) subjects _Social Affect (SA) subscale , the Socsubjects .As shown in In this study, the nine selected ICs were subsets of the large six major resting-state networks (RSNs) based on 90 ROIs relating to the triple-network model identified by a previous study : ICs 2, post hoc test was not significant , the ASD+ADHD group demonstrated significantly decreased connectivity in the left and inter-hemispheric precuneus of the IC 23, which was identified as the vDMN , Table 2nificant . TherefoP < 0.05; post hoc tests showed that ASD+ADHD group had significantly higher dDMN (IC 12)–vDMN (IC 23) and LECN (IC 24)–vDMN (IC 23) between-network connectivity than the ASD and TD groups, which indicated dysfunctional FC between the vDMN and dDMN and between the DMN and ECN; meanwhile, the ASD group had higher connectivity than the TD group, but the effect was not significant , and the altered vDMN (IC23)–LECN (IC24) between-network connectivity was positively correlated with SRS_communication T-scores in all samples . However, the results were not corrected for multiple comparisons. There was no significant correlation between the abnormal within-network connectivity of the vDMN, and clinical characteristics measured by SRS and ADOS_2_SA scores were not detected.As shown in In this study, we demonstrated the dysconnectivity within and between the SN, DMN, and ECN in ASD with and without co-occurring ADHD, on the basis of the triple-network model. ASD+ADHD group showed decreased within-network connectivity in the left and inter-hemispheric precuneus of the vDMN compared with ASD group. Notably, ASD+ADHD group also demonstrated increased between-network connectivity between the dDMN and vDMN and between the vDMN and LCEN, which suggested the presence of atypical dynamic interactions of the triple network in the ASD with co-occurring ADHD. These results provide evidence of aberrant connectivity patterns across the core neurocognitive networks of triple-network models in ASD with co-occurring ADHD.Social functioning is a major and central domain of impairment in both disorders, which significantly affects prognosis. Studies have reported that social awareness, social cognition, emotion recognition, and social communication may be poorer in children with ASD+ADHD than those with ASD alone . In thisNew achievements have been made relative to the triple-network aberrant connectivity in other psychiatric conditions, such as schizophrenia. In 2020, Luo et al.  found anThe DMN participates in evaluative social processes , mentaliAs in the proposed triple-network model, the SN, DMN, and ECN did not function independently. The DMN represented the task-negative processing mode for the human brain, whereas the ECN characterized the somewhat contrary task-positive processing mode. Increasingly, research has revealed the important role of cooperation between the SN, ECN, and DMN in maintaining cognitive functions , 57. In This study has some limitations. First, our analyses were performed on people with ASD who had comorbid ADHD and people with ASD who did not have comorbid ASD based on the dataset; however, we did not have ADHD symptom scores for the participants. Further research including both ASD and ADHD symptom scores is required. Moreover, this study ignored the diagnoses of other psychiatric comorbidities.In conclusion, our data show that, in addition to impaired FC within the DMN in people with ASD and comorbid ADHD, they also demonstrate aberrant functional interactions between the vDMN and dDMN and between the vDMN and LCEN. This triple-network model provides a new and powerful framework for understanding the dysfunctional brain architecture of ASD with co-occurring ADHD.The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.KW designed this study. KW and KL performed data preprocessing and analysis. XN and KL drafted the manuscript. All authors approved the final version for publication.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Evidence from functional neuroimaging studies support neural differences between the Attention Deficit Hyperactivity Disorder (ADHD) presentation types. It remains unclear if these neural deficits also manifest at the structural level. We have previously shown that the ADHD combined, and ADHD inattentive types demonstrate differences in graph properties of structural covariance suggesting an underlying difference in neuroanatomical organization. The goal of this study was to examine and validate white matter brain organization between the two subtypes using both scalar and connectivity measures of brain white matter. We used both tract-based spatial statistical (TBSS) and tractography analyses with network-based Statistics (NBS) and graph-theoretical analyses in a cohort of 35 ADHD participants (aged 8–17 years) defined using DSM-IV criteria as combined (ADHD-C) type (n = 19) or as predominantly inattentive (ADHD-I) type (n = 16), and 28 matched neurotypical controls. We performed TBSS analyses on scalar measures of fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivity to assess differences in WM between ADHD types and controls. NBS and graph theoretical analysis of whole brain inter-regional tractography examined connectomic differences and brain network organization, respectively. None of the scalar measures significantly differed between ADHD types or relative to controls. Similarly, there were no tractography connectivity differences between the two subtypes and relative to controls using NBS. Global and regional graph measures were also similar between the groups. A single significant finding was observed for nodal degree between the ADHD-C and controls, in the right insula (corrected p = .029). Our result of no white matter differences between the subtypes is consistent with most previous findings. These findings together might suggest that the white matter structural architecture is largely similar between the DSM-based ADHD presentations is similar to the extent of being undetectable with the current cohort size. Characterized by clinical deficits in attention, hyperactivity, and impulsivity, attention deficit hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental condition with an estimated global prevalence of 3.4% of children worldwide . Presentscalar measures to evaluate the ADHD subtypes, Svatkova, Nestrasil [Research from task and resting-state functional connectivity studies reveal neural differences between the ADHD-C and ADHD-I types with atypical patterns of increased and reduced activation in the cingulo frontal parietal attentional (CFP) and default mode (DMN) networks . The regestrasil  reportedestrasil . Other sestrasil , increasestrasil  for ADHDestrasil ,20. Consestrasil . Based oThe evolving framework of ADHD pathophysiology is shaped by the application of neuroimaging measures which include the more recent connectomic approach in assessing possible disruptions in brain network connectivity. An example of this paradigm shift can be seen in the proposal of a neurocircuitry based model in ADHD, which incorporates knowledge on the role of inter-regional network organization involving frontal, temporal and parietal regions, from the historical view of dopaminergic regulation and frontal-striatal circuitry deficit . NetworkThis study utilized DTI data to assess whether structural WM microstructural properties and connectivity may distinguish the ADHD- C and ADHD-I types, and comparatively to neurotypical controls. Firstly, we applied tract-based spatial statistics (TBSS), using DTI derived scalar measures  of fractParticipants were recruited as part of the International Study to Predict Optimized Treatment in ADHD (iSPOT-A) study. A detailed account of the inclusion/exclusion criteria protocols for participant recruitment, diagnostic measures, and procedures for the iSPOT-A study has been previously published  and is dn = 11 ADHD-C; n = 5 ADHD-I) and were withdrawn from methylphenidate for at least 5 half-lives. Participants were all fluent in English and had no history of brain injury, any significant medical condition affecting brain function , or any contraindications for MRI. All participants and/or their guardians provided written informed consent to participate in the research, in accordance with the National Health and Medical Research Council guidelines.Confirmation of ADHD diagnosis (DSM-IV criteria) and subtype (i.e. presentation in DSM-V) was measured by the Mini International Neuropsychiatric Interview (MINI Kid) , and theMagnetic resonance images were acquired using a 3.0 Tesla GE Signa HDx scanner  using an 8-channel head coil. Diffusion tensor images were acquired using a spin-echo DTI-echo planar imaging sequence. Seventy contiguous 2.5mm slices were acquired in an axial orientation with an in-plane resolution of 1.72mm x 1.72mm and a 128 x 128 matrix (repetition time (TR) = 17000 ms; echo time (TE) = 95 ms; fat saturation: on; number of excitations (NEX) = 1; frequency direction: right/left). A baseline image (b = 0) and 42 different diffusion orientations were acquired with a b-value of 1250. Total acquisition time for the DTI protocol was 13 min 36s. Three-dimensional (3-D) T1-weighted magnetic resonance images were also acquired in the sagittal plane using a 3D SPGR sequence . A total of 180 contiguous 1 mm slices were acquired with a 256 × 256 matrix, with an in-plane resolution of 1 mm × 1 mm resulting in isotropic voxels.http://www.fmrib.ox.ac.uk/fsl) [Diffusion tensor imaging data pre-processing and analytic methods utilized the Oxford Centre for Functional MRI of the Brain (FMRIB) diffusion toolbox and TBSS software tools as part of the FMRIB Software Library release 4.1.3 (.uk/fsl) ,27. Raw .uk/fsl) .We have previously described in greater detail, the methods employed for the TBSS Analysis of the DTI data . In briehttp://surfer.nmr.mgh.harvard.edu/) analysis of the T1 MRI scan. This resulted in an 84 x 84 interregional connectivity matrix of number of probabilistic tracts for each participant. Based on standard protocols and methods for MRI cortical parcellation described in our previous study [http://surfer.nmr.mgh.harvard.edu) standard pipeline segmentation of the 3-D T1-weighted structural images, using the Deskilian- Killiany [DTI based structural connectome matrices for each individual participant were generated using probabilistic tractography . Tractogus study , FreesurKilliany  atlas a Killiany . FurtherNetwork-based statistical Analyses (NBS) was then applied to examine regional connectivity differences in the interregional 84 x 84 connectivity matrix between the ADHD-C (n = 19) and ADHD-I (n = 18) types and controls (n = 26). This method has been previously described in detail in Korgaonkar, Fornito .http://www.brain-connectivity-toolbox.net/) [p value corrected for a number of global measures, i.e., p < 0.025 (.05/2), and for the number of nodes in regional measures, i.e., p < 0.0006 (.05/84). This method applied has been previously described in detail [Graph theoretical analyses were performed on the inter-regional 84 x 84 connectivity matrices using the Brain Connectivity Toolbox (ox.net/) . Global n detail .Correlation analyses were performed to measure any associations between: FA values (for the JHU WM atlas tracts) and the global and regional graph network measures, and the dimensional measures of the ADHD-RS scores; total inattention items, total hyperactive/impulsive items, and total item scores, while controlling for age and gender.p < .05). Of the ADHD-I type participants, one participant qualified for seven items out of 9 hyperactive/impulsive subscale items, less than four 4 items (n = 4), 3 items (n = 2), 2 items (n = 1) and ≤1 item (n = 11).Demographic and clinical characteristics for the ADHD-C type, ADHD-I type, and control participants are summarized in No significant differences were found between the subtypes or relative to controls for any of the DTI scalar measures FA, AD, RD, or MD using voxel-wise analysis. No significant differences were observed for the FA average values for the 46 defined WM regions, however findings from the ROI analyses which were significant at the uncorrected level is shown in Forrest plots showing FA values for 46 defined White Matter Regions using region of interest analysis comparing the combined and inattentive ADHD types , CombineNBS analysis also did not identify any inter-regional connectivity differences between the ADHD-C and ADHD-I types or when compared to controls after correcting for multiple comparisons.p < .05 corrected for multiple comparisons) in the right insula . There were no significant differences found between the two ADHD subtypes, or the ADHD-I type compared to controls. Regional nodal degree measures which were significant but did not survive after correcting for multiple comparisons are illustrated in Neither of the global topological measures: clustering coefficient or global characteristic path length, showed significant differences between the ADHD-C and ADHD-I groups or compared to controls. Group comparison of the regional nodal degree revealed a single significant finding between the ADHD-C and control group,  and inattentive (ADHD-I) DSM-V presentations of ADHD. TBSS analysis of FA, AD, MD, and RD values, ROI analysis of FA values for 46 white matter tracts defined by the JHU WM atlas and NBS analyses of inter-regional connectivity of 84 cortical-subcortical brain regions revealed no significant differences between the subtypes or compared to controls. Of all the white matter measures, only graph properties of nodal degree for the insula were found to significantly differ in the ADHD-C type relative to controls after controlling for multiple comparisons. Studies of WM microstructural properties between the subtypes of ADHD are limited. In line with the only two previous TBSS studies ,17 availAnother possible reason for null findings in our study may be due to a number of treatment-experienced participants in our study compared to the previous subtype-based studies, which recruited participants who were treatment-naive or with treatment history < 6 months ,18,22. SConsistent with the two previous subtype comparison studies utilizing TBSS, we found no differences in FA values ,17 or ADAdditionally, we performed a region of interest (ROI) analysis and did not find significant differences in FA values between the two types. Despite the absence of significant differences between groups at the corrected thresholds, increased FA values in ADHD-C compared to ADHD-I and controls were observed at uncorrected thresholds. That is, the bilateral posterior corona radiata characterized the ADHD-C type from ADHD-I and controls, the left posterior limb of internal capsule and left anterior limb of internal capsule in ADHD-C relative to ADHD-I, and the left uncinate fasciculus in ADHD-C compared to controls. Interestingly, similar findings from a previous study comparing an ADHD group reported reduced FA values in the ADHD groups in the posterior corona radiata, the uncinate fasciculus with reduced MD in the posterior limb of internal capsule, relative to controls .In our study, we also used tractography to evaluate white matter connectomic differences. Our study did not find WM connectivity differences between the ADHD-C and ADHD-I subtypes or compared to controls. However, previous findings from Hong, Zalesky , the onlAlthough the availability of DTI studies which specifically examine subtype differences are sparse, significant findings have been reported, albeit equivocal. Undoubtedly, further studies are warranted to establish structural connectivity alterations in ADHD types, however, emerging evidence from DTI studies examining an all-inclusive ADHD group with controls have reported significant findings. For example, studies investigating basal ganglia and thalamic connectivity have found lower FA values in ADHD-C relative to controls ,20. Falln = 35, and n = 49 for the FA derived atlas-based region of interest analysis and regional nodal degree, respectively, would be required would be required for effects to be significant at the Bonferroni corrected threshold of 0.001.There were several limitations to the study. It is quite likely that the lack of significant findings in our study is due to the small available sample size and should any differences be present, then these would be of minimal size, and only detectable in larger cohorts. Using the trend findings from the comparison analysis between the two ADHD subtypes, a power analysis indicated that at least This limits the statistical power of our results and thus may explain why we were not able to detect differences between groups after appropriate correcting for multiple comparisons. We have reported uncorrected findings in the supplementary section and replication studies with larger sample sizes utilizing these measures are warranted to further explore possible differences in microstructural integrity between the ADHD types. In a previous study utilizing the same cohort, we did observe differences in structural covariance between the two ADHD subtypes. It may be that interregional structural covariance relates better to functional networks and it is likely that functional differences are more pronounced between the ADHD types ,52. It iWe applied standard established analytical methods and hence our null findings are important to consider in the context of the paucity of DTI studies comparing ADHD presentations. However, an important consideration relates to common limitations of DTI analyses, in particular tract-based spatial statistics (TBSS) where TBSS is subject to inaccuracies relating to FA-based projections in regions of crossing fibers and incapable of obtaining a complete measure of the total number of white matter axons; combining within voxel microscopic fiber density and macroscopy . The TBSOur study examined the combined and inattentive type only, as data for the predominantly hyperactive-impulsive type was not available, thereby analysis between all three types was not possible. Medication effects and stimulant treatment history may bias the findings from this study; however, this confounding effect is difficult to eliminate. Although, recent ADHD DTI research studies which investigated possible medication effects on WM structure and connectivity produced inconclusive findings . ChangesIn summation, we did not find white matter microstructural properties or network connectivity to differentiate the two subtypes from each other or relative to controls. However, we did find the ADHD-C group to differ in regional nodal degree in the insula relative to controls. While the overall results of this study may be inconsistent with the findings of previous ADHD subtype DTI studies, the absence of evidence for differences in WM microstructural properties relative to FA values between the two subtypes is in line with previous research. To the best of our knowledge, this is the first study to utilize both voxel-wise analysis of scalar white matter measures in addition to tractography incorporating network and graph theoretical measures to examine differences between these two ADHD subtypes.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


In recent years, there has been growing interest in investigating the effect of specific pharmacological treatments for ADHD not only on its core symptoms, but also on social skills in youths. This stands especially true for ADHD patients displaying impulsive aggressiveness and antisocial behaviors, being the comorbidity with Disruptive Behavior Disorders, one of the most frequently observed in clinical settings. This systematic review aimed to synthesize research findings on this topic following PRISMA guidelines and to identify gaps in current knowledge, future directions, and treatment implications. Search strategies included the following terms: ADHD; methylphenidate and other ADHD drugs; empathy, theory of mind and emotion recognition. Full-text articles were retrieved and data from individual studies were collected. Thirteen studies were finally included in our systematic review. Ten studies assessing changes in empathy and/or theory of mind in patients with ADHD treated after pharmacological interventions were identified. Similarly, seven partially overlapping studies assessing changes in emotion recognition were retrieved. Despite a great heterogeneity in the methodological characteristics of the included studies, most of them reported an improvement in emphatic and theory of mind abilities in youths with ADHD treated with psychostimulants and nonstimulant drugs, as well as positive but less consistent results about emotion recognition performances. Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders, with a pooled worldwide prevalence of 7.2% among children and adolescents . In addiInterestingly, ADHD core symptoms per se may interfere with adequate social interactions. Indeed, attention deficits interfere with a proper coding and interpretation of social information, i.e., focusing and sustaining attention during conversations or appropriately reading social cues during play . On the Social cognition is essential for successful social interaction and, as a whole, refers to the ability to understand other people’s behaviors. It involves codification, representation and interpretation of social cues and includes (1) recognizing others’ affects from face and prosody perception , (2) making inferences regarding others’ mental states ), 3) sharing and understanding the emotional perspective of others   sharing , from whEmpathy is a complex multidimensional construct including an affective component—affective empathy (AE)—that is, the capacity of sharing emotions and responding to emotional displays of others, and a cognitive one—cognitive empathy (CE)—namely, the ability to understand the perspective of another person ,11,12,13These two components may have different neuroanatomical correlates, the former implying the contribution of limbic and paralimbic structures and developing earlier than the latter, which assumes, in turn, a fine-tuned maturation of prefrontal and temporal networks . HoweverAlthough the two systems work independently, as previously suggested by the Perception–Action Model of empathy ,21, theyOn the other side, the appropriate recognition of emotional cues represents a fundamental milestone in the early development of social cognition skills. Indeed, the ability to identify emotions from facial expressions and prosody is acquired during childhood and further develops during adolescence. Besides, nonverbal channels of communication seem to play an important role in helping individuals to interact appropriately with each other. Intact emotion recognition is required for the inhibition of aggressive behavior and its deficiencies might lead to aggressive reactions toward others . At the In healthy individuals, facial expressions usually elicit neural changes over frontotemporal and parieto-occipital cortices, while right-sided peri-sylvian areas are engaged in the processing of emotional prosody . Face emClinical evidence suggests several psychopathological disorders to be characterized by deficits in social cognition ,33. ImpoOn the other hand, several studies have also demonstrated that children with ADHD exhibited AE deficits compared to healthy controls ,41,44, eChildren and adolescents with ADHD also exhibit an impaired emotion recognition ability and a nonverbal receptive language deficit ,48,49, wAccording to Uekermann and colleagues , empathyRecent literature has suggested that pharmacological interventions in ADHD patients may provide beneficial effects on social cognition deficits. Indeed, psychostimulants, including methylphenidate (MPH), and amphetamines, the gold-standard drug treatment for ADHD , have beThe aim of the present study was to perform a systematic review of the literature on the effects of psychostimulants and nonstimulant drugs on empathy and related constructs in patients with ADHD. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines; the corresponding checklist is available in (1)Study design: any type of clinical trial;(2)Comparison: either case versus control, drug versus placebo or pre-to peri-/post-treatment;(3)Participants: patients non-retrospectively diagnosed with ADHD according to the international classification systems DSM-IV, ICD-9, or later versions; no restriction for participants’ age, gender, or IQ;(4)Intervention: either one-day, single-dose administration or prolonged daily administration of psychostimulants  or nonstimulant drugs ;(5)Measures: any type of measurement  assessing empathy, theory of mind, and emotion recognition.Our search strategy was used to retrieve potentially relevant abstracts; duplicates from different bibliographic databases were initially removed, whereas additional records were identified through reference lists and the inspection of screened articles, as stated above, were also included. Two researchers (GS and PF) screened all titles and abstracts to identify relevant articles. Full texts of selected papers were then retrieved and carefully screened to finally identify the included studies according to eligibility criteria. Any disagreements were resolved by consensus. The PRISMA flowchart  shows thExclusion criteria are detailed in For each included study, we extracted relevant information, whenever available, including sample size, demographic data (age and gender), ADHD diagnosis and subtypes, intellectual functioning and psychiatric comorbidities, previous and current medication (including dosage and administration), follow-up duration, as well as information about the clinical measure used to assess changes in empathic competencies and related constructs and main findings of the study. When datasets were not fully available, authors of the included studies were contacted to attain the relevant data. Extracted information are available in Details of the screening process and the identification and selection of papers are available in Ten studies ,65,66,67All studies were conducted on children and adolescents aged 6 to 18 years old. Diagnoses were based on DSM-IV or DSM-5 systems  and inclFive studies ,61,66,67A recent study  corroborFive additional studies ,60,62,65Interestingly, a multimodal approach including drug treatment plus cognitive behavior therapy resulted in significantly greater improvements in frequency indicators on skillful reactions of empathy than the medication-only approach in ADHD patients . FinallySeven studies ,68,69,70Two studies ,68 examiFour studies ,58,60,70Two more recent studies ,60 compaThe present systematic review aimed to synthesize research findings on the effect of psychostimulants and nonstimulant drugs on social cognition in patients with ADHD. As far as we know, our study is the first review that systematically and specifically addressed this topic; former narrative but still comprehensive reviews ,6 were rMost of the studies we identified through our search were conducted on children as expected, since ADHD is a neurodevelopmental condition with greater incidence in childhood  and sociAs for the assessment of empathy and ToM, both paper-and-pencil questionnaires, including self  and parent reports , and standardized tests  were used. On the other hand, only standardized tasks were used instead to assess the emotion recognition abilities of participants . Among the available treatment options for ADHD, most studies assessed the effect of psychostimulants, and first of all MPH, which represents the gold-standard pharmacological intervention for the disorder . Schulz Study designs significantly varied across the included papers, most of which were based on longitudinal trials. Indeed, several studies assessed the effect of a mid-term treatment with MPH and/or other pharmacological and non-pharmacological interventions administered on a regular daily basis for 3–12 weeks to 4–6 months, typically in drug-naïve ADHD patients, except for a few samples including individuals previously exposed to psychostimulants that were washed-out from 3 days to 1 month prior to testing. Some additional studies assessed the effects of a single-dose administration of MPH, either alone or versus placebo in drug-naïve ADHD patients or subjects that were already regularly taking drugs, whereas only one study  applied Eight studies demonstrated significant improvements in empathy and/or ToM skills after a single-dose administration or prolonged treatment ,60,61,62As for emotion recognition abilities, most studies showed a significant improvement after the implementation of pharmacological treatment ,58,60,68Based on our review, we could speculate that, in patients with ADHD, drug treatment improves social cognition skills, namely emotion recognition, empathy and ToM abilities. Psychostimulant treatment has been also likely associated with a long-term improvement in prosocial behavior and other outcomes of social functioning , includiStructural and functional neuroimaging studies have documented abnormalities in brain anatomy and function in individuals with ADHD ,74,75. MInterestingly, it has been suggested that the efficacy of psychostimulants on the core symptoms of the disorder—i.e., inattention, hyperactivity, and impulsivity—is due to the increased central dopaminergic and noradrenergic activity in the brain regions that include the cortex and the striatum, regions involved in the regulation of attentional and behavioral outcomes . ADHD paAmong these, emotion regulation (ER) is also known to be affected in ADHD patients. According to what Posner and colleagues  termed tInterestingly, previous studies demonstrated a positive correlation between EF/ER and empathy/ToM competences in healthy subjects ; inhibiFrom a neuroanatomical point of view, strong evidence supports a model of two separate, yet interacting, systems for empathy, as previously mentioned in Pharmacological treatments, especially with MPH, through a direct modulation of central dopaminergic and noradrenergic transmission in cortex and striatum, an indirect action on other neuropeptides such as oxytocin, and by regulating neural activity in these systems acting on top-down and only partly on bottom-up circuits , can conLittle literature evidence is available to discern whether the impacts of stimulants on social cognition could be mediated by the complementary effects on the different core symptoms of ADHD, namely inattention and hyperactivity/impulsivity. Indeed, the studies conducted so far have not specifically addressed the effects of MPH on different ADHD subtypes, but it may be argued that different subtypes could present different empathy profiles. Children with a predominant Inattentive subtype are typically less aggressive and less likely to have comorbid ODD/CD than children with the combined or the Hyperactive/Impulsive subtype that seem to be less empathic than youths with the inattentive one ,58. We cEmpathy deficits have been implicated in several neurodevelopmental disorders, among which ASD is the most studied ,95. SomeThe current review indicates several limitations of the studies on this topic. First, the limited number of eligible studies. Second, the heterogeneity of the recruited samples and the study protocols (single dose of MPH versus mid-term treatment). Third, the use of self- and parent-rated measures of empathy, which should be integrated with experimental paradigms. In future investigations, empathy/ToM abilities and emotion recognition skills should be assessed in separate samples of ADHD patients including the Inattentive, Hyperactive/Impulsive, and Combined subtype carefully matched on age, gender and medication status. In addition, it would be interesting to investigate possible different responses on the bases of the comorbidity such as other neurodevelopmental disorders, specially ASD, or psychiatric comorbidity.This review provides a contribution for a better understanding of the possible effects of the MPH. Some evidence support the notion that the timely and affective treatment of ADHD symptoms may have beneficial effects not only on core symptoms of ADHD, but also on the social difficulties of youths with ADHD. Future studies on the association of several measures of empathy with comorbid disorders, such as ASD and disruptive behavioral problems, are warranted. At the same time, future studies concerning gender effects are desirable. One important issue for future studies would be the question of whether empathy/Tom/emotion recognition impairments can be observed in all subtypes and, in this case, whether the underlying mechanisms are the same for ADHD subtypes.