Children with ADHD face deficits in interference control due to abnormalities in brain structure. A low body mass index and high physical activity are factors promoting brain health and may have the potential to reduce ADHD-related cognitive deficits. We aimed to investigate the predictive values of ADHD, body mass index and physical activity for interference control and the potential mediation of these associations by brain structure.At 9 and 11 years, 4576 children with ADHD and neurotypical peers from the ABCD-cohort completed a Flanker task, anthropometric assessments and reported physical activity. Additionally, T1- and T2-weighted magnet resonance images were collected at both measurement time points.ADHD, lower physical activity and higher body mass index at baseline predicted lower interference control. Gray matter volume, surface area and gray-white matter ratio contributed to interference control. The longitudinal association between body mass index and interference control was mediated by gray-white-matter ratio. This mediating effect was stronger for children with ADHD than neurotypical peers and mainly restricted to regions associated with cognitive control.The maintenance of a lower body mass index contributes to interference control by a tendency to normalize regional alterations in grey-white-matter ratio. Being compliant with physical activity also promises higher interference control, but brain structure does not seem to underlie this association. International consensus recommends behavioral approaches as first line treatment in children with ADHD, except for cases with more severe symptoms . Even thCognitively enhancing effects of physical activity appear to be crucial during the transition to adolescence, when children with ADHD experience a delay in executive function development . A role In preadolescent children, we investigated longitudinal associations of ADHD status, physical activity and BMI with interference control. Based on the existing literature, we expected that higher physical activity and lower body mass index predicted better interference control. We further examined whether brain structure  in regions underlying interference control mediated these associations.22.1Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5] criteria) (N = 4576) that completed both the baseline and 2-year follow-up assessments (N = 22) approved the study protocol. Children provided verbal assent and written informed consent was obtained from their parents and/or caregivers. The reporting of the study is in line with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist  Study. The ABCD study distributes information material and offers researcher-led presentations at local school to recruit children aged 9–10 years. Our analysis was restricted to ADHD children (based on riteria)  and neuressments . The inshecklist .Table 1P2.2The ABCD study examines children aged 9 to 10 years and follows them up 10 years into young adulthood. Longitudinal data is collected on physical health, mental health, neurocognition, brain function and structure, substance abuse, culture and environment as well as other aspects. For the present analysis, we selected data from the baseline assessment and two-year follow-up Procedures during both assessment time points were standardized and identical across all study sites. This was further supported by the requirement that each site had to have the research expertise and the equipment to collect data according to the ABCD study protocol . Presele2.3Parents or caregivers of study participants completed a computerized version of the Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5 . For cur2.4In the Flanker Inhibitory Control and Attention Test of the National Instruments of Health Cognition Toolbox, a central target arrow flanked by two similar stimuli on each side (left and right) was presented on an iPad . Depending on the trial type, the flanking arrows faced in the same (congruent) or different direction (incongruent) compared to the target arrow. Participants were instructed to indicate the direction of the central stimulus by pressing an on-screen button corresponding to left or right. Following a fixation period (random variation between 1000 and 1500 ms), a cue (1000 ms) reminded participants to focus on the central arrow. The presentation of the flanking arrows commenced 100 ms before the central arrow and the whole test stimulus remained onscreen over 10000 ms or a response was given. When participants responded correctly on 75 % of the practice trials, they advanced to the test items. Otherwise, two additional practice blocks were administered. During practice, a voice prompted participants to correct their response, if an incorrect response was given. The subsequent test block consisted of 16 congruent and 9 incongruent trials, which were presented in pseudorandom order . Scoring of the Flanker task was based on accuracy  or accuracy and reaction time . The two-vector method and equations underlying the calculation of the score has been described in a previous validation study .2.5Participants completed the Youth Risk Behavior Survey  and for 2.6Fully preprocessed morphometric and image intensity measures were provided by the ABCD study . T1- andmeta-analytical findings highlighting regions sensitive to ADHD-related deficits in interference control  and image intensity measures (T1- and T2-weighted gray-white ratio) for each of the 148 Destrieux atlas regions of interest (ROIs). For the present analysis, we focused on 16 ROIs in each hemisphere: ACC, midcingulate cortex (MCC), IFC, insula, and IPL . Our sel control . For the2.7All statistical analyses were conducted with R Studio (version 1.1.463). For the examination of longitudinal associations within the cross-lagged panel , we used33.1ADHD , lower physical activity  and higher BMI  at baseline predicted lower interference control at follow-up. The association between BMI see . The ini3.2When MRI data and confounders were added, interference control at follow-up was associated with T1 GWMR (31 regions), T2 GWMR (22 regions), surface area (14 regions) and grey matter volume (3 regions) A, but noLow T2 GWMR in bilateral IFC, IPL, and left insula partly mediated the relation between ADHD and interference control at follow-up B. MoreovModerated mediation analyses revealed interactions of ADHD status with BMI for T1 GWMR (1 region) and T2 GWMR (10 regions) . Post-ho4Compared to neurotypical peers, children with ADHD performed worse on the Flanker task at follow-up, partly due to regional GWMR abnormalities. In both groups, lower physical activity and higher BMI at baseline independently predicted lower interference control after two years, when autoregressive effects were accounted for. Regression coefficients further indicated that both variables individually explained a proportion of variance in interference control that was similar or even greater than the proportion that was attributed to the ADHD diagnosis. Alterations in GWMR partly accounted for the predictive value of BMI in children with ADHD, but did not underlie the association of physical activity and interference control.In ADHD, gains in interference control are observable in early years , but theThe low GWMR we found in children with ADHD reflects more similar gray and white matter signal intensity. A similar pattern was found in pre- and postcentral cortices as well as parts of the frontal cortex in children showing mental problems and low cognitive ability . IndividAbnormalities in GWMR further accounted for the prediction of interference control by BMI. Despite the linear relation between these variables, the low proportion of participants in the 5th percentile range and a high proportion of participants in the 95th percentile range provides an indication that overweight and obesity have detrimental effects on GWMR. The mediating role of GWMR was more pronounced in children with ADHD compared to neurotypical peers. Previous findings have shown that young adults with a higher BMI show a variety of brain abnormalities, including increased intracortical myelination in regions involved in somatosensory processing and inhibitory control . We exteEven though our findings provide first indications on pathways by which BMI influences interference control in children with ADHD, their interpretation is limited by a very low strength of the interrelations. Major factors contributing to less pronounced differences in behavioral performance between patients with ADHD and neurotypical peers include a restriction of the study period to only two years and specific recruitment procedures. In the ABCD study, children with externalizing and/or internalizing problems were over-represented at baseline , but not5During the transition from childhood to adolescence, children with ADHD show lower interference control relative to neurotypical peers due to abnormalities in brain structure. Compared to the ADHD diagnosis, a higher BMI and lower physical activity seem to have at least the same predictive value for this cognitive function. The prevention of a higher BMI has a positive effect on inteference control as it tends to normalize ADHD-related alterations in brain structure. Consequently, practitioners may encourage the monitoring of weight status and physical activity levels to predict deficits in interference control and eventually support the ADHD treatment in children.Sebastian Ludyga: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Validation, Writing – original draft. Toru Ishihara: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing – review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Individuals with attention-deficit hyperactivity disorder (ADHD) often display over-response to stimuli that are irrelevant to the ongoing task, and their attentional abilities disproportionately worsen in the presence of competing stimuli. Auditory event-related potentials (ERPs) such as mismatch negativity (MMN) and P3a using the passive oddball paradigm have been studied in children and adolescents with ADHD. Still, there is no such data for adults with ADHD. This study aimed to compare the MMN and P3a and their clinical and neurocognitive correlations between drug-naive adults with ADHD and control adults.We recruited 52 adults with ADHD (26.5 ± 6.2 years), and 62 age-matched controls (25.6 ± 5.6 years). They received the psychiatric interviews, auditory ERP, the Conners' continuous performance test (CCPT), and the Cambridge gambling test (CGT). They also completed the questionnaires about ADHD symptoms and real-world executive functions. MMN and P3a were assessed during a passive duration-deviant auditory oddball paradigm from the midline electrodes Cz.Adults with ADHD demonstrated smaller Cz MMN amplitude, more severe ADHD symptoms, poorer attention profiles (CCPT), and a wide range of executive dysfunctions than controls. As for the correlates, Cz peak amplitude of MMN correlated with inattention symptoms, executive dysfunctions, attentional vigilance (CCPT), and decision-making (CGT) in ADHD adults but only with decision-making in controls.Our findings that smaller amplitude of MMN and its differential associated pattern with inattention, real-world executive dysfunction, and decision-making, in drug-naive adults with ADHD from adult controls, provide evidence to support the potential electrophysiological biomarker for adult ADHD. Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder that affects 11% of children in the USA  was used to assess the brain's electrical activity in response to the auditory stimulation , suggested that children with ADHD demonstrated reduced MMN amplitude compared with healthy children. However, these studies are limited by a very small sample size (<15 for each group), restricted on children and adolescents, possible medication effect as MMN reported to be influenced by methylphenidate  found attenuated P3a in children with ADHD without group difference in MMN. Rydkjaer et al. (N = 28) showed marginally smaller MMN amplitudes for midline electrodes than controls without significant group differences in P3a amplitude for midline electrodes (Fz/FCz/Cz).There have been few studies measuring P3a in ADHD patients, and some of them collected P3a during a distracting task , adults with ADHD may still have reduced MMN amplitude compared to healthy adult controls, which are correlated with inattention and hyperactivity-impulsivity of ADHD core symptoms. Second, we hypothesize that the brain responses towards novelty detection and attention reorientation measured by MMN and P3a can predict the real-life and neuropsychologically assessed attention deficits and executive dysfunctions in adults with ADHD.This study was approved by the Research Ethics Committee of National Taiwan University Hospital, Taipei, Taiwan . All the participants provided written informed consent after a detailed explanation of the procedures and purpose of the study.s.d.): 26.5 ± 6.2 years] conducted by the corresponding author for childhood ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria  from the same school via teachers' referrals or the same community via advertisement according to the age and sex distribution of the adult ADHD group. All the participants received clinical evaluation and psychiatric interviews with modified ADHD supplement  interview  . The participants reported their ADHD-related symptoms on the first 18 items of SNAP-IV . The BRIEF : inhibit, shift and emotional control and (2) metacognition index (MCI): initiate, WM, planning and organizing, organization of materials and monitor; as well as an overall index . Items are rated as 1 (never), 2 (sometimes), and 3 (often). The BRIEF in Chinese has been used in epidemiological  variability, and Hit RT standard errors (s.e.); (2) cognitive impulsivity: commission errors and perseverations; and (3) vigilance: Hit RT and Hit RT s.e. changed across different ISIs.The CCPT (see online Supplementary methods) is a widely used computerized task to assess attention performance by non-X type CPT test of go/no-go paradigm  risk adjustment: the mean risk-taking score (points) for each box ratio for both conditions where points to gamble differ relative to box ratio, and (3) Risk-taking: the total difference between risk-taking scores (points gambled) in both the ascending and descending conditions (delay aversion).Cambridge gambling test (CGT), one of the tasks of the CANTAB (Cambridge Cognition Ltd) tasks, is designed to assess decision-making ability  and deviant  tones were presented in a pseudorandom order with at least 2 standards are presented before each deviant. All stimuli were 1000 Hz and 80 dB with 1 ms rise–fall time and presented at a fixed 500 ms onset-to-onset asynchrony. Electroencephalographic (EEG) acquisition was terminated when a minimum of 225 artifact-free deviant trials were collected, while the whole session took over ~30 min in duration.MMN and P3a were collected and processed following the standard protocols  from MMN/P3a if showing significant group differences, and clinical and neuropsychological measures. All tests were done as two-tailed tests with an α-level of p < 0.05. To control for the inflation of Type I error in computing multiple bivariate correlations, multiple linear regression models with the backward elimination procedure were conducted to determine the relationship between MMN (Cz) amplitude, treated as a dependent variable, and the clinical and neuropsychological measures, treated as independent variables. In order to investigate disease-specific patterns in adults with ADHD, which was hypothesized to be different from the patterns in adult controls, we conducted the above-mentioned multiple regression analyses stratified by the ADHD and control groups. To validate the results of the backward elimination procedure, we also performed forward and stepwise selection, as well as the least absolute shrinkage and selection operator (Lasso) for model selection to identify the variables which were consistently associated with MMN or P3a parameters in the ADHD group. Lasso is a regression analysis method that performs both variable selection and regularization in order to enhance the prediction accuracy and interpretability of the statistical model . To compare the variables between the ADHD and control groups Student's Demographics, ADHD symptom profiles, and MMN/P3a parameters are demonstrated in r = 0.212, p = 0.024) (online Supplementary Table S1). For MMN, comparing to matched controls, ADHD adults revealed the trend of less negative values in Cz, indicating a smaller MMN amplitude . For P3a, there was no significant group difference in any of the P3a indexes between the ADHD and control groups. Fig. 1c reflect MMN/P3a. Figure 2a and b demonstrate scalp topography with peaks of MMN and P3a revealed fronto-central maximum for the control and ADHD groups, respectively. The distribution of MMN (c) and P3a (d) amplitudes was visualized by rain cloud plots with boxplots.There was no sex effect on MMN and P3a parameters, while MMN amplitudes decreased with increasing age , attention performance (CCPT), and decision making (CGT), we found that compared to controls, ADHD adults demonstrated poorer real-world executive functions on all domains assessed by BRIEF , and pooR2 = 0.30) and risk adjustment and risk-taking on the CGT in the control group (R2 = 0.21). The results of the forward and stepwise selection generally supported the findings in backward elimination procedures (data not shown). We found that the results of backward selection in the ADHD group were also supported by the Lasso method with five-fold cross-validation, showing that MCI of BRIEF, and Hit RT ISIs of CCPT were predictive of Cz MMN amplitude in the ADHD group (online Supplementary Table S2). Using different selection methods, we found that inattention, MCI, variables of CGT and Hit RT ISIs of CCPT were generally consistently selected by at least two methods of model selection for MMN amplitude in ADHD, while risk-taking and risk adjustment were consistently selected in the model for the control group.To determine the relationship between MMN (Cz) amplitude and clinical/neurocognitive parameters, multiple linear regression models with the backward elimination procedure were conducted for the ADHD and control group . The reset al. With attention deficits and executive dysfunctions as the core features of ADHD across the lifespan  assessed young adolescents (12 to 17 years of age) using a four-tone auditory oddball task (with deviant stimuli on frequency/duration/combination) and found that P3a amplitudes in ADHD youths were not significantly different from those of healthy controls and first-episode psychosis patients. Our study, using a simpler auditory paradigm in ADHD adults, discovered that there was no significant difference between ADHD and controls in P3a.Similar to MMN, there was no previous research that focused on P3a in adults with ADHD either. Rydkjaer et al. et al. et al. Our finding that smaller MMN at Cz was correlated with inattention symptoms and executive dysfunction is of particular interest. Deficits in preattentive change detection measures by MMN were related to higher inattentive symptoms but not hyperactivity or impulsivity. To our knowledge, there was only one study with a smaller sample size focusing on the relationship between MMN and ADHD-symptom severity  implied that MMN at Cz differentiated ADHD adults from adult controls not only on the dimensions of attention but executive functions as well. MMN represents the preattentive process of auditory discrimination and is associated with the function of auditory memory and involuntary attention shifting  or vigilance (captured by the CCPT) on MMN amplitude within the ADHD population. Vigilance refers to the brain alertness for the objective stimuli, including the concentration of attention and the capability to respond to emergencies. Evidence has shown that the MMN amplitude reduces significantly when unattended vigilance on the modified Mackworth Clock Test is going down  in patients with ADHD reflects the underlying neuropathology of ADHD or the consequences of a compensatory neurodevelopment process cannot be determined in this cross-sectional study.This study provides the first data that the passive auditory paradigm (MMN) is highly associated with inattention symptoms, real-world executive dysfunctions , vigilance on the CCPT, and risk adjustment on gambling task in adults with ADHD compared to adult controls of comparable age, education level, employment status, and IQ. Our findings of decreased MMN amplitude as well as differential correlates for the preattentive process of novelty detection in ADHD adults from those in controls provide strong evidence to support the validity of adult ADHD based on the electrophysiological marker for adult ADHD (i.e. Cz amplitude of MMN). It is warranted to investigate other neurophysiological markers theoretically associated with ADHD neuropathology, and to collect longitudinal data to shed light on the developmental trajectories in ADHD.


P < 0.001), while a midline shift >5 mm was more frequently observed in the PEEK group than in the titanium group . The PEEK material was the only factor associated with subgaleal effusion after cranioplasty . Logistic regression analysis further showed that age was a protective factor against midline shift in the PEEK cranioplasty group . Patients who underwent cranioplasty with PEEK implants were more likely to develop severe subgaleal effusion and significant brain midline shifts than those with titanium mesh implants.Cranioplasty with polyetheretherketone (PEEK) has recently shown better cerebral protection performance, improved brain function, and aesthetic contour compared with titanium mesh. However, whether patients undergoing PEEK cranioplasty tend to develop subgaleal effusions remains elusive. This retrospective study included patients who underwent cranioplasty with PEEK implants or titanium mesh after decompressive craniectomy between July 2017 and July 2020. Patient information, including general information, location, size of the defect, subgaleal depth, and brain midline shift was collected and statistically analyzed. There were 130 cases of cranioplasty, including 35 with PEEK implants and 95 with a titanium mesh. Patients who underwent cranioplasty with a PEEK implant had a higher subgaleal effusion rate than those who underwent cranioplasty with titanium mesh (85.71% vs. 53.68%,  Cranioplasty is most commonly performed after a previous craniectomy for traumatic brain injury, stroke, intracranial tumour resection, or other aetiologies, which provides a combination of cerebral protection and aesthetic improvement. Autologous bone flaps and bone grafts are the most commonly used implant materials because of their biocompatibility. However, several pitfalls, including difficulties with long-term preservation , high inTitanium mesh is a widely used metallic implant in cranioplasty because of its non-corrosive properties and high overall strength . HoweverThe polyaromatic semicrystalline polymer, PEEK, is commonly used as an implant material in spine reconstruction –14 and hCranioplasty was associated with significant complications . During We performed a retrospective review of patients who underwent cranioplasty after decompressive craniectomy with complete clinical data between July 2017 and July 2020 at the Neurosurgery Department of Shanghai Tenth People's Hospital. General information, indication, location, size of the defect, maximum depth of subgaleal effusion, offset distance of midline, and other complications were extracted from the medical records. Written informed consent was obtained from all patients. Before surgery, a presurgical discussion with radiologists and anaesthesiologists was performed. Both PEEK and titanium cranioplasties were performed by three experienced neurosurgeons in our department. This study was approved by the Institutional Review Board of Shanghai Tenth People's Hospital (No. 051219019).P < 0.05.Statistical analyses were performed using Prism version 8.0  and SPSS Statistics 25 . Continuous data were presented as mean ± standard deviation (SD) and compared using the Student's t-test or Mann–Whitney U test, as appropriate. Frequency data were compared using Fisher's exact test or chi-square test, as appropriate. Binary logistic regression analysis was performed to determine associated factors. All tests were two-tailed. Statistical significance was set at 2 , while there were 85 (89.47%) unilateral and 10 (10.53%) bilateral skull defects in the titanium mesh group, with a bony defect measuring 83.55 ± 26.04 cm2 . The subgaleal effusion depth was 6.30 ± 3.72 mm in the PEEK group compared with that in the titanium mesh group , whereas only 53.68% (51/95) of patients in the titanium mesh group developed subgaleal effusion. The median drainage volume on the first day after cranioplasty was 165.00 ± 83.94 ml and 152.90 ± 65.87 ml in the PEEK and titanium groups, respectively , whereas effusion depth was not , than in the titanium group, with an incidence of 6.32% (6/95) (2 defect in the left frontal–parietal region (A 29-year-old man went into a progressive coma due to a traffic accident and underwent decompressive cranioplasty 3 months before admission to our hospital. Physical examination found a 90.22 cml region . A PEEK l region . In the l region , while nl region  and the Cranioplasty is associated with significant complications , and a cTitanium is relatively cost-saving, and reduced operation time and intra-operative haemorrhage have been observed during covered cranioplasty with a titanium mesh  since thTherefore, PEEK seems to be a more appropriate choice than other alloplastic materials for calvarial reconstruction because of the reduced infection and donor site morbidity, sufficient tensile property, and aesthetic contour seen in PEEK cranioplasty , 34–36. In accordance with this, our results showed that subgaleal effusion brain midline shift was more likely to develop in patients who underwent PEEK cranioplasty within the first week after surgery. Among several clinical factors, including sex, age, interval, defect size, and material type, PEEK was the only predictor of subgaleal effusion. Of note, individual surgical nuances such as the type of dural closure may affect the rate of subgaleal fluid collection . The durIn the case of subgaleal effusion, a timely subgaleal puncture could provide satisfactory management, and none of the patients underwent secondary surgery. It is suggested that vascularised tissue coverage of the implants during cranioplasty may be a safe and effective way to prevent subgaleal effusion by minimising the subgaleal dead-space , 41. AltOur study has several limitations. First, the present study focused on short-term complications during hospitalisation, and extended follow-up is needed to determine the correlation between subgaleal effusion and long-term outcomes, including mortality rates, cerebral blood flow, and cognitive function. The second limitation was the retrospective nature of this study. Future prospective studies on larger patient cohorts may provide more reliable evidence for this phenomenon. Third, our study is not sufficient to conclude the relationship between the properties of PEEK and the higher incidence of epidural effusion. Insights into the biomechanics of PEEK, surface design patterns, and communication between subgaleal and extradural/subdural spaces may further facilitate the choice of cranioplasty material . FinallyAlthough several studies have compared the outcomes of titanium and PEEK cranioplasty, subgaleal effusion has not been thoroughly investigated. The present study described a single-institution observation of subgaleal effusion as a short-term complication that was more frequently observed in patients who underwent PEEK cranioplasty than in those who underwent titanium cranioplasty. Routine postoperative CT is suggested within the first week after PEEK cranioplasty, and subgaleal puncture can be performed if needed. Future multicentre, randomised controlled trials focusing on subgaleal effusion after cranioplasty may provide more solid evidence.


Attention Deficit/Hyperactivity Disorder (ADHD) is a neurobiological condition characterized by developmentally inadequate levels of inattention, hyperactivity, and impulsivity, and a neurobiological disruption in brain neurotransmitters and circuitry causing abnormal responses to rewards. Playing electronic games generates a biological response that activates the neuronal circuits linked to pleasure and reward, and there is a growing attention to this type of activity, which can also turn into a mental health condition. The existence and the boundaries between the functional and the dysfunctional are still a source of debate, with the recognition of ‘Internet Gaming Disorder’ (IGD) as a condition belonging to the broader area of addiction requiring more in-depth study with respect to the DSM-5, while ‘Gaming Disorder’ (GD) was officially recognized as a new diagnosis by the World Health Organization (WHO) in the updated revision of the International Classification of Diseases (ICD-11). Notwithstanding, the suggested criteria for the diagnosis of Gaming Disorder are still debated. Since ADHD has been reported as a risk factor for developing addictions, this narrative review aims to provide the current state-of-the art of the knowledge about the comorbidity between ADHD and Gaming Disorder. For this aim, a literature search was conducted using a combination of specific keywords and the results are discussed within the R-Do-C framework and dimensions, and implications for treatment are considered. Attention Deficit/Hyperactivity Disorder (ADHD) is a neurobiological condition characterized by developmentally inadequate levels of inattention, hyperactivity, and impulsivity, causing interference with functions in several key domains in life. Epidemiological studies indicate a worldwide prevalence of ADHD in children and adolescents of 5–10% . There iWhen not adequately treated, ADHD can exert significant personal and socioeconomic burdens, determining a very deleterious impact on an individual’s functioning at home, school, in social contexts, and job settings, and causing high costs on society . Adoleschttps://icd.who.int/en (accessed on 3 July 2022)) [After the inclusion of Internet Gaming Disorder (IGD) in DSM-5  as a cony 2022)) . In the y 2022)) . Comparey 2022)) . The exiy 2022)) . TherefoDue to the widely recognized association between ADHD and substance and behavioral addictions , over thIn this paper, in view of the growing popularity that video-game-based treatments are receiving as a potential rehabilitation tool in ADHD ,18, we bADHD” OR “Attention Deficit Hyperactivity Disorder” AND “Gaming disorder” OR “Video-game addiction” OR “Videogame addiction” OR “Gaming addiction” OR “Internet gaming disorder” OR “Pathological video-game use” OR “VGA” OR “comorbid psychopathology”. Firstly, two authors (L.S. and L.B.) independently searched the databases and reviewed titles and abstracts. Thereafter, the two researchers screened full texts to define the eligibility of the study according to the inclusion criteria, i.e., original papers that investigated the ADHD–GD comorbidity with a sample population with an age ≤18. Exclusion criteria were papers not written in English, dissertations, book reviews, and studies that examined that comorbidity in only adults with ADHD. References cited in the selected articles were reviewed and included if considered relevant. The articles referenced for the purpose of this narrative review were published between 2012 and 2022. In case of disagreement during the process, consensus was attained by discussion. The process of eliminating non-relevant papers can be seen in the following flowchart  utilizing a combination of the following keywords and word variants: “hart see . Only 20 studies were found that explored the comorbidity between ADHD and GD and responded to the inclusion criteria. As visible in Children and adolescents with ADHD and GD have been described to be more dysfunctional video gamers, spending more time engaging in online chatting and gaming daily and during the weekends ,36. A diRegarding the ADHD–IGD/GD relationship, several authors reported ADHD as a risk factor for developing Internet Addiction Disorder (IAD) and IGD ,31,32, wRegarding the ADHD core symptom dimensions that were most associated with GD, some authors reported a key role of impulsivity ,38 and tChildren and adolescents with ADHD and IGD/GD were characterized by poor interpersonal relationships ,25, moreSubjects with both ADHD and GD appeared as a heterogeneous group, with some characterized by higher internalizing problems, such as anxiety/depression, withdrawal, and socialization problems at CBCL, and others by externalizing problems and aggressive and rule-breaking behaviors . Therefop < 0.001) and significantly higher odds of relapse within 1-year . Notably, the family environment scores had the greatest impact on GD symptomatology among the clinical covariates and better family conditions were negatively associated with GD symptoms over time. Participants who received psychiatric intervention during the past year had a significantly decreased severity of GD symptoms, leading the authors to state that the assessment and treatment of ADHD and interventions in a family context in children and adolescents with GD may be key factors for improving GD prognosis [The presence of comorbid ADHD in GD patients has been found to be associated with a poor clinical course of GD . Thereforognosis . The imprognosis , who reprognosis . Indeed,rognosis .A comparative meta-analysis of whole-brain voxel-based morphometry (VBM) studies found disorder-specific grey-matter volume (GMV) abnormalities in the putamen in patients with IGD and in the orbitofrontal cortex in those with ADHD, while both conditions shared a lower GMV in the prefrontal cortex . FunctioAnother study that investigated whether ADHD and IGD share a similar degree of brain functional connectivity (FC) between the frontal and subcortices  found thA quantitative electroencephalography (qEEG) study performed by Park and colleagues  found loThe main goal of this review was to examine the current state of the literature regarding the ADHD–GD comorbidity in order to inform clinicians about potential underpinnings that may explain their frequent co-occurrence and implications for treatment. Regarding the clinical features of such a co-occurrence, our review confirmed that multiple ADHD symptoms may be risk factors for problematic gaming, but not all studies confirmed the presence of a bidirectional relationship between the two conditions. As previously reported, males with ADHD show a high risk of developing pathological gaming behaviors ,39,40,41The importance of shedding light on the reasons for such a frequent comorbidity is due to the data indicating that having ADHD is associated with a more persistent course of IGD, decreased recovery rates, and higher rates of recurrence ,43, and Notwithstanding the negative consequences of gaming in youth with ADHD, there is increasing evidence supporting the notion that video games may enhance cognitive performance thanks to continuous feedback , therebyCurrently, it is not clear why some ADHD individuals are more susceptible to an excessive and pathological gaming behavior than those without ADHD, and whether there is a subgroup that could take advantage of video games for rehabilitation. We believe that in order to clarify this important issue, clinical assessments of the related disability, and not just quantitative assessments, as well as insights into their underlying neural disturbances could help.In this regard, in the ADHD–GD relationship, it is possible to hypothesize a disorder of connectivity in some areas of the brain that largely overlap, while others seem to have their own specificity. Research on common structural and functional aberrations in ADHD and GD found that both GD and ADHD are characterized by deficits in the reward circuitry, including the anterior cingulate cortex (ACC), the prefrontal and orbitofrontal cortex (PFC and OFC), the striatum , the amygdaloid nucleus, and the thalamus ,63,64. AUsing a Research Domain Criteria (R-Do-C) framework, ADHD deficits appear to fit the domains of cognitive systems, because of the impairment of attention , workingIt is also true that recent reviews have reported how video games and playing serious games can improve several areas that are impaired in ADHD, such as attention, executive functions, hyperactivity and impulsivity, emotional regulation, and motor and visual skills ,18,89, aHow can we use the collected information to understand the pros and cons of using video games in ADHD rehabilitation, considering the vulnerability of developing addictive behaviors with respect to video games and the positive association between ADHD symptoms severity and excessive gaming? Our review confirmed the existence of several factors implicated in the development of GD in ADHD. Children and adolescents with the disorder can use gaming for overcoming their impairment in social functioning and a sense of loneliness, and, therefore, as a coping modality to escape problems of daily life , negativIt is important to point out that the collected findings should be considered in light of several limitations. Although our data provide confirmation of the link between ADHD and GD, since this was a narrative review, we did not test the strength of such an association and did not assess the quality of the studies included or the data’s extraction. The same frequency of co-occurrence of these conditions may be rather variable depending on the different instruments and criteria used for the diagnosis. Indeed, the studies vary with respect to the tools that have been used, with some carried out before the definition of the criteria of GD/IGD in the DSM-5 and ICD-11, and others using measures of internet addiction developed through an adaptation of gambling disorder or more general addiction criteria. Therefore, not all these tools can be considered suitable for the diagnosis of GD, confirming the criticalities reported regarding the diagnostic criteria and the danger of overdiagnosis ,109,110.Collectively, our findings led us to state that although there is an increasing number of publications on the subject, there are several aspects that future research should address to better define the common and specific underpinnings of the ADHD+GD comorbidity that can inform treatments and promote prevention. A shared definition of gaming disorder and the development of reliable diagnostic tools with specific cut-offs are necessary to avoid the risk of its overdiagnosis and the failure to clearly identify the dysfunctional neural mechanisms underlying its frequent co-occurrence with ADHD, as well as the eventual recognition of new subtypes of the ADHD plus GD condition. Indeed, treatments will be necessarily different depending on the dysfunctions in the positive valence or negative valence systems  that will be found in the already heterogeneous ADHD population. Only with a clear identification of all the psychopathological dimensions involved and the underlying neural mechanisms will it be possible to enhance the translation of clinical research into practice, and develop the best treatment for a given individual, including the emerging non-invasive neuromodulation techniques, in line with a personalized approach.


KTN1) most significantly increased the gray matter volume (GMV) of the putamen and modestly regulated the risk for attention deficit hyperactivity disorder (ADHD). On the other hand, ADHD is known to be associated with a reduction in subcortical and cortical GMVs. Here, we examined the interrelationships of the GMVs, rs945270 alleles, and ADHD symptom scores in the same cohort of children. With data of rs945270 genotypes, GMVs of 118 brain regions, and ADHD symptom scores of 3372 boys and 3129 girls of the Adolescent Brain Cognition Development project, we employed linear regression analyses to examine the pairwise correlations adjusted for the third of the three traits and other relevant covariates, and examine their mediation effects. We found that the major allele C of rs945270 modestly increased risk for ADHD in males only when controlling for the confounding effects of the GMV of any one of the 118 cerebral regions (0.026 ≤ p ≤ 0.059: Top two: left and right putamen). This allele also significantly increased putamen GMV in males alone  and modestly increased other subcortical and cortical GMVs in both sexes (α < p < 0.05), whether or not adjusted for ADHD symptom scores. Both subcortical and cortical GMVs were significantly or suggestively reduced in ADHD when adjusted for rs945270 alleles, each more significantly in females  and males (3.5 × 10−6 ≤ p < α), respectively. Finally, the left and right putamen GMVs reduced 14.0% and 11.7% of the risk effects of allele C on ADHD, and allele C strengthened 4.5% (left) and 12.2% (right) of the protective effects of putamen GMVs on ADHD risk, respectively. We concluded that the rs945270-GMVs-ADHD relationships were sex-different. In males, the major allele C of rs945270 increased risk for ADHD, which was compromised by putamen GMVs; this allele also but only significantly increased putamen GMVs that then significantly protected against ADHD risk. In females, the top two GMVs significantly decreasing ADHD risk were left pallidum and putamen GMVs. Basal ganglia the left putamen in particular play the most critical role in the pathogenesis of ADHD.Previous genome-wide association studies (GWAS) reported that the allele C of rs945270 of the kinectin 1 gene ( The gray matter volumes (GMVs) of the basal ganglia (BG), including putamen , 2, pallKTN1) showed the most significant positive effect on putamen GMV (p = 1.1 × 10−33)   associations between rs945270 allele C and GMV were observed for the putamen  in males. Pallidum GMV and the major allele C were also correlated but slightly short of significance  in males. These four associations were only nominally significant (α < p < 0.05) but also ranked at the top four in females (Table α < p < 0.05) associated with the GMVs of 22 other regions (Supplementary Table α = 2.1 × 10−4), though all trending in the same direction (β > 0). Finally, the significance levels and directions of association did not change significantly if the ADHD T-scores were not adjusted for (Table The results of Model II showed that the only significant α = 2. × 10−4 aβ < 0) of cortical and subcortical GMVs in males and females.Both Models I and II showed that ADHD T-scores were significantly associated with reduction (α = 2.1 × 10−4) associated with reduction of GMVs of frontal , parietal , and left insular cortices , when adjusting for rs945270  and left rectus (p = 1.5 × 10−4) gyrus (Supplementary Table α ≤ p < 0.05) associated with reduction of GMVs of 80 other cortical and subcortical regions, including the BG  ] Table .Table 2Sα = 2.1 × 10−4) associated with reduction of BG GMVs , and eight cortical regions , when adjusting for rs945270 , but became much larger for BG (3.5 × 10−5 ≤ p ≤ 4.7 × 10−4), as compared to models with adjustment for rs945270 (Table α ≤ p < 0.05) associated with the reduction of GMVs of 85 other cortical and subcortical regions (Supplementary Table β > 0) of GMVs of the cerebellar vermis, section 3 (0.016 ≤ p ≤ 0.021)  . Step 2 showed that the only significant associations were between rs945270 allele C and putamen GMVs  in males  and putamen GMVs   in males (data not shown). Step 3 showed significant effects of putamen GMVs  on ADHD in males. No other significant mediation effects of rs945270 can be claimed either in males or females.In the analysis on the mediation effects of rs945270 on the ADHD-GMV associations, Step 1 showed that the association between ADHD T-scores and putamen GMVs was significant in males  data  and prevThe GMVs of many cortical and subcortical regions were significantly reduced in ADHD in both sexes. In males, the most significant ADHD-related GMV reduction was observed for the frontal (eight regions), left supramarginal, insular cortices, and left gyrus rectus, which were reduced only at suggestive significance in females. In females, the most significant ADHD-related GMV reduction was observed for the BG , and two parietal, one occipital, four temporal cortical, and one cerebellar, regions, which were only suggestively significant in males. Higher cortical GMVs significantly protected against ADHD risk in both sexes, in accord with previous findings , 7–14. Tα2) than total effect (α1) of allele C of rs945270 on ADHD risk , indicating an indirect, protective effect (α1−α2 < 0) of putamen GMVs underlying the association between ADHD and rs945270 in males. In support, the left and right putamen GMVs reduced 14.0% and 11.7% [=|α2−α1|/α2] of the risk effects of allele C on ADHD, respectively.To explore the potential mediation effects of putamen GMVs underlying the risk effects of rs945270 on ADHD, we performed a mediation analysis that showed a larger direct effect (α1) than the direct protective effect (α2) of putamen GMVs on ADHD , indicating an indirect protective effect (α1−α2 < 0) between putamen GMVs and ADHD as mediated through allele C of rs945270, in males. This indirect effect measured the amount of mediation, reflecting the protective effect of putamen GMVs on ADHD due to allele C. In support, allele C of rs945270 strengthened 4.5% (left) and 12.2% (right) [=(|α1 − α2|)/α1] of the protective effects of putamen GMVs on ADHD risk, respectively. This also suggests that a larger regulatory effect of allele C on putamen GMVs that protects against ADHD risk than its regulatory effect on ADHD that increases ADHD risk, resulting in an overall diminished risk, as observed previously [KTN1 alleles reliably increased risk for ADHD [Regarding the mediation of allele C of rs945270 of the protective effect of putamen GMVs on ADHD, the findings showed a larger and much more significant total protective effect (eviously , 22. In for ADHD  and allefor ADHD , comorbiIn summary, the primary regulation target of rs945270 was putamen GMV, which served as the main depressor of the risk effect of allele C of rs945270 on ADHD in males; and allele C was the primary enhancer for the protective effect of putamen GMVs on ADHD in males; putamen GMVs may play the most critical role in the pathogenesis of ADHD in both sexes.Supplementary Table S1Supplementary Table S2Supplementary Table S3


Previous research has suggested that children with attention‐deficit/hyperactivity disorder (ADHD) symptoms commonly show emotion dysregulation difficulties. These difficulties may partly explain the strong tendency for internalizing problems such as anxiety and depression to co‐occur with ADHD symptoms. However, no study has yet provided a longitudinal analysis of the within‐person links between ADHD symptoms, emotion dysregulation, and internalizing problems necessary to examine this hypothesis from a developmental perspective.n = 9,619, 4,885 males) and fit gender‐stratified autoregressive latent trajectory models with structured residuals (ALT‐SR) to disaggregate within‐ and between‐person relations between ADHD symptom, emotion dysregulation, and internalizing problem symptoms.We used data from the age 3, 5, and 7 waves of the large UK population‐representative Millennium Cohort Study (We found that emotion dysregulation significantly mediated the longitudinal within‐person association between ADHD symptoms and internalizing problems.Results underline the promise of targeting emotion dysregulation as a means of preventing internalizing problems co‐occurring with ADHD symptoms. Attention‐deficit/hyperactivity disorder (ADHD) is characterized by significant difficulties in the domains of attention and/or hyperactivity/impulsivity  are helpful for disaggregating within‐ and between‐person effects and are thus growing in popularity within developmental psychopathology   received full ethical approval from the National Health Service Multi‐Centre Research Ethics Committee at each wave , who participated up until wave 4.Millennium Cohort Study is a longitudinal study of a representative sample of children born into 19,244 families in the United Kingdom between 1 September 2000 and 31 August 2001 for England and Wales, and 24 November 2000 and 11 January 2002 for Scotland and Northern Ireland Plewis, . The iniEmotional Dysregulation subscale of Child Social Behaviour Questionnaire  to “Certainly true” (2). Respondents could also select a “Can’t say” option, which was treated as missing in the analyses. Sum scores were calculated after reverse scoring items where relevant (range 0–10). Paraphrases of item contents are provided in The psychometric properties the SDQ have been extensively examined  are also provided at this link. These were similar to those in the gender‐stratified models. Standardized parameter estimates for males and females are provided in Descriptive statistics are provided in Table b = 0.04, 95% CI = 0.03–0.06, p < .001) but the direct effect was not .Unstandardized parameter estimates are provided in Figure b = 0.04, 95% CI = 0.03–0.06, p < .001) but direct effect was not .Unstandardized parameter estimates are provided in Figure Internalizing problems often co‐occur with ADHD symptoms (Jarrett & Ollendick, Our results suggest that, consistent with a developmental cascades model (Masten & Cicchetti, There are a number of potential clinical implications of our findings. Our findings confirm the importance of emotion regulation issues in relation to ADHD, and can thus inform debates about the role of emotion dysregulation in diagnostic criteria for ADHD (Faraone et al., A primary limitation of the current study was that parents were the only informants, whereas a multi‐informant perspective would be important for capturing symptoms in different settings, and in interaction with different adults (Murray, Booth, Ribeaud, & Eisner, Finally, we used a community ascertained sample. While this has the advantage of providing a picture of how ADHD symptoms, emotion regulation, and internalizing problems are related in the general population, it would be valuable to extend this work into samples of children with a clinical diagnosis of ADHD. It is possible that these relations differ in clinical versus nonclinical populations.Emotion dysregulation mediates the association between ADHD symptoms and internalizing problems in childhood, suggesting that it is an important target for intervention for preventing important co‐occurring issues in ADHD.Appendix S1. Questionnaire items.Figure S1. Standardized autoregressive and cross‐lagged estimates from the ALT‐SR fit to the male subsample.Figure S2. Standardized autoregressive and cross‐lagged estimates from the ALT‐SR fit to the female subsample.Click here for additional data file.


DRD4,MAOA, and 5-HTTLPR genotypes on parent-reported ADHD symptoms at three time points  in 1730 adolescents from the TRacking Adolescents’ Individual Lives Survey (TRAILS). Growth Mixture Modeling in Mplus identified four ADHD symptom trajectories: low, moderate stable, high decreasing, and high persistent. Perceived parental rejection predicted class membership in the high persistent trajectory compared to the other classes . Gene-environment interactions were not significantly related to class membership. Our results indicate a role of perceived parental rejection in the persistence of ADHD symptoms. Perceived parental rejection should, therefore, be taken into consideration during prevention and treatment of ADHD in young adolescents.Despite a general decrease of attention-deficit/hyperactivity disorder (ADHD) symptoms during adolescence, these may persist in some individuals but not in others. Prior cross-sectional studies have shown that parenting style and their interaction with candidate genes are associated with ADHD symptoms. However, there is a lack of longitudinal research examining the independent and interactive effects of parenting and plasticity genes in predicting the course of attention-deficit/hyperactivity disorder (ADHD) symptoms across adolescence. Here, we investigated how children perceived their parents’ parenting style  at the age of 11, and their interaction with  Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset disorder with core symptoms of inattention and hyperactivity/impulsivity, which may persist into adulthood . ADHD syNegative parenting styles have been associated in cross-sectional studies with ADHD symptoms in childhood and adolescence; examples are maternal overprotection and control , parentadopamineD4receptor gene (DRD4) and parenting factors  in association with ADHD or externalizing symptoms, for better or for worse  genotype, i.e., negative parenting predicted inattention symptoms only among boys with high-activity MAOA , severity of ADHD symptoms at T1 , but had a higher socio-economic status , and were more likely to be of Dutch ancestry  when compared to those without complete genetic data. Subsequently, subjects were excluded if there was no information available at all on perceived parenting (n = 10) or ADHD symptoms (n = 21). The final sample consisted of 1730 adolescents of which 1364 adolescents  were from the population-based cohort and 366 adolescents  from the clinic-referred cohort.At T1, the total sample consisted of 2773 adolescents from the population-based . The overprotection scale comprised 12 items about fearfulness and anxiety for the child’s safety, and intrusiveness (Cronbach’s α = 0.90). The 18 items of the emotionalwarmth scale refer to giving special attention, praise, and unconditional love (Cronbach’s α = 0.94). We computed a single mean score as in previous studies, to increase comparability and to reduce the number of tests .At T1, adolescent’s current perception of parental rearing were assessed with the short version of the Egna Minnen Beträffande Uppfostran (My Memories of Upbringing) for Children (EMBU-C ). The 47ngs, see ; Cronbacs e.g., , 36). An. Anrejecn = 1443) or buccal swabs with a Cytobrush (n = 287) and was collected at T2 for the clinic-referred cohort and at T3 for the population-based cohort. Genotyping of the length polymorphisms DRD4,MAOA,HTTLPR, and SNP rs25331 (A/G SNP in LHTTLPR) was done at the Research lab for Multifactorial Diseases within the Human Genetics department of the Radboud University Nijmegen Medical Centre in Nijmegen, The Netherlands. Genotyping of the HTTLPR polymorphism in the promoter region of SLC6A4  gene was performed by simple sequence length analysis. Call rate was 91.6%. A custom-made TaqMan assay (Applied Biosystems) was utilized to genotype the single nucleotide substitution (A–G), which is present in the HTTLPR long (l) allele (rs25531). Call rate was 96.5%. Concordance between DNA replicates showed an accuracy of 100%. All lg alleles were recoded into S, because it has been shown that this polymorphism represents low serotonin expression comparable to the S allele . Model fit indices of perceived parental emotional warmth  and perceived parental overprotection  were not significant. Subsequent pairwise class comparisons  = 17.02, p = 0.001], whereas, again, parental emotional warmth  and overprotection  were not significant in the overall model. Pairwise comparisons between classes of ADHD symptom trajectories indicated higher odds of adolescents perceiving more parental rejection in the high persistent class , p = 0.001), the high decreasing class , p = 0.043), and in the moderate stable class  compared to the low class; and of those in the high persistent class compared to the moderate stable class . While, again, there was no difference between the moderate stable and high decreasing class regarding perceived parental rejection , the difference between the high decreasing and high persistent class was no longer significant .The main results were confirmed when using weighted variables taking the probability of class membership into account Table . Parentaχ2 (3) = 38.59, p < 0.001], and thus unaffected by the other two parenting factors, whereas perceived parental overprotection remained not significant . The model without perceived parental rejection and overprotection now showed a significant effect for emotional warmth . Adolescents in the high persistent class , high decreasing class , and moderate stable class  perceived less emotional warmth from their parents than those in the low class. Results thus suggest an opposite pattern for perceived emotional warmth, predicting membership in the low trajectory, compared to parental rejection which was related to a high persistent trajectory. Finally, sensitivity analyses using data without missing data imputation with Expectation Maximation did not show a notable change of results.Furthermore, the sensitivity analyses with a sole parenting predictor of ADHD symptom trajectories not adjusting for the other two parenting variables showed that perceived parental rejection was still significant , overprotection , and emotional warmth  in predicting class membership in ADHD symptom trajectories. Also, no significant interactions were found between the 5-HTTLPR genotype and perceived parental rejection , overprotection , and emotional warmth , nor between the MAOA genotype and perceived parental rejection , overprotection , and emotional warmth . Although variables of non-interest, the main effects of the DRD4,5-HTTLPR,andMAOA genotypes in differentiating between the ADHD symptom trajectories were also not significant in the multivariate analyses. In contrast to the univariate analysis  after correcting for sex, and in a post hoc analysis conducting analyses separately for boys and girls, which is important as the MAOA genotype is linked to the X chromosome.There were no significant interactions between the tion [χ2  = 2.70, MAOA variant with the high decreasing and high persistent classes is in line with previous studies pointing to a role of low-activity MAOA in externalizing behaviors [In the present study, we examined perceived parental rejection, overprotection, and emotional warmth, as well as their interaction with three plasticity genes as predictors of class membership in ADHD symptom trajectories across adolescence (age range 10–18 years) in a large pooled population and clinic-referred sample. We identified four different ADHD symptom trajectories across adolescence: low, moderate stable, high decreasing, and high persistent. While G × E’s with three different plasticity genes did not predict class membership in ADHD symptom trajectories, perceived parental rejection discriminated between the high persistent and the other three classes. More specifically, adolescents following the high persistent ADHD symptom trajectory perceived more parental rejection during early adolescence than adolescents in the other trajectories. In contrast, higher perceived parental emotional warmth was linked to the low ADHD symptom trajectory, suggesting a protective role, at least in a model without the other two parenting styles. Finally, the association of the low activity ehaviors .Our study points to developmentally distinct patterns of ADHD symptoms across adolescence, showing that a small group 10.6%) of youth from the general population and an additional high-risk sample is at risk of persistently high levels of ADHD symptoms. This percentage should be seen in light of our mixed sample, pointing to persistence of a high class of ADHD symptom levels in 4.3% of adolescents from the general population cohort and 33.9% of adolescents from the clinic-referred cohort, respectively. Therefore, the high persistent trajectory confers to the broader spectrum of ADHD symptoms and includes adolescents with clinical and subclinical levels of ADHD symptoms, as well as a small proportion with non-clinical symptom levels which were yet higher than those of others in the non-clinical range. Nevertheless, our findings are broadly in line with previous studies that also identified four ADHD symptom trajectories across childhood or adolescence, with 2.8–5% following a high persistent ADHD symptom trajectory in population-based samples  and 17.5% of youtAn important new contribution of this study to the existing literature is that perceived parental rejection in early adolescence is linked to risk of a trajectory of persistently high ADHD symptoms across adolescence. Our study thus points to a long-term predictive role of perceived parental rejection that exists beyond childhood, across early to a later stage of adolescence. Our finding is in line with Sasser and colleagues  who demoAlthough our study does not allow for making inferences about causality of parenting, as is inherent to observational studies, some literature does suggest causality between parenting and child behavior over time. For example, a twin study found that hostile parenting behavior of adoptive mothers prospectively predicted ADHD symptoms 1.5 years later in 6-year-old children . In revePerceived parental overprotection did not predict class membership in ADHD symptom trajectories, while emotional warmth was significant only when examined as a single parenting predictor in the model. Thus, negative parenting  seems more strongly related to ADHD symptom trajectories than positive parenting. Still, adolescents following the low trajectory of ADHD symptoms perceived more emotional warmth from their parents in early adolescence as compared to adolescents in the moderate stable, high decreasing, and high persistent trajectories who experienced lower emotional warmth. The association of parental emotional warmth in our study with a low ADHD symptom trajectory is in line with a study that showed that positive parenting was linked with good adolescent mental health over time . It has DRD4,MAOA, and 5-HTTLPR genotype on ADHD symptom trajectories across adolescence. The absence of an interaction with the DRD4 genotype was in contrast with Berry and colleagues [DRD4 7-repeat was associated with trajectories with low levels of inattention across childhood, whereas insensitive early maternal care in children with the DRD4 7-repeat polymorphism was associated with high levels of inattention. Unlike our study, Berry and colleagues [We did not find G × E interactions involving the lleagues  who founlleagues  examinedlleagues . This milleagues  showed slleagues , 28 werelleagues , a studyA strength of this study was the use of a large longitudinal dataset of adolescents, which consisted of a population sample enriched by data from a clinic-referred cohort. This enabled us to identify ADHD symptom trajectories in relation to parenting style covering the full continuum from non-clinical to clinical ADHD symptom levels across adolescence, an age range that is still underrepresented in the ADHD literature. While we focused on a measure that most closely mirrors ADHD criteria of the DSM, a potential limitation of the use of the DSM-oriented ADHD subscale is that it does not capture all 18 ADHD symptoms of the DSM; however, this subscale has been shown to have adequate diagnostic accuracy . MoreoveMoreover, despite the EMBU’s good psychometric properties , 62, theFinally, the literature has raised criticism about inconsistent G × E studies with likely false positive findings . HoweverOur study highlights that perceived parental rejection in early adolescence is a predictor of persistently high ADHD symptoms into later adolescence. In contrast, positive parenting may have a protective role associated with low symptom levels. To address causality, future studies are needed to clarify the specific directions through which effects between parenting and adolescents’ ADHD symptoms are operating, preferably investigating a broad set of parenting variables across multiple time points. Clinical interventions, particularly parent training programs for children with ADHD, are advised to focus on the prevention of parental rejection and improvement of parenting skills in mitigating ADHD symptoms which might have beneficial long-term effects.DRD4, MAOA, and 5-HTTLPR in interaction with parenting in the prediction of ADHD symptom trajectories. Future family-based studies that separate genetic and familial influences, as well as genetic studies utilizing polygenic risk scores or gene-sets, may be better suited to capture the contribution of genes and environment on the course of ADHD.We could not find support for a role of the individual plasticity genes


P. vulgaris germplasm in the Lazio region. Molecular analyses on 456 samples (four for each of the 114 accessions) revealed that the P. vulgaris germplasm in the Lazio region exhibited a high level of genetic diversity (He = 0.622) and that the Mesoamerican and Andean gene pools were clearly differentiated, with the Andean gene pool prevailing (77%) and 12% of landraces representing putative hybrids between the two gene pools. A model-based cluster analysis based on the molecular markers highlighted three main groups in agreement with the phaseolin patterns and growth habit of landraces. The combined utilisation of morphological, biochemical, and molecular data allowed for the differentiation of all landraces and the resolution of certain instances of homonymy and synonymy. Furthermore, although a high level of homozygosity was found across all landraces, 32 of the 66 examined (49%) exhibited genetic variability, indicating that the analysis based on a single or few plants per landrace, as usually carried out, may provide incomplete information.Common bean cultivation has historically been a typical component of rural economies in Italy, particularly in mountainous and hilly zones along the Apennine ridge of the central and southern regions, where the production is focused on local landraces cultivated by small-scale farmers using low-input production systems. Such landraces are at risk of genetic erosion because of the recent socioeconomic changes in rural communities. One hundred fourteen accessions belonging to 66 landraces still being grown in the Lazio region were characterized using a multidisciplinary approach. This approach included morphological (seed traits), biochemical (phaseolin and phytohemagglutinin patterns), and molecular (microsatellite loci) analyses to investigate their genetic variation, structure, and distinctiveness, which will be essential for the implementation of adequate ex situ and in situ conservation strategies. Another objective of this study was to determine the original gene pool (Andean and Mesoamerican) of the investigated landraces and to evaluate the cross-hybridization events between the two ancestral gene pools in the  Phaseolus vulgaris L., 2n = 2x = 22) is the most important legume for human nutrition worldwide since it is a valuable source of high-quality proteins, carbohydrates, vitamins, minerals, fibres, phytonutrients (mainly phytosterols and flavonoids), and antioxidants  and/or with historical traditions or religious connections , currently poorly investigated. A multidisciplinary approach to the common bean landrace collection of the Lazio region was used to (i) evaluate the inter- and intrapopulation diversity and genetic structure, (ii) investigate the genetic relationships between landraces to also identify possible homonymy and synonymy cases, (iii) identify the original gene pool (Andean and Mesoamerican) of the collection studied, and (iv) evaluate the possible cross-hybridization events between the two gene pools of origin in the P. vulgaris germplasm in the Lazio region.In the present study, a large Protection of autochthonous genetic resources of agricultural interest”. According to historical information, only seed lots grown on a single farm for many generations (at least 50 years) were collected and each lot was considered a single accession. Information about the farm, use, local names, geographical data , traditions, and social context were recorded for each seed lot included in the ARSIAL collection. One hundred fourteen accessions, grouped into 66 putative different landraces based on the local names attributed by the farmers, were collected in farms located in the five provinces into which the Lazio region is divided: 33 each from the province of Rieti (RI) and Frosinone (FR), 26 from the province of Viterbo (VT), 18 from the province of Rome (RM) and 4 from the province of Latina (LT)  in the entire Lazio region and conserved ex situ at the ARSIAL repository, within the framework of the Regional Law no. 15 dated 1 March 2000 “ina (LT) . The mapP. vulgaris [Seed traits were measured in a random sample of 20 seeds for each accession investigated according to the International Board for Plant Genetic Resources (IBPGR) , using tvulgaris . Among qvulgaris , a last The plant growth habit of the 114 accessions was determined directly in the field by visiting the farms where they are cultivated. The accessions were classified as determinate (type I growth habit) or indeterminate .w/v), whereas PHA was extracted using a 10 mM NaCl pH 2.4 solution (1/10 w/v) under the same conditions. Both the suspensions for PHAS and PHA were centrifuged for 30 min at 10,000× g and the supernatant was mixed with an equal volume of a buffer of 20 mM Tris-HCl pH 8.6 containing 1% SDS, 8.3% glycerol and 1% DDT. Fifteen microliters of the extracts of the two protein fractions were heat-treated at 100 °C for 5 min and then separated on 15% SDS-PAGE (Sodium Dodecyl Sulphate-Polyacrylamide Gel Electrophoresis) according to Bollini and Chrispeels [Four seeds of each accession were used to determine the PHAS and PHA protein patterns. After removing the coat, each seed was cut into two parts and the half without the embryo was finely ground in liquid nitrogen before PHAS and PHA extraction according to Limongelli et al. . In partrispeels . The gel® Plant II kit , according to the manufacturer’s instructions. Andean  and Mesoamerican (BAT and G12873) accessions were used as references for a total of 460  samples. Both 0.8 (w/v) agarose gel stained with ethidium bromide (0.001%) and a Nanodrop Bioanalyzer ND1000  were used to determine the integrity and concentration of DNA. Twelve SSRs were selected from previous genetic studies of Italian bean collections [Total DNA was extracted from the four seedlings for each accession obtained from the germination of the part of the seeds with the embryo used for PHAS and PHA investigation by the NucleoSpinlections ,41,42,43lections ,51,52. Plections , using pFor the 66 landraces, the frequency distribution for PHAS and PHA protein patterns and qualitative data relative to seed morphological traits and growth habits were evaluated using JMP PRO 15 . Seed weight data were converted into categorical classes of seed size based on a classification commonly used for beans ,30: (1) The mean and standard error of the four quantitative seed morphological traits  were calculated for each landrace. The coefficient of variation , expressed as a percentage, was used to analyse the variability of the four quantitative traits between and within landraces. All these statistical analyses were performed using JMP PRO 15.a), the effective number of alleles (Ne), the number of rare  and private alleles, expected (He) and observed heterozygosity (Ho), and the inbreeding coefficient (F), by using GenAlEx6 [The screening power of SSR loci was evaluated by investigating the PIC index  using PoGenAlEx6  and PoweGenAlEx6 . AllelicGenAlEx6 . The anaGenAlEx6 . The varFst) [Phylogenetic analysis was performed to estimate the overall relationship among genotypes, accessions, and landraces. The distance-based dendrogram with Nei’s genetic distance  and the Fst)  was alsoFst)  and visuThe Mantel test  was usedK, to prevent an overestimation of subgroup number by STRUCTURE. Samples with membership probabilities ≥ 0.80 were assigned to the corresponding subgroup. The likelihood-ratio chi-square test was used to test for dependence between PHAS type/growth habit and cluster membership of the landraces, and the strength of association was determined by calculating Cramér’s V [Bayesian clustering of the collection studied was performed using STRUCTURE software , as descamér’s V .a and AR in FSTAT [e, He, and Ho in GenAlEx6 [e and Ho among groups, Kruskal–Wallis  and Wilcoxon  nonparametric tests were performed using JMP PRO 15. AMOVA was carried out to partition the genetic variation between and within groups of landraces, as described above.Based on the results of model-based cluster analyses of SSR loci and PHAS type, the genetic diversity of common bean landraces was evaluated by classifying the landraces into two and three groups. The individuals of the accessions that were found to be of “mixed origin” and those that did not show correspondence between PHAS type and cluster membership in STRUCTURE were excluded from further analysis. The genetic diversity of each group of landraces was determined by calculating Nin FSTAT  as well GenAlEx6  and PoweGenAlEx6 . To deteA total of nine seed morphological traits, five qualitative and four quantitative, were used to evaluate 114 accessions belonging to 66 putative different landraces collected from different geographical areas of the Lazio region . The relThe accessions assigned to the same landrace based on the local name and the available information showed mainly the same “seed morphotype”, except for the accessions named “Regina”, and three accessions called by the farmers “Suricchio” in which two distinct morphotypes were described . In detaHigh diversity across the collection was found through the four quantitative seed traits used . AccordiRegarding the plant growth habit of the 66 common bean landraces, 41 exhibited an indeterminate growth habit and 25 a determinate one .The SDS-PAGE showed three different electrophoretic patterns for the PHAS protein fraction , allowinIn contrast, a higher variability for the PHA protein fraction was observed, with 11 different patterns distributed across the 66 landraces investigated B. The paIn contrast to the PHAS, a considerable level of heterogeneity for the PHA protein fraction was detected among the accessions of the same landrace. In particular, eight out of the 66 landraces (12%) showed two or three distinct PHA patterns , one of p < 0.0001; Cramér’s V = 0.94). The landraces with the C and T types showed mainly the PHA patterns of the TG2 groups (patterns 1 to 6), whereas the landraces belonging to the Pinto UI 111, VG2, and SG2 groups were characterized by the S type . Plants with indeterminate growth habits were exclusively present in landraces with the S type. Moreover, plants with indeterminate growth habits were prevalent in the landraces showing the C type, whereas plants with determinate growth habits were prevalent in those containing the T type , seed shape , and seed weight .Finally, seed morphological traits were distributed differently among the three PHAS types , with a e) (mean 0.622) and considerable discrimination power, with a PIC value > 0.5 for eight SSR used (67%). The mean observed heterozygosity (Ho) was 0.014 and the inbreeding coefficient (F) ranged from 0.951 to 1 due to the absence of heterozygotes in five out of the twelve loci used (The main genetic parameters for each SSR are reported in oci used .o = 0.000) and 34 of them were genetically uniform (He = 0.000)  . Overall= 0.000) . Thirty = 0.000) .Although most of the SSR markers variability was attributable to differences among landraces (89%), AMOVA analysis showed that a considerable fraction of genetic variation (11%) had also occurred within them . Except Phylogenetic analysis on both the accessions and genotype levels was performed to estimate the inter- and intravariability among landraces included in the germplasm investigated. Overall, all samples belonging to the same landrace were grouped in the same main branches , suggestPhylogenetic analysis grouped the landraces into two well-supported clusters  corresponding to Mesoamerican and Andean origins of landraces , and in Considering the large number of landraces investigated, only one putative case of synonymy was found, related to two accessions from the Viterbo province named “Occhietto” and “Giallostoppa” . These aOn the other hand, cases of homonymy were also detected for some couples or groups of landraces. The largest group is represented by the landraces called “Regina”, which in total are nine: four from the province of Roma, three from the province of Rieti, and two from the province of Latina. These nine landraces, despite having the same name or a name that includes the term “Regina”, showed different SSR profiles . Two othFst values  were grouped in two distinct branches , whereas the landraces characterized by PHAS T- (red) and PHAS C type (blue) were split into other different branches. Interestingly, as also reported in the UPGMA tree, one main branch (“a”) was nearly accounted for (88%) by samples with the PHAS C type. In contrast, cluster “b” gathered mainly landraces (71%) showing the PHAS T type.A high and significant degree of genetic differentiation was found among the 66 landraces by using t values . Six mai2 = 0.0006; r = 0.025 p > 0.05).A nonsignificant correlation between geographic and genetic distance matrices was observed for the 114 accessions assigned to the 66 putative different landraces when the Mantel test was applied  as well as genetic cluster membership and PHAS pattern . A total of 15 accessions belonging to 13 different landraces showed an admixture profile , the Andean group of landraces showed higher values of AR, He, and Ho than the Mesoamerican group, but the differences were not statistically significant following the Kruskal–Wallis test  revealed that the Andean group “A1” had the highest AR value, whereas the Andean group “A2” and the Mesoamerican group M showed the highest He and Ho values, respectively. However, the differences among groups were not significant . These findings were consistent with those of other Italian regions, such as Basilicata , AbruzzoP. vulgaris is a self-pollinating species with little cross-pollination, which could justify the rare occurrence of alternative PHAS and PHA pattern combinations.In agreement with previous findings ,69, our Interestingly, the landraces “Arsolana”, “S. Anna”, and “Bianco Rieti”, characterized by the S PHAS type, showed the PHA-deficient pattern of Pinto UI 111, strongly correlated with the absence of agglutinating activity . To the P. vulgaris germplasm from Sardinia [The evaluation of molecular diversity using 12 SSR markers allowed us to detect in our collection a total of 75 alleles with a mean of 6.3 alleles per locus, a higher value than those discovered in the Sardinia  and CalaSardinia , and notSardinia ,40,41,44Sardinia ,40,41,42Sardinia ,29,30, hThe occurrence of 30 rare alleles, 14 of which were private, found approximately in 62% of landraces, highlighted the high differentiation of the common bean collection here investigated. A major priority in the ARSIAL seed bank will be given to the landraces possessing rare and private alleles, whose presence is an important feature for collection because it has been shown to be informative for genetic conservation .Thirty-two out of the 66 landraces analysed (49%) displayed genetic variability, showing significant diversity both between the different accessions of the same landrace and within a single accession. The detected intragenetic variability recorded from one to six different loci for the landrace  highlighted the presence of several distinct genotypes for each landrace. These results indicated that, despite autogamy and the intralandrace uniformity in seed shape and colour, most of the landraces examined in this study could be considered mixtures of genetically distinct pure lines. Therefore, the sampling of one or few individuals per landrace would not be enough to describe their whole genetic background. However, the UPGMA trees, considering both the 456 distinct genotypes or the 114 accessions, and the STRUCTURE analysis showed that all the genotypes or accessions belonging to the same landrace were grouped within a similar genetic pool, underlining that the genetic background within landraces could reflect their variability. All of these findings imply that strategies to encourage on-farm conservation of common bean landraces within the area of cultivation would be important to preserve genetic variability. Negri and Tiranti  demonstrThe detected genetic profiles allowed all of the landraces belonging to our collection to be distinguished, with the only exception of two accessions from the Viterbo province, called “Occhietto” and “Giallostoppa”, which likely represent a case of synonymy. Surprisingly, this distinction was unrelated to the geographical separation among landrace cultivation locations, as no significant correlation between the geographic distances and the genetic differentiation among landraces was found. This lack of correlation may be the consequence of an extensive gene flow resulting from traditional seed exchange practices, such as trading between farmers’ families and neighbours or at local markets. These activities resulted in the preservation of the common bean genetic diversity in the Lazio region, as evidenced by the presence of all three detected clusters in the STRUCTURE analysis in each of the five provinces of the region, and by the AMOVA analysis in the classification of the landraces into two and three groups, which showed that 50% of SSRs diversity could be attributed to differences within groups. Furthermore, no significant correlation between genetic and geographical distances was found in domesticated accessions of American bean germplasm, which could be explained by seed-based gene flow following domestication . Seed-baFst analyses of the 66 landraces from the Lazio region reflect the two independent domestication events that occurred, separating into specific branches, the common bean cultivated forms into Mesoamerican and Andean genotypes. Indeed, the optimum number of groups in our structure analysis was K = 2, with 15% of landraces of Mesoamerican origin  and 77% of Andean origin (with a C or T PHAS pattern), whereas 8% of landraces represent putative hybrids between gene pools. Our results are consistent with the findings of previous studies in that the Italian, and, more broadly, European common bean germplasm originates from both Mesoamerican and Andean gene pools, with the latter being more frequently found [Overall, the phylogenetic, population structure, and ly found ,37,82. Ily found ,84,85. Sly found . In Chinly found ; howeverly found . In Soutly found . Numerouly found .K = 2 is attributable to the considerable genetic differentiation between these two gene pools, which could conceal other possible substructures in our collection. Indeed, at K = 3, the genotypes belonging to the Andean group showed two subpopulations, with a split based on the PHAS pattern and growth habit. Other Italian collections also showed the presence of heterogeneity in common beans of Andean origin. For instance, a study using 12 SSR polymorphic loci classified 146 Italian common bean landraces into three groups: one consisted primarily of Mesoamerican accessions with S-type PHAS, while the others did not show a clear distribution pattern for Andean samples with T and C PHAS types. The authors attributed these profiles to the adaptation to different environmental conditions [The well-supported separation between Mesoamerican and Andean groups at nditions . Anothernditions .A sequence of consecutive bottlenecks during common bean domestication, initial introduction to Portugal and Spain, and subsequent expansion across the Italian peninsula could explain the nearly full consistency of classifications based on PHAS analysis and model-based grouping using SSRs, as well as the strong association between group membership and growth habit in the germplasm from the Lazio region. The Mesoamerican group of landraces together with the Andean group “A1” were largely made up of accessions with indeterminate growth habits, whereas the Andean group “A2” included most landraces with determinate growth habits. Similarly, a strong association between PHAS pattern and growth habit was already reported by Raggi et al.  and CaroThe comparable level of genetic diversity recorded in the present study for landraces of Andean and Mesoamerican origin was previously reported in Iberian and Croatian landraces ,87 and, Structure analysis highlighted a low proportion of hybridization (12%) between Mesoamerican and Andean gene pools in the Lazio landraces analysed. This “admixture” level was similar to that observed in a large common bean collection from Italy  but signThis study gives the first thorough overview of the genetic diversity, structure, and distinctiveness of common bean landraces from the Lazio region. The high genetic diversity discovered and analysed in the common bean collection highlights its potential economic value for identifying adaptive characters to environmental stresses and low-input conditions, which are highly prevalent in marginal areas where bean cultivation in Italy, including the Lazio region, is currently confined. Regardless of a low estimated rate of outcrossing and admixture, common beans from the Lazio region retain an appreciable level of intra-landrace diversity, a factor that must be carefully addressed when planning in situ/on-farm conservation strategies. Moreover, morphological and molecular analyses enabled us to identify some redundancies that are relevant for defining an ex situ core collection. Furthermore, the morphological, biochemical, and molecular data obtained in this study can assist the landrace protection schemes that are currently being developed in Italy and could facilitate the registration of the landraces still cultivated in the Lazio region in the National Catalogue of “conservation varieties” that enables their seeds to be commercialized. Both of these activities can aid the future survival of these landraces in situ. Finally, the genetic and morphological characterization of examined common bean landraces could be relevant for their utilization in breeding activities to face climatic changes as well as to meet the need for novel cultivars for marginal lands and/or organic agriculture.