There was no indication that either form of NF was superior to WMT. No severe adverse events were reported during the trial, whereas transient stress-related problems were quite frequent. Overall, the results from this pragmatic trial do not provide convincing support for broad implementation of NF in child and adolescent psychiatric services. Future research should try to clarify for whom and under what circumstances NF might be a viable treatment option.Neurofeedback (NF) as a treatment for Attention Deficit Hyperactivity Disorder (ADHD) has been evaluated in several trials, but the specificity and generalizability of effects remain unclear. This four-arm randomized controlled trial evaluated the efficacy of Slow Cortical Potential  and Live Z-score  delivered in high-frequency format (five sessions per week during five weeks), compared to Working-memory training  and Treatment-as-usual . N = 202 children/adolescents aged 9 to 17 years with ADHD participated. The primary outcome measure was multi-report  ADHD core symptoms on the Conners-3, assessed at baseline, posttreatment, and 6-months follow-up. Data were analyzed using a linear mixed model. Between-group differences were scarce and did not show a distinct pattern. Superiority of LZS over TAU at endpoint were observed for teacher-rated measures only, while significant differences between SCP and TAU were restricted to posttreatment measurements. Contrary to our expectations, LZS outperformed SCP at endpoint for teacher-rated hyperactivity (-5.37; 95% CI: -10.14 to -0.60; p = .028; The online version contains supplementary material available at 10.1007/s10802-021-00858-1. Attention Deficit and Hyperactivity Disorder (ADHD) is a heritable and disabling neurodevelopmental condition, defined by age-inappropriate patterns of inattention, hyperactivity and impulsivity Thapar, , and witMethylphenidate in children and adolescents, and amphetamines in adults, are the preferred first-choice medications for the short-term treatment of ADHD  is a non-invasive neurocognitive training method, which aims to improve cortical functioning by training the brain’s electrical activity through operant conditioning principles; thereby, enhancing the brain’s ability for self-regulation, i.e. the flexibility to adapt brain activity to more effectively meet the changing demands of the environment -interventions that mimic the active NF set-up  are mostly well understood and implemented in NF Kamiya, , the optFurthermore, it is important to evaluate the ecological validity in trials reflecting the clinical reality of child and adolescent psychiatry. This encompasses ineluctable factors such as common comorbidities (e.g. learning disabilities and ASD), end-user friendly equipment and software, and staff who are trained, but not necessarily experts.The effect of a high-intensity standard NF protocol (SCP) on ADHD core symptoms is superior to common passive  and active (WMT) comparators in a clinical setting.The effect of a high-intensity non-standard NF protocol (LZS) on ADHD core symptoms is superior to both passive (TAU) and active (WMT) comparators in a clinical setting.The effect of SCP-NF on ADHD core symptoms is superior to LZS.The objective of the present study was to address the above-mentioned research gaps by providing data from a clinical setting. In order to make optimal use of the collected data, the study was designed as a multi-arm randomized controlled trial , a single site, four-arm, randomized controlled pragmatic trial of neurocognitive training interventions in child and adolescent ADHD, conducted at a child and adolescent psychiatric outpatient clinical research unit in Stockholm, Sweden  as their primary diagnosis within the Swedish public healthcare system . The final five participants were randomized simultaneously, in order to avoid predictability.The interventions were led by 19 trainers . However, the number of sessions completed by each trainer varied considerably. All trainers underwent in-house training for all three interventions. Initially, trainers practiced the different interventions on staff members at the clinic and attended sessions lead by experienced trainers. Their initial sessions were supervised by experienced trainers before being permitted to conduct sessions independently. To further ensure consistency, a step-by-step guide for each intervention was developed, and all trainers communicated frequently with each other.SCP. Slow Cortical Potentials are Event Related Potentials that are either electrically negative or positive and last from several hundred msec. to several seconds , using Ag/AgCl electrodes. Impedance was kept under 5 k Ohm. During the task, participants had to steer an object up or down by intentionally creating negative or positive slow cortical potentials. Each trial lasted 10 s.: a 2 s.-baseline calculation and an 8 s. feedback phase. A reward was displayed when the SCP amplitude exceeded ± 40 µV, respectively for 2 s. during the last 4 s. of the trial. The number of so-called transfer trials, where no direct feedback was given except for the potential reward at the end, increased during first three weeks . Each SCP session consisted of 144 trials split into four blocks , and lasted around 60 min. Self-regulation success is reported , with AgCl snap connectors. We implemented a 2-channel LZS using the ANI database . The sessions consisted of two blocks with 20 min continuous feedback. Electrode placements were at C3 and C4 for the first block, and Fz and Cz during the second block. Impedance was kept under 5 k Ohm. During the first 5 to 10 min. of each session, feedback was given using BrainCells™ (BrainMaster Ltd.), where the participant has to collect ‘brain cells in a jar’. Thereafter, participants could choose visual stimuli from Netflix™ or Youtube™ on the screen to operationalize the NF. A transparent dimmer window  was placed on top of the stimuli, which turned dark when the participant’s brain activity deviated too much from the target amplitudes. The targeted Z-score corridor was kept between at ± 1.5 SD, and the threshold was adjusted manually to enable a reward rate of 60–70%. No specific instructions on strategies were provided, and sessions lasted around 60 min.WMT. For WMT, a computerized software program with visuospatial and auditory tasks called Minneslek Flex™ (www.flexprogram.org) was used. It is a training tool that is widely used across Sweden in school settings . Parents were instructed to remind the participant.Primary. The ADHD-index and the inattention and hyperactivity/impulsivity subscales of the Swedish full lengths version of the Conners Rating Scales 3rd edition   covering 47 discomforting problems on 4-point Likert scales, from “no problem” to “highly-problematic/intolerable” , and why they believed so . It was not feasible to keep the parents blinded, as parents were closely involved and had received thorough information during the application process.In accordance with the intention-to-treat principles, primary and secondary analyses included all randomized participants for whom data were available at baseline. The number of participants per arm was set in advance at 50, providing a power (1-beta) of > 0.99 for a large effect and 0.80 for a medium effect at alpha = 5% and an expected attrition rate of 10% (G*Power 3.1.7). The originally planned MANOVA was replaced by linear mixed-effects modeling (random regression), which currently is the preferred choice for analysis of repeated-measures data  = 6.748, p = 0.009). The use of medication was somewhat lower for SCP, but there was only a statistically significant difference between SCP and TAU  = 4.608, p = 0.032). See Table The mean age ranged between 12.21 and 12.61 years across the groups, and the male to female ratio was about 3:1. There were no meaningful group differences in IQ, sex, age, nor ADHD severity. Mean scores for parent-ratings were markedly higher  than for teacher-ratings (62–67) and self-ratings (67–72). ASD was somewhat more prevalent (but not significantly different) in the TAU group. The ratio of ADHD sub-types (predominantly hyperactive or combined/ predominantly inattentive) was 3:2 in the NF groups, 4:1 in WMT and almost 1:1 in TAU, but there was only a statistically significant difference between WMT and TAU (d = 0.34) and the parent raters . The parent-rated ADHD-index differed significantly at post , but no significant difference remained at follow-up. On the secondary measure, BRIEF, both parent and teacher ratings on the metacognition scale showed a significant difference between SCP and TAU at post , as well as at follow-up . Sensitivity analysis of the baseline imbalance in medication use did not change the general pattern of results. No significant differences against WMT were found, with the exception of the teacher rating of the ADHD-index at follow-up suggesting that SCP was less effective than WMT . No significant group differences were found for any of the self-rated measures , hyperactivity/impulsivity , metacognition , and ADHD-index both at posttreatment  and at follow-up . On parent ratings, a significant difference was found at posttreatment for the ADHD-index  and for metacognition , but did not remain at follow-up. No significant differences were found when comparing LZS to WMT. Overall, no significant group differences were found for any of the self-rating measures  and ADHD-index . See Online resource Table There were no significant differences between SCP and LZS on any primary or secondary measures posttreatment. At follow-up, LZS was superior to SCP on teacher ratings for hyperactivity/impulsivity . Metacognition also differed significantly from TAU for the parent rating , but only at posttreatment  and LZS . WMT showed significant effect compared to TAU at follow-up .d = 0.29–0.65), while LZS showed significant differences for nine of the 14 measures (d = 0.26–0.57), and WMT showed significant results for 10 measures (d = 0.20–0.53). The highest effect sizes were observed for teacher-rated ADHD-index , metacognition , and parent metacognition in SCP (d = 0.65). In TAU, self-rated hyperactivity/impulsivity (d = 0.20) and parent-rated inattention (d = 0.22) improved significantly. No changes on HRQoL were noted. Mean scores for complete cases can be found in Online Resource Table We found significant within-group differences over time for all interventions (Online Resource Table d = 0.69) and behavior regulation  at posttreatment  were aware of their students’ participation in a research study. However, they were less accurate at correctly pin-pointing the specific intervention the student received (21–66% across intervention arms), even though many had been informed by the students or their caregivers (45–74% across intervention arms). See Online Resource Table No serious or long-lasting adverse events were reported. Nonetheless, a broad array of side effects were reported during the intervention period, with small differences between the groups. Most side effects concerned sleep and tiredness , increase in excitability and agitation , cognition , mood , and headaches  and a non-standard protocol (LZS) delivered at high-frequency (five sessions/week) in a child and adolescent psychiatric setting. The protocols were compared head-to-head, and against both an active and a passive control condition. Overall, between-groups differences were scarce and did not show a distinct pattern. Furthermore, we did not find any clear indications that treatment effects were moderated by age. Contrary to our expectations, LZS was superior to SCP on a few measures . While both forms of NF seemed to have some beneficial effects compared to TAU, none of the protocols outperformed WMT on any of the outcome measures.While all groups receiving an active intervention saw improvements in ADHD core-symptoms over time, meaningful differences between the interventions were few and far between. This aligns well with the lack of clear differences between SCP and active-/semi-active control conditions observed in previous studies , the sheer number of reported events indicates that the training period can be stressful and may temporarily have some negative effects. The most frequently reported events concerned the subjects’ energy levels, impacting their sleep and calmness negatively. Many subjects receiving SCP frequently struggled to stay awake towards the end of the training session. However, the excessive tiredness did not remain once the session was over. These issues still deserve more attention, and more instruments that can capture specific events relevant to NCTs, as these may have an impact on both adherence and outcome.The modest between-groups effects, and especially the failure to demonstrate superiority compared to WMT, cast doubt on the suitability of NF as a broadly implemented ADHD intervention in a clinical setting. This conclusion is in line with what we currently know about the effectiveness of other non-pharmacological interventions for children and adolescents with ADHD. A recent update on evidence-based treatments classifies several behavioral interventions as well-established treatments, while NF is classified as possibly efficacious and cognitive training as experimental  participants in SCP were classified as learners. Also, many participants showed relatively high differentiation values, which may indicate artifact corruption. Fourth, while the sample size was relatively large for an RCT of non-pharmacological treatment for ADHD, it was still quite modest when considering the heterogeneity of the target population. Consequently, undetected relevant differences between the interventions cannot be ruled out. Conversely, the significant differences observed between groups should be interpreted with caution due to the large number of comparisons. Fifth, the use of the default ± 40 µV reward threshold in SCP may have made successful trials too difficult, and hindered optimal learning of self-regulation. Moreover, this may have incited participants to implement physiological strategies, and generate regulation via muscular artefacts Below is the link to the electronic supplementary material.


Children with ADHD showed poorer motor performance and less participation in ADL . These findings contribute to understand the functional consequences of ADHD in motor-based ADL and its relationship with DCD.Children with Attention Deficit and Hyperactivity Disorder (ADHD) often present with Developmental Coordination Disorder (DCD) or motor coordination problems that further impact their daily functioning. However, little is known about the prevalence of co-occurring DCD and ADHD in the Spanish context, and research about the impact of ADHD on performance and participation in motor-based activities of daily living (ADL) is scarce. The aims of this study were to explore the prevalence of co-occurring DCD in children with ADHD, and to examine differences in performance and participation in motor-based ADL between children with ADHD and typically developing children. We conducted a case-control study including 20 children with ADHD and 40 typically developing controls randomly matched for exact age and sex  years). Presence of probable DCD (p-DCD) was confirmed with the Developmental Coordination Disorder Questionnaire (DCDQ). The DCDDaily-Q was administered to assess performance and participation in ADL. A 75% prevalence of p-DCD was found in the ADHD group (OR = 27;  Neurodevelopmental disorders are present in 4–18% of children, and these disorders significantly affect the child’s daily functioning ,3,4. SomADHD is characterized by three core symptom domains  , but thiAs previously mentioned, there are several neurodevelopmental disorders that affect the child’s performance and participation, and some of them usually present with ADHD. For instance, DCD is a motor neurodevelopmental condition with the highest co-occurrence with ADHD ,15,16,17Co-occurring deficits in motor performance of children with ADHD may have further consequences on their well-being and participation, as these children also encounter significant difficulties in performance and participation in those ADL that require attention or inhibitory control skills . PreviouAs described by the Occupational Therapy Practice Framework and the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY), satisfactory participation in meaningful daily activities is a major component of health and well-being ,27. PrevIt is important to study the impact of ADHD on children’s motor daily functioning, and to identify potential limitations in motor performance and participation restrictions. In Spain, research interest in ADHD has increased during the last two decades, but studies regarding its association with DCD are scarce . BecauseTherefore, the aims of this study are: (a) to explore the prevalence of co-occurring DCD in Spanish children with a clinical diagnosis of ADHD in comparison to typically developing peers; and (b) to examine differences in performance and participation in motor-based activities of daily living between children with a clinical diagnosis of ADHD and typically developing children in the Spanish context.We conducted a case-control study with a total sample of sixty children. This sample size was estimated in order to explore expected differences in prevalence of DCD between children with and without ADHD using a 1:2 case-control ratio with minimum bias  > 0.90) . ChildreThe final sample was formed by twenty children with a medical diagnosis of ADHD  years), and forty children without any known developmental or learning disorders (TD group) randomly matched for exact age and sex. Detailed sociodemographic information of the sample is shown in Children in the ADHD group were recruited from two private rehabilitation centers in Spain. Children in this group had a previous DSM-IV or DSM-5-based ADHD diagnosis given by a clinical practitioner , and they did not have co-occurring diagnosed disorders.Children in the control group attended seven randomly selected elementary schools in three Spanish regions and were excluded beforehand if their parents reported a medically diagnosed neurodevelopmental or learning condition . ChildreEthical approval for this study was granted by the Autonomic Research Ethics Committee of Galicia, Spain (code 2018-606).The European Spanish version of the DCDQ ,30 was uChildren who scored at or below age-specific 15th percentile in DCDQ total score (criterion B of the DSM-5 DCD diagnosis) were identified as having probable DCD (p-DCD) ,31. Critr = 0.406–0.638) [The European Spanish version of the DCDDaily-Q ,33 was u6–0.638) ,33,34.t-tests. In addition, the effect size of these differences was examined with Cohen’s d [Statistical analyses were performed using IBM SPSS version 25 . A 1:2 case-control ratio was used to improve statistical power . Differeohen’s d .Prevalence of p-DCD was statistically higher in the ADHD group in comparison to control group . Co-occud > 0.8), and the strongest difference between groups was found for participation total score .Children with ADHD scored significantly higher in all subscales and total score of the DCDDaily-Q, indicating a poorer daily performance and less level of participation in self-care, fine motor, gross motor and general ADL than children without ADHD . All difA descriptive analysis of the results of the DCDDaily-Q between ADHD children with and without p-DCD can be found in Co-occurrence between DCD and ADHD is highly common, but the impact of deficits in motor coordination skills on performance and participation in motor-based daily activities needs to be further explored, particularly in the Spanish context. Therefore, this study aimed to examine co-occurring DCD and differences in performance and participation between children with and without ADHD. In our sample, prevalence of p-DCD in the control group was 10%, which is consistent with previous research in epidemiological studies in Spain ,9,10. CoA recent study involving Spanish high school students found an overlap between ADHD and risk of DCD of approximately 60% . To the Links and similarities between ADHD and DCD are well documented in scientific literature. There is substantial evidence that children with ADHD show poorer motor skills than their typically developing peers, affecting not only gross motor but also fine motor skills . ChildreApart from the high co-occurrence of ADHD and p-DCD, children in the ADHD group showed significant poorer performance and participation in motor-based self-care, fine motor, gross motor, and general ADL. This particular outcome contributes to the understanding of the impact of ADHD on motor-based performance and it makes a counterpart to the findings from previous research on motor competence in Spanish individuals with ADHD . OverallThese findings need to be interpreted cautiously given the limited sample size of this study. As most of the children in the ADHD group showed p-DCD as well, it cannot be concluded if the reported problems in motor performance and participation are better explained by the ADHD or the by the co-occurrent p-DCD. The descriptive analyses between children with ADHD and co-occurrent p-DCD and children with ADHD alone showed a persistent poorer performance and lower participation in the first group across all ADL, except for the gross motor play activities. If confirmed by future research, this finding could suggest that children with co-occurring ADHD and p-DCD have a higher risk of poor daily performance and participation due to motor coordination difficulties, which is in line with previous studies reporting worse outcomes in children with co-occurring ADHD and DCD ,7,14. MoThe main limitation of this study is that we could only established presence of p-DCD and a formal diagnosis of DCD was not possible, as we only assessed two of the four DSM-5 diagnostic criteria of DCD ,32. HoweFindings from this study can be used in research and clinical practice. Future studies should explore the longitudinal display and outcomes of performance and participation in motor-based ADL in children with ADHD and co-occurring ADHD and DCD. In addition, future research can study the relationship between DCD, motor performance and participation, and the different ADHD domains . Regarding clinical implications, occupational therapists and other social and health practitioners can use our findings to systematically assess children with ADHD for risk of DCD or motor coordination problems, and to design tailored intervention approaches aimed to address the potential consequences of motor coordination deficits in daily performance and participation.The present study provides relevant and novel information regarding the co-occurrence of ADHD and DCD in the Spanish context, as well as the impact of ADHD on performance and participation in motor-based daily living activities. These findings contribute to highlight the need to assess motor skills in children with ADHD. Given the complex nature of ADHD symptoms and its co-occurrence with other developmental disorders, these children should be referred to multidisciplinary teams that include occupational therapists, psychologists, and educational practitioners to address the inattention, impulsivity-hyperactivity, and coordination symptoms and functional outcomes of this disorder, moreover, if ADHD is present with DCD as well.


Approximately a third of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) experience significant irritability; despite this, no study has reviewed whether interventions for youth with ADHD can improve irritability. This mini review sought to address this gap in the literature by discussing existing pharmacological and psychosocial interventions for irritability among children and adolescents with ADHD. A literature search was conducted in April 2021, with a total of 12 intervention articles identified . Studies were excluded if they did not involve an intervention, a measure of irritability, or the population was not youth with ADHD. Of these articles, two were with an ADHD only sample; seven included ADHD with comorbid disruptive behavior, disruptive mood dysregulation disorder (DMDD), or severe mood dysregulation (SMD); and three included ADHD with comorbid autism spectrum disorder (ASD). Findings suggest that central nervous system stimulants used alone or in combination with behavior therapy are effective at reducing irritability in youth with ADHD only or comorbid ADHD and DMDD/SMD. Less evidence was found for the efficacy of guanfacine and atomoxetine for youth with ADHD only or comorbid ADHD and ASD. Parent training alone or in combination with atomoxetine was found to be effective at reducing irritability in youth with comorbid ADHD and ASD. Future research assessing the efficacy of other psychosocial interventions, particularly cognitive behavioral therapy is necessary, as are randomized trials assessing intervention sequencing and intensity among youth with ADHD. Researchers are advised to utilize well-validated measures of irritability in future research. Despitebe added . Supportbe added . Additiobe added –5. DespiAlthough no review has discussed the efficacy of interventions targeting irritability in youth with ADHD specifically, insight can be gathered from recent reviews of psychosocial and pharmacological interventions targeting irritability for youth broadly , 7. KircA search was conducted by the first author (RB) in April 2021. All articles were reviewed by the first and second author (RB and NC). We excluded studies that: (a) were in foreign language, (b) included only adults, (c) did not involve an intervention, (d) did not involve irritability as an efficacy outcome , and (e) the population did not have a primary diagnosis of ADHD or meeting ADHD diagnostic criteria was not an inclusion criteria. A total of 12 published manuscripts were identified see . Next, wSix articles were identified that utilized pharmacological interventions. Two utilized CNS stimulants , 19, oneMage = 12 years) using a 4-week, open-label trial. Results indicated a significant improvement in self-reported ratings of irritability . Similarly, Baweja et al. (Mage = 9 years) with comorbid ADHD and DMDD during a 6-week open trial of CNS stimulant . Results indicated a significant decrease in parent-reported irritability . In the third article with an ADHD and DMDD/SMD population, Pan et al. (Mage = 10 years). The combination of aripiprazole and MPH resulted in significant improvements in parent-reported irritability . Finally, Towbin et al. (Mage = 11 years). Although participants were required to display SMD to be included in this study, this study was retained as all participants received a 5-week open trial of MPH to address ADHD symptoms, and 89.8% of participants had an ADHD diagnosis. For their primary outcome of the Clinical Global Impression's for Chronic Severe Irritability, a significant decrease in irritability was found (d = 0.60), with the estimated response differing between the citalopram (35%) and placebo (6%) groups   .Mage = 9 years) during a 6-week, randomized controlled crossover trial where participants were assigned to either atomoxetine or a placebo condition. Despite Aberrant Behavior Checklist—Irritability (ABC-I) symptoms decreasing in the atomoxetine condition (d = 0.32), this decrease was not significantly greater than the placebo condition (d = 0.61), p = 0.12. Second, Scahill et al. (Mage = 8 years) with ASD and ADHD symptoms using an 8-week randomized clinical trial comparing guanfacine to a placebo. Results showed that extended-release guanfacine resulted in a decrease in ABC-I (d = 3.87); however, this decrease was not significantly greater than the placebo condition (d = 1.13), p = 0.20.In the first study with an ADHD and comorbid ASD population, Arnold et al.  examinedl et al.  exploredMage = 9 years). Findings showed that the integrative group therapy was associated with a significantly greater improvement in parent-rated irritability than stimulant community care only . In addition to this non-pharmacological intervention study, five combined intervention studies were identified.The only non-pharmacological intervention included in this mini review provided an optimized dose of stimulant medications to both conditions prior to the 11-week randomized clinical trial . Specifipost-hoc analysis to compare the response to treatment in youth with ADHD with and without elevated levels of SMD. The study also examined the change in mood symptoms in the subset of 33 participants (Mage = 8 years) with SMD. The ADHD and SMD group experienced significant improvements in irritability/aggression . In a similar study, Gadow et al. (Mage = 8 years) and co-occurring ODD/conduct disorder. Results suggest that adding risperidone resulted in a significant decrease in parent-reported anger/irritability , but not teacher-reported anger/irritability .In an ADHD treatment study designed to assess the impact of different intensities of pharmacological and psychosocial treatments, Waxmonsky et al.  conductew et al.  assessedMage = 8 years) who were assigned to one of four conditions in a 14-month randomized controlled trial: CNS stimulant management, behavioral management, combined CNS stimulant and behavioral management, or a community care control. Although irritability decreased over time across all conditions, the improvement was significantly greater in the CNS stimulant (d = 0.63) and combined (d = 0.82) groups relative to the behavioral management (d = 0.42) and community comparison (d = 0.48) groups. In contrast, Handen et al. (Mage = 8 years) with comorbid ADHD and ASD using a 10-week randomized controlled trial. Results indicated that despite the atomoxetine and parent training group (d = 0.68) and atomoxetine (d = 0.64) group displaying moderate parent-reported improvements in irritability, only the parent training condition (d = 0.96) resulted in a significantly greater decrease in irritability than placebo (d = 0.51). No significant differences were found across groups for teacher-reported irritability. In a 24-week extension to Handen et al., (Mage = 8 years). Despite large improvements from baseline to week 22 among families who received parent training (d = 0.94), this improvement was only marginally larger than the group that did not receive parent training (d = 0.62), p = 0.08. Additionally, families in the atomoxetine and parent training condition showed a significant decrease in irritability from baseline to week 20 , whereas there was not significant improvement in the atomoxetine only group.Three studies compared the relative efficacy of standalone and combined interventions. First, de la Cruz et al.  sought tn et al.  compared et al.,  and SmitInconsistent findings regarding the efficacy of existing interventions for improving irritability among youth with ADHD were present across included studies. Some of the differences appear to differ based on comorbid conditions (ASD vs. DMDD/SMD), and types of pharmacological interventions used (CNS stimulants vs. non-stimulants). Specifically, across the four pharmacological interventions with youth with comorbid ADHD and DMDD/SMD , 18, 19,A somewhat different pattern of efficacy for other approved ADHD medications (atomoxetine or guanfacine) was found for youth; however it is important to note these medications, unlike the CNS stimulants, were examined in youth with comorbid ADHD and ASD. Specifically, the two pharmacological and one combined intervention studies failed to find evidence of either atomoxetine or guanfacine being effective at significantly reducing irritability relative to a placebo , 17, 23;The literature targeting irritability among youth with ADHD is limited by a large reliance on small sample sizes and open trials. In the current mini review, only four studies had a sample of more than 100, with only one of these having a sample larger than 200 see . FurtherOf the seven studies utilizing a randomized trial, two compared a pharmacological intervention (atomoxetine and guanfacine) to a placebo , 17, oneFurther, given the evidence of CNS stimulants alone or in combination with parent training for reducing irritability, it will be critical for future research to utilize cutting-edge research methodologies to assess intensity and sequencing of these interventions to improve outcomes and reduce costs. For example, Sequential Multiple Assignment Randomized Trial  designs Existing studies are also limited by inconsistencies in measurement of irritability which until recently was primarily measured only as side effect of ADHD medications, using largely unstructured spontaneous report. Specifically, only six of the included studies utilized an established scale for irritability, with four using the ABC-I subscale , 23, 24,Interestingly, only one of the psychosocial or combined interventions examined psychosocial interventions other than parent training, with this study utilizing an integrative group therapy that involved behavioral parent training along with CBT and social cognitive training. There is evidence from reviews of psychosocial interventions that CBT is effective for reducing irritability in youth across diagnoses that CBT is effective for these purposes . CBT hasThis mini review addresses an important gap in the literature by discussing the existing pharmacological and psychosocial interventions targeting irritability among youth with ADHD. Findings suggest that CNS stimulants used alone or in combination with behavioral therapy  are effective at reducing irritability in youth with ADHD only or comorbid ADHD and DMDD/SMD. Less evidence was found for the efficacy of alpha agonists and atomoxetine, with existing studies focusing on youth with comorbid ASD. One study found evidence for benefits of adding a selective serotonin reuptake inhibitor  to MPH for reducing irritability in youth with ADHD and DMDD/SMD. Parent training alone or in combination with atomoxetine was found to be effective at reducing irritability in youth with comorbid ADHD and ASD. Future research assessing the efficacy of other psychosocial interventions, particularly CBT is necessary, as are randomized trials with large samples using well-validated scales designed to measure irritability that assess intervention sequencing and intensity among youth with ADHD.RBr conducted the review of the literature and took lead on drafting this manuscript. ND reviewed all included articles and assisted with writing the manuscript. CS, JW, and RBa assisted with writing and revising the manuscript. All authors contributed to the article and approved the submitted version.The authors would like to thank the Virginia Tech Open Access Subvention Fund for covering the processing charges of this article.In the past three years, JW has received research funding from Supernus and served as a consultant for Adlon Therapeutics and Intracellular Therapies. The remaining 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.


Attention-deficit/hyperactivity disorder, the most prevalent developmental disorder in childhood, is a biologically heterogenous condition characterized by impaired attention and impulse control as well as motoric hyperactivity and anomalous motor skill development. Neuropsychological testing often demonstrates impairments in motivation and reward-related decision making in attention-deficit/hyperactivity disorder, believed to indicate dysfunction of the dopamine reward pathway. Development of reliable, non-invasive, easily obtained and quantitative biomarkers correlating with the presence and severity of clinical symptoms and impaired domains of function could aid in identifying meaningful attention-deficit/hyperactivity disorder subgroups and targeting appropriate treatments. To this end, 55  8–12-year-old children with attention-deficit/hyperactivity disorder and 50  age-matched, typically-developing controls were enrolled in a transcranial magnetic stimulation protocol—used previously to quantify cortical disinhibition in both attention-deficit/hyperactivity disorder and Parkinson’s Disease—with a child-friendly reward motivation task. The primary outcomes were reward task-induced changes in short interval cortical inhibition and up-modulation of motor evoked potential amplitudes, evaluated using mixed model, repeated measure regression. Our results show that both reward cues and reward receipt reduce short-interval cortical inhibition, and that baseline differences by diagnosis (less inhibition in attention-deficit/hyperactivity disorder) were no longer present when reward was cued or received. Similarly, both reward cues and reward receipt up-modulated motor evoked potential amplitudes, but, differentiating the two groups, this Task-Related-Up-Modulation was decreased in children with attention-deficit/hyperactivity disorder. Furthermore, more severe hyperactive/impulsive symptoms correlated significantly with less up-modulation with success in obtaining reward. These results suggest that in children with attention-deficit/hyperactivity disorder, short interval cortical inhibition may reflect baseline deficiencies as well as processes that normalize performance under rewarded conditions. Task-Related-Up-Modulation may reflect general hypo-responsiveness in attention-deficit/hyperactivity disorder to both reward cue and, especially in more hyperactive/impulsive children, to successful reward receipt. These findings support transcranial magnetic stimulation evoked cortical inhibition and task-induced excitability as biomarkers of clinically relevant domains of dysfunction in childhood attention-deficit/hyperactivity disorder. In this study of reward effects in motor cortex in children with attention-deficit/hyperactivity disorder (ADHD) compared to their typically developing peers, Detrick et al. report that transcranial magnetic stimulation-evoked short-interval cortical inhibition and task-related up-modulation significantly differed between groups and may therefore represent measurable biomarkers in ADHD.  Altered responses to reward cues and outcomes may contribute to long-term risk-taking behaviour and addiction in ADHD.The overlapping and integrated neural circuitry governing inhibitory and reward processesFinally, the present paediatric ADHD study builds on studies in adults using TMS during reward paradigms.This study compares M1 physiology and reaction times (RTs) during a reward task in 105 children, ages 8–12 years: 55 ADHD; 50 Typically Developing (TD) controls. Analyses were performed both with ADHD as a categorical diagnosis and with parent-rated ADHD symptoms as a dimension of behaviour.All participants were recruited concurrently from two urban medical centers via advertisements, from 2011 to 2017. Written informed consent was obtained from the legal guardians of study participants. The study was approved by the Johns Hopkins Medicine and Cincinnati Children’s Hospital Medical Center Institutional Review Boards.,,For ADHD evaluation, the ADHD Rating Scale IV (ADHD-RS-IV)® transcranial magnetic stimulators (TMS)  connected through a Bistim® module to a round 90 mm coil, as well as identical amplifiers, filter settings, disposable surface electrodes, and Cambridge Electronic Design 1401 and Signal® 6 software for monitoring responses in real time and automated off-line extraction of peak-to-peak MEP amplitudes for analysis. We recorded EMG (electromyelography) from the relaxed first dorsal interosseous. All EMG tracings were observed in signal in real time and participants were reminded to maintain a fully relaxed hand. Trials with visible artefact were tagged and removed offline. The TMS coil was placed flat near the vertex, with coil-current direction counterclockwise to optimally evoke MEPs. All protocols implemented by our laboratories in hyperkinetic children have been previously described,Study personnel trained together for consistency. Both sites used Magstim 200®  while comfortably seated with ulnar aspects of both upper limbs on a body-surrounding pillow. The dominant right hand index finger operated a computer mouse. The program presented a ‘money bag’ with a background colour that cues the child about whether a reward may be achievable  or not . Participants were instructed through a standardized script that their job is to ‘catch’ the coin or chip before it disappeared into the bag to earn it at the end of the game. To do this, they must respond to the coin/chip as quickly as possible by pressing the mouse button. Participants were also informed that it is more difficult to ‘win’ the 25-cent coin in red-background trials because the coin disappears more quickly than in green trials. Trials were administered in pseudo-randomized order. Successes were tracked with cumulative earnings displayed on the game screen. No money was added or subtracted for a failure-to-catch or any grey-background trials.TMS was administered during the Money Bags Task see  in childIn two-thirds of red-cue trials and one-third of green-cue trials, the coin disappeared in 150 ms, ensuring failure but giving participants the impression that they were not quite fast enough to succeed. Conversely, in two-thirds of green-cue and one-third of red-cue trials, the coin remained on the screen until they push the button, for up to 1250 ms, ensuring success while giving the perception the reward was due to their effort/fast response time. Grey-cues were evenly divided between fast and slow disappearance. The red-cue thus should have elicited highest motivation. Reaction results supporting the theory of this paradigmnot to move/respond when the coin or chip appeared, unless the cue was framed in yellow , the purpose of which was to verify ongoing attention only.Red, Green and Grey-Cue Trials occurred at a 1:1:1 ratio. For the first 35 participants, the game included only TMS during the Cue-phase: 96 trials (32 of each cue type). As children tolerated this procedure without requiring breaks, for the remaining 70 participants the number of trials was increased from 96 to 186 and pulse timing was randomized to occur during the cue or receipt phases see . Finallyt-tests and Chi Square as appropriate. For ‘method of means’ analyses, SICI and ICF are expressed as ratios of average paired to average single pulse-evoked, MEP amplitudes.Motor, physiological, behavioural and demographic data were compared across diagnostic groups using ® version 9.4 , using repeated measures mixed models with subject as a random effect. For SICI and TRUM (M1 physiology), MEP amplitude is the dependent variable; for behaviour, RT is the dependent variable. ADHD diagnosis was evaluated primarily as a categorical variable and secondarily as a dimensional variable based on Conners-scale parent-ratings T-scores. Age, Sex and Site were included in all models. A P value less than 0.05 was considered significant.All models were analysed using SASIncreased MEP amplitudes may result from increased excitatory, reduced inhibitory (disinhibition), or some combination of inputs into M1. Faster RTs may result from greater motivation for a reward, related to perceived difficulty. We aimed to determine whether SICI, TRUM and RTs were associated with diagnosis, symptom severity, cue type , or reward receipt , or their interactions.RT is the ‘behavioural output’ of this task.post hoc these hypotheses were evaluated within the full task and within the sections of the task.After evaluation of the standard model residuals showed heteroscedasticity, MEP amplitudes were log transformed. The dependent variable was ln(MEP amplitude). In these models, SICI was estimated from the ratio of the Least Squares Means estimates for PulseType . The models evaluated: (i) the relationship between SICI and Cue and Receipt—hypotheses: both higher reward probability (green cue) and reward receipt (success), would be associated with increased SICI; (ii) SICI differences across diagnostic groups—hypotheses: the effects of Cue and Receipt on SICI would be diminished in ADHD; and (iii) the relationship between SICI and ADHD symptom severity—hypotheses: the effects of Cue and Receipt on SICI would be more diminished with more severe ADHD. These hypotheses were evaluated using all trials, both reward task and rest, then TRUM was estimated based on ratios of the Least Square Means estimates for Task . A higher ratio above 1.0 indicates more TRUM. The models evaluated: (i) the relationship between TRUM and Cue and Receipt—hypotheses: higher reward probability (green cue), and reward receipt (success), would be associated with increased TRUM; (ii) TRUM differences across diagnostic groups—hypotheses: the effects of Cue and Receipt on TRUM would be diminished in ADHD; and (iii) the relationship between TRUM and ADHD symptom severity—hypotheses: the effects of Cue and Receipt on TRUM would be more diminished with more severe ADHD.Additional exploratory analyses were performed by including in the models baseline physiological measures .The data supporting the findings of this study are available, anonymized for any reasonable request.Demographic, clinical and physiological variables were compared by group see . The recF = 10.0, P = 0.02]  = 7.97, P = 0.0055; Conners Hyperactive/Impulsive F = 15.3, P = 0.0001]. RT variability was not significantly different between groups .Across cue types, RTs averaged 32–34 ms slower in ADHD versus TD children [.02] see . RTs werF = 269.3, P < 0.0001]  = 0.15, P = 0.86]. As expected, older children had faster responses , approximately 3% faster  per each one year older.As shown previously in healthy adults performing this task,001] see . The CueF = 23.51, P < 0.0001]. Baseline (rest) physiological measures were not associated with RTs (not shown). See Larger MEP amplitudes were associated with faster RTs . SICI was significantly reduced (higher ratio) during the reward task compared to rest . Stratifying by phases of the task, SICI reduction compared to rest was significant for both reward cue  and reward receipt .The All-Participants, initial model , top useF = 9.16, P = 0.0025] and during the reward task compared to rest . This reward-task-change in SICI was significantly less in ADHD . However, the smaller rest→ task difference occurs because the SICI ratios differed at baseline (P < 0.0001) but converged during reward  = 3.77, P = 0.05]  = 0.17, P = 0.68]. Findings for children with higher hyperactive–impulsive scores were similar for both success  and failure . Analysing trials with TMS pulses during reward-cue phase, we found no evidence of relationships between SICI and ADHD severity ratings.To determine whether there were greater reductions in SICI among children with more severe symptoms, the regression models for reward-cue and reward-receipt trials were re-run, replacing the categorical diagnoses with the ADHD Conners Scores. Analysing trials with TMS pulses during reward-receipt, SICI marginally achieved significance among children with higher inattentive scores after successful reward-receipt outcomes  and Grey/Neutral . Within Cue phase, higher hyperactive–impulsive scores were significantly correlated with less SICI in TD children during only Red trials , but were not associated with SICI in ADHD children in any cue. Within the Receipt phase, no associations were significant for SICI and inattentive nor hyperactive–impulsive scores.Regression models were re-run separately with only TD and with only ADHD participants. During the task Cue phase, within the TD cohort, inattentive scores showed varying degrees of association with SICI. Higher inattentiveness was associated with less SICI during Green . Stratifying by phases of the task, TRUM was significantly increased from rest in both receipt phase  . Reduced TRUM in ADHD occurred in both the receipt phase  and the cue phase . Separating trial types—both reward receipt success/failure, and reward cue red/green/neutral types—produced similar results  = 62.00, P < 0.0001] and failure outcomes . Findings for children with higher hyperactive/impulsive scores were similar for both successful trials   = 48.93, P < 0.0001). These differences in TRUM related to symptom severity were not significantly affected by cue type (not shown).To determine whether the reduction in TRUM was greater among children with more severe symptoms, the regression models were re-run with the ADHD Conners Scores. Analyzing trials with TMS pulses during reward-receipt, TRUM was more reduced among children with higher inattentive scores after both successful trial outcomes [001] see  and failF = 4.03; P = 0.05]. More reduced TRUM was significantly correlated with higher hyperactive/impulsive scores for TD children for all Cues: Red , Green , and Grey/Neutral . No within-diagnoses associations of TRUM and inattentive or hyperactive–impulsive scores were found for children with ADHD during the Cue phase.Regression models were re-run, stratified by diagnosis. For cue phase, more reduced TRUM was marginally associated with higher inattentive scores among TD children during Red trials  and failure outcomes . No significant associations were present for inattentive scores within the ADHD cohort. Within the TD cohort, higher hyperactive–impulsive scores were highly significantly associated with more reduced TRUM in both success . Within the ADHD cohort, higher hyperactive–impulsive scores were significantly correlated with more reduced TRUM after successful outcomes only .Stratifying receipt phase data by diagnosis, within the TD cohort, in children with higher inattentive scores, TRUM was marginally associated in success  and reduced SICI . Further detailed analyses based on diagnosis and symptom severity, and comparisons of non-movement trials to movement trials, were not performed due to the small number of non-movement trials per participant.To explore if this reward task induced TRUM and reduced SICI in the absence of a requirement for movement to catch the coin, the additional block of non-motion trials was analysed in the same statistical manner used for the main task. That is, MEP amplitudes were the dependent variable and factors of interest were (i) effects of task  and (ii) effects of PulseType . Even without a requirement to move, this reward task induced TRUM [Task ,,The main, novel findings of this study of ADHD in childhood are that (i) reward task participation, in both the cue phase and the receipt phase, significantly affects both Transcranial Magnetic Stimulation (TMS)-evoked short interval cortical inhibition (SICI) and Task-Related-Up-Modulation (TRUM); (ii) effects of reward on SICI and TRUM differ in children with ADHD versus typically-developing (TD) controls; and (iii) associations of reward-induced M1 changes with symptom ratings are most robust for reduced TRUM during reward receipt, among children with greater hyperactive/impulsive symptoms. In this study, we employed paired pulse TMS to probe modulation of motor cortex (M1) physiology in 105 comprehensively-evaluated 8 to 12-year-old children. We replicated prior studies showing reduced SICI in ADHD in resting M1.,Both SICI and TRUM were affected by participation in this reward task in ways that are unlikely to be explainable simply because the task involved movement. It has been shown previously that during a time-window of 100–150 msec prior to movement, SICI is reduced and MEP amplitudes are up-modulated.The premise that our Expectancy Theory of Motivation,As reported in multiple published studies,Consistent with our findings evaluating M1 physiology during a Slater-Hammel stop signal, response inhibition task,Notably, among children who participated in both of these studies, preliminary analysis suggests task correlations (both TRUM and SICI) are weak, and therefore TRUM and SICI across both tasks could create distinct clinical subtypes.Findings in our study are broadly consistent with prior TMS studies in healthy adults showing that M1 physiology reflects neural circuits active during reward-cueing. For example, one study found that the presence and greater salience of reward increases TMS-evoked MEP amplitudes in healthy adults.Findings in our study also broadly support studies in adults showing that SICI reflects mechanisms related to reward. For example, a study of SICI in healthy adults using a slot-machine reward paradigm showed that during the anticipation/cue phase SICI was reduced (ratios approached 1.0). However, we did not replicate their finding that SICI changes varied based on reward probability.Comparing results of this study to similar studies of reward responsivity using other modalities supports the idea of cerebral hypo-responsiveness in ADHD. For example, fMRI studies have reported subcortical As with all studies of behavioural diagnoses, there may be misclassification of subjects due to the lack of objective criteria. ADHD has substantial heterogeneity. One study has suggested that ADHD children may have non-overlapping deficits in separate networks of cognitive control, reward processing, and temporal control (timing), indicating that the diagnosis of ADHD could potentially be further subclassified,Another limitation in comparing across studies is variable requirements for action. We did query whether movement was required for this task to influence M1 physiology and our findings suggest it may not be. However, interpretation requires caution because there were fewer non-move trials and the non-move block was always performed after the movement blocks, possibly resulting in a priming effect whereby the participants might have imagined moving. A more valid comparison would involve randomization with counterbalancing the order of move versus non-move versions, or simply a parallel design, randomization of ADHD and TD participants to a movement version versus a non-movement version.We utilized structured diagnostic interviews and standardized rating scales for all participants at study visits, with diagnostic thresholds for ADHD confirmed with clinical impression. We attempted to systematically address problems with categorical diagnosis by also using rating scale severity, however these scales too are subjective and may obscure important behavioural or neurobiological variability. This study controlled for psychoactive medications at the time of study visit with sufficient two-day washout time, which is important for eliminating confounding effects of stimulants on SICIThe Money Bags Reward task was designed such that participants would perceive their actions as necessary for success or failure given the colour cue.Here, we report, for the first time, that children with ADHD show reduced TMS-evoked TRUM of motor cortex under the influence of reward and that this reduction specifically after reward success is more significant among children with higher hyperactive/impulsive symptoms. These findings are in keeping with those from prior studies using TMS and overall reveal a pattern of children with ADHD showing reduced inhibitory (SICI) and modulatory (TRUM) physiology in primary motor cortex. By designing TMS-compatible paradigms evaluating several relevant domains of function, differences in SICI and TRUM may provide opportunities to develop biomarkers useful for identifying ADHD subtypes. These subtypes might predict differential responses to behavioural or pharmacological therapies.This research was funded by National Institutes of Health R01 MH095014 and R01 MH085328. J.A.D. received funding from the American Academy of Neurology 2019 Medical Student Research Scholarship. E.M.W. receives funding from the National Institute of Neurological Disorders and Stroke Intramural Research Program.S.W. reports receives salary support for consulting for Medtronic, Inc. E.P. receives research support from National Institutes of Health, Autism Speaks, Fragile X Research foundation, and Cincinnati Children’s research foundation. EVP receives past research support from the American Academy of Child and Adolescent Psychiatry and past compensation for consulting for Proctor & Gamble, Eccrine Systems, Inc. and Autism Speaks. He receives book royalties from Springer. E.V.P. has no conflicts of interest with the current manuscript. D.L.G. has received honoraria and/or travel support from the Tourette Association of America/Centers for Disease Control and Prevention, the Child Neurology Society and the American Academy of Neurology. He has received compensation for expert testimony for the U.S. National Vaccine Injury Compensation Program, through the Department of Health and Human Services, He has received payment for medical expert opinions through Advanced Medical/Teladoc. D.L.G. has received research support from the NIH (NIMH) and the DOD. He has received salary compensation through Cincinnati Children’s for work as a clinical trial site investigator from Emalex  and EryDel . He has received book/publication royalties from Elsevier, Wolters Kluwer and the Massachusetts Medical Society. All the other authors report no potential competing interest.


Working memory (WM) deficits are key in attention deficit hyperactivity disorder (ADHD). Nevertheless, WM is not universally impaired in ADHD. Additionally, the neural basis for WM deficits in ADHD has not been conclusively established, with regions including the prefrontal cortex, cerebellum, and caudate being implicated. These contradictions may be related to conceptualizations of WM capacity, such as load (amount of information) versus operational-complexity . For instance, relative to neurotypical (NT) individuals, complex WM operations could be impaired in ADHD, while simpler operations are spared. Alternatively, all operations may be impaired at higher loads. Here, we compared the impact of these two components of WM capacity: load and operational-complexity, between ADHD and NT, behaviorally and neurally. We hypothesized that the impact of WM load would be greater in ADHD, and the neural activation would be altered. Participants ; 82 NT ) recalled three or four objects (load) in forward or backward order  during functional magnetic resonance imaging scanning. The effects of diagnosis and task were compared on performance and neural engagement. Behaviorally, we found significant interactions between diagnosis and load, and between diagnosis, load, and complexity. Neurally, we found an interaction between diagnosis and load in the right striatum, and between diagnosis and complexity in the right cerebellum and left occipital gyrus. The ADHD group displayed hypo-activation compared to NT group during higher load and greater complexity. This informs mechanisms of functional problems related to WM in adolescents and young adults with ADHD  and remedial interventions . A promiOne of the complicating factors in WM research is differences in defining WM constructs. Some WM theories differentiate between maintenance and manipulation, qualifying only manipulation as true WM, with maintenance being simply recall , whereas. Very few studies have tested this by directly comparing maintenance at higher load with manipulation  individuals have been studied extensively, and while the prefrontal cortex (PFC), parietal cortex (PC), supplementary motor area (SMA) and superior temporal areas  are clasTo directly compare the impact of different definitions of WM capacity in ADHD, we tested the effect of WM load (low versus high) and complexity  within a unitary fMRI paradigm, in a group of individuals with ADHD and a NT control group. We hypothesized that WM performance would be impaired in the ADHD compared with the NT group and that this difference in performance would be accompanied by alterations in WM-related neural activation. Furthermore, based on the results of previous behavioral studies examining the impact of WM load in ADHD e.g., ; we hypoUnderstanding the specificity of the impact of ADHD on WM capacity (complexity versus load) could elucidate what aspects of WM difficulty present a challenge for those with ADHD. Additionally, it could inform the design of personalized WM training interventions by guiding efforts toward specific aspects of WM operations. As suggested in earlier work, using external storage, cues, or incrementally adding new information may reduce WM load and interventions focused on these aspects may be more beneficial .22.12.1.1We collected imaging data (see following sections for information on imaging parameters and recruitment details) from 78 adolescents and young adults (AYA) with Combined presentation of ADHD  and a comparison group of 86 NT AYA, part of a longitudinal study. We recruited participants from the University of California, Davis (UCD), MIND Institute-based subject recruitment system, UCD and community outpatient psychiatric and neurodevelopmental disorders clinics, UCD campus bulletin boards and the community via targeted advertising on flyers and social media. Twenty participants with ADHD and four NT participants were excluded due to low behavioral accuracy , and 8 ADHD participants due to excessive head movement during scanning (defined as having more than 25% volumes omitted due to exceeding a volume-to-volume motion limit of 1 mm). We analyzed MRI data from the remaining participants, including 50 ADHD and 82 NT participants.Participants were 12–23 years of age and included 41/41 and 18/32 females/males in the NT and ADHD groups, respectively . Of the 2.1.2Two licensed psychologists in our team (JBS and JFD) evaluated screening data to determine eligibility for the study based on the Diagnostic and Statistical Manual of Mental Disorders – 5th Edition (DSM 5). Parent  and teacher rating scales   were com2.1.3n = 91) or the Wechsler Adult Intelligence Scale , depending on age); (b) testing positive for a mathematical or reading learning disability  scores < 80); (c) any parent-reported history of head trauma, neurological disorder or major medical problem; (d) prescribed psychoactive medication besides ADHD medications ; (e) meeting DSM criteria for any other Axis I diagnosis besides ADHD, oppositional defiant disorder, or conduct disorder; (f) a positive drug screen on the day of the imaging session for illicit drugs; (g) a positive pregnancy test ; (h) any MRI contra-indications.Study inclusion criteria required participants to be between the ages of 12–25 years of age, be typically developing for the NT group or meet DSM-5 criteria for ADHD, Combined or Hyperactive/Impulsive Presentation for the ADHD group. . Study exclusion criteria included (a) Full Scale IQ score < 80  with a 32-channel head coil for imaging. T2* functional images were acquired  = 2.0 s, excitation time (TE) = 25 ms, flip angle = 90°, matrix 64 × 64, field of view (FOV) = 220 mm). The WM task included four runs, each run comprising of 182 volumes. Additionally, MPRAGE anatomical scan was collected . Experimental stimuli were presented using E-Prime 2.0 .2.3. In this task, each of four runs consisted of a fixation period of 4000 ms, followed by 15 trials. Each trial started with an encoding block, consisting of four images show at 1000 ms intervals. The load was varied by replacing the fourth picture with an asterisk in the 3 load trials, which participants were instructed to ignore. This was followed by a 5000 ms instruction block, during which participants were told to recall the items in the order presented  or in reverse order . This was the main period of interest as this was when the objects would be either maintained (forward order) or manipulated (reverse order). After a fixation period (1000 ms), a probe block occurred, during which participants recalled the objects that had been previously presented over a 8000 ms period. An inter-trial interval of 4000 ms, 6000 ms, 8000 ms (mean 6000 ms) followed each trial. Conditions were randomly distributed within a run.Participants performed a version of the Picture Order Memory Paradigm  using an. In this2.4We used SAS version 9.4.  to analyze behavioral performance. We derived average accuracy and reaction time for the 3 item (3F and 3B), 4 item (4F and 4B), forward (3F and 4F), and backward (3B and 4B) trials. Analyses were performed using mixed-effects linear models  since da2.52.5.13. Volumes exceeding a volume-to-volume motion in excess of 1 mm were excluded from further analysis. Participants with more than 25% omitted volumes were excluded.We analyzed fMRI data using FSL and AFNI . The fir2.5.2General linear model analyses fit hemodynamic responses with a boxcar activation function using onset times of each condition. Movement parameters were also included as nuisance-variables. Regressors modeled encoding, instruction, recall, and manipulation periods.2.5.3To identify brain regions recruited for WM complexity and load in each group, factoring out the effect of age, we carried out a linear mixed-effects modeling analysis, implemented by 3dLME in AFNI, at the whole-brain level. The fixed effects in our model were diagnosis, complexity, and load. We included interactions between diagnosis, complexity and load, diagnosis and complexity, diagnosis and load, age and load, age and complexity, age and diagnosis. Participant was treated as a random intercept. Age was included as a covariate.p-value of 0.005, resulting in a minimum cluster size of 182 voxels required to achieve a probability of 0.05 of significant cluster surviving by chance. Simulations were calculated using 3dClustSim with autocorrelation function (ACF), avoiding assumptions about Gaussian noise distribution .To ensure that group differences were not influenced by head motion, we compared average movement parameters  between groups, using independent samples t-tests . No significant group difference was found (33.1p = 0.048). We found a significant interaction between diagnosis and load (p = 0.04), but not diagnosis and complexity (p = 0.62). We found a significant effect of age (p = 0.03). The interaction effect of age and load was significant (p < 0.001). We also tested for a quadratic effect of age on performance, but it was not significant (p = 0.06) and thus was not included as a term in fMRI data analyses.3.23.2.1For the neuroimaging analyses, we began by testing for the main effects of load and complexity across participants, and we identified regions previously associated with WM, including the ventrolateral and dorsolateral PFC, striatum, and cerebellum. A conjunction analysis of the main effects of load and complexity identified large parts of the occipital, parietal, middle temporal gyrus, precentral gyrus, DLPFC, cerebellum, and striatum bilaterally. Additionally, a main effect of complexity included large clusters in the medial PFC, bilateral precuneus, and cerebellum. The main effect of load further included bilateral occipital gyrus, striatum, left VLPFC, and right precentral gyrus. The main effect of diagnosis included a cluster in the cerebellum, with peak activity in the declive. The main effect of age showed large, significant clusters with peaks in the left lentiform nucleus and including the bilateral caudate, bilateral cerebellum extending over the uvula and culmen, bilateral inferior frontal gyrus (IFG), precentral gyrus, middle frontal gyrus and bilateral inferior parietal lobule .Fig. 2Ma3.2.2Within both groups, tests for the effect of load and complexity identified significant activation bilaterally in standard WM regions, including lateral PFC, parietal cortex, striatum, and cerebellum .3.2.3,We did not find a significant three-way interaction effect (group × load × complexity). A significant interaction effect of group and complexity was found in the right cerebellum and in the left lingual gyrus. We also found a significant interaction effect of group and load in the right caudate Fig. 3,.Fig. 3In3.2.4There was a significant interaction effect of age and load in the left paracentral lobule, and for age and complexity in the right caudate .3.2.5There was no significant interaction effect of age and group.4WM deficits have been widely reported in ADHD , and theOur results demonstrate that across all conditions, individuals with ADHD produce more errors, compared to NT. Both groups responded less accurately for more difficult tasks – either due to increased load (4 versus 3) or greater complexity . However, in the ADHD group, increase in load had a greater impact on WM performance accuracy, compared to the NT group.The neural data showed that all participants recruited brain regions that are typically associated with WM, such as the PFC, PC, SMA, superior temporal gyrus , cerebelAcross groups, older participants responded more accurately for all conditions, consistent with the common finding that WM improves with age . AdditioThe lingual gyrus has been associated with encoding complex images  or wordsOur results indicate that the caudate and the cerebellum may play an important role in WM impairments in ADHD, for load and complexity respectively. The contribution of the striatum and the cerebellum to WM has been highlighted in earlier studies . The strDue to the proposed role of the striatum in gating information into WM , our resThe importance of fronto-striato-cerebellar networks in ADHD, across modalities, has been repeatedly highlighted . SpecifiA strength of our study lay in our inclusion criteria which resulted in relative homogeneity in the clinical symptoms in our ADHD group; All participants were required to demonstrate clinically-impairing impulsivity, in addition to other ADHD symptoms. A potential limitation of this study is the stringent criteria of excluding participants with low performance , which could bias our results towards higher-performing individuals with ADHD, limiting the clinical implications. This tradeoff was required to compare brain-activation more reliably for the majority of our population. As this study is part of a longitudinal study, we also chose to use a task with a condition where the load gave room for the participants to improve in performance  as our participants mature and all reach adulthood, when a 3 item task may result in performance with a ceiling effect. As our current data are cross-sectional, future work should also investigate how relationships between executive function and fronto-striatal-cerebellar systems in ADHD vary longitudinally with development with respect to working memory and other critical functions. We aim to investigate these questions in the future as our longitudinal dataset grows.There was a significant difference in intellectual functioning between our groups with the ADHD group testing at a lower intellectual level than our NT group. The disorder is associated with lower cognitive ability and full scale intellectual quotient (FSIQ) often is significantly lower in ADHD than neurotypical controls . This isWM deficits are key in ADHD . WM is lA notable caveat of WM studies in ADHD is the heterogeneity in findings of WM deficits in ADHD . AlthougIn conclusion, although WM is impacted in ADHD, the literature is mixed regarding the nature of the relationship between ADHD and WM . That is10.13039/100000025National Institute of Mental Health grants R01 MH091068 (Schweitzer) and U54 HD079125 (Abbeduto).This work was supported by Dr. Hinshaw receives book royalties from Oxford University Press and St. Martin’s Press. Mr. Hartanto and Drs. Mukherjee, Fassbender, Iosif, van den Bos, Guyer, Pakyurek, McClure, and Schweitzer report no competing interests.Prerona Mukherjee: Conceptualization, Methodology, Software, Formal analysis, Data curation, Investigation, Writing - original draft, Writing - review & editing, Visualization, Project administration. Tadeus Hartanto: Investigation, Software, Data curation. Ana-Maria Iosif: Formal analysis, Writing - review & editing. J. Faye Dixon: Investigation, Writing - review & editing. Stephen P. Hinshaw: Writing - review & editing. Murat Pakyurek: Investigation. Wouter van den Bos: Writing - review & editing Amanda E. Guyer: Writing - review & editing. Samuel McClure: Conceptualization, Methodology, Writing - review & editing, Supervision. Julie B. Schweitzer: Conceptualization, Investigation, Writing - review & editing, Supervision, Funding acquisition, Project administration. Catherine Fassbender: Conceptualization, Methodology, Investigation, Writing - review & editing, Visualization, Supervision, Project administration.


Objective: This study investigates whether the dynamic functional connectivity (dFC) of the amygdala subregions is altered in children with attention-deficit/hyperactivity disorder (ADHD).Methods: The dFC of the amygdala subregions was systematically calculated using a sliding time window method, for 75 children with ADHD and 20 healthy control (HC) children.Results: Compared with the HC group, the right superficial amygdala exhibited significantly higher dFC with the right prefrontal cortex, the left precuneus, and the left post-central gyrus for children in the ADHD group. The dFC of the amygdala subregions showed a negative association with the cognitive functions of children in the ADHD group.Conclusion: Functional connectivity of the amygdala subregions is more unstable among children with ADHD. In demonstrating an association between the stability of functional connectivity of the amygdala and cognitive functions, this study may contribute by providing a new direction for investigating the internal mechanism of ADHD. Globally, nearly 1 in 20 youth suffers from attention-deficit/hyperactivity disorder (ADHD), making it one of the most prevalent psychiatric disorders among children . InattenStudies on anxiety over the last few decades have further clarified the impairment associated with ADHD . AbundanIt is important to study the complex mechanisms underlying ADHD, together with the functional impairments of the diseased brain, to ensure effective diagnosis, treatment, and prevention. Resting-state functional magnetic resonance imaging (rs-fMRI) is a safe and non-invasive tool that can detect spontaneous activity in the brain . The amyReliance on the implicit assumption that participants’ brain activity remained static throughout the rs-fMRI scan was a common feature of many previously mentioned studies. However, a growing body of research confirms that brain activity changes dynamically over time . Most rsTo address this gap, we first used the sliding window method to study the abnormal dFC of the amygdala subregions of children with ADHD, specifically focusing on anxiety symptoms and cognitive functions, and further studied the relationship between the dFC of the amygdala subregions and anxiety symptoms and cognitive functions. Based on previous studies, we hypothesized that (1) higher dFCs of the amygdala subregions can be observed in children with ADHD; (2) higher dFC is positively associated with anxiety symptoms among children with ADHD; and (3) higher dFC is negatively associated with the cognitive functions of children with ADHD.Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The Schedule for Affective Disorder and Schizophrenia for School-Aged Children Present and Lifetime Version (K-SADS-PL) was used to interview the participants and their parents  ≥ 70 estimated by the Wechsler Intelligence Scale for Children, Fourth Edition. Participants who currently or previously had psychological disorders or who had serious physical disorders, neurological disorders, or brain injuries were excluded from this study. This study was approved by the Medical Research Ethics Committee of the Shenzhen Children’s Hospital. All children agreed to participate, and written informed consent was obtained from their parents.Conner’s Parent Rating Scale  is a widThe neuropsychological test battery consisted of the Stroop color-word and N-back tests. The two tests were considered representative of two areas of cognitive function: response inhibition and working memory.The Stroop test, translated from the Victorian version , consistThe N-back task consists of three subtasks, namely, 0-back, 1-back, and 2-back tasks. The 0-back task requires participants to press the left mouse button when a gray square appears at the top left of the central fixation (“ + ”) and to press the right mouse button when the square appears at the top right or right bottom of central fixation (“ + ”). The 1-back (2-back) task requires participants to identify whether the orientation of the X square displayed on the screen is the same as that of the X-1 (X-2) square. If the orientation is the same, they press the right mouse button; otherwise, they press the left button.2; matrix size = 94 × 94; 32 axial slices; and slice thickness = 3 mm and 130 volumes.The rs-fMRI data for all participants were obtained using a 3.0-T system scanner (Siemens Magnetom Skyra), and all participants were instructed to close their eyes, relax, stay awake, and try not to move their head during the scan. Participants were checked after the scan to ensure that they remained awake during the procedure. The rs-fMRI data were obtained using an echo-planar imaging sequence with the following parameters: repetition time (TR) = 2,000 ms; echo time = 30 ms; flip angle = 90°; field of view = 220 × 220 mmhttp://rfmri.org/dpabi; f < 0.10 Hz).rs-fMRI data preprocessing was performed using the Data Processing and Analysis of Brain Imaging (DPABI) toolbox  and a step of 1 TR. Moreover, the entire rs-fMRI time series was segmented into 71 windows for each participant. The resting-state r value matrix was obtained by computing the partial correlation coefficients, and the z value matrix was obtained via Fisher-z transformation. Before the statistical analyses, the result maps were smoothed out with a 4-mm full-width at the half-maximum Gaussian kernel. Furthermore, to exclude the influence of window width on the results, the window width was set as 32/64 TR to repeat the calculations. The results were similar with the results of the 50TR and are detailed in the A sliding window method was used in this study to formulate dFC maps for each participant. This method can elucidate the temporal features of FC over the entire duration of the scan and calculate the time-varying covariance of interregional neural signals, which is the variance of dFC. The window length is a key parameter based on the sliding window method. According to t test was used to evaluate differences in age, grade, FSIQ, mean FD, anxiety scores, and cognitive scores between the ADHD and HC groups. Moreover, dFC maps were analyzed using the two-sample t test based on DPABI to distinguish dynamic changes in FC between the two groups. Previous studies based on rs-fMRI have shown that FC in the brain is significantly associated with intelligence  in DPABI , the dFC of the amygdala subregions showed significant differences in some areas, and the right SFA exhibited a significantly higher dFC in the right PFC, the left precuneus, and the left post-central gyrus. However, no regional differences in dFC were found between the children with ADHD and those in the HC group with regard to the bilateral BLA, CMA, and the left SFA. Detailed information is shown in r = -0.234, p = 0.043) and a positive correlation with the IS (error)   . HoweverTo our knowledge, this study is the first to use the dFC method to explore the amygdala subregion network of children with ADHD. We observed that compared with the HC group, the right SFA of the ADHD group showed a higher dFC; this highlights greater temporal variability in FC with the right PFC, the left precuneus, and the left postcentral gyrus. Another key finding is the correlation between the subregion of the amygdala and cognitive functions of patients with ADHD. The dFC of the amygdala subregions showed a specific association with working memory and response inhibition among patients with ADHD. These outcomes suggest that the FC of the amygdala is more unstable among children with ADHD, and the dFC of the amygdala subregion network is related to the cognitive functions of children with ADHD.Unlike the resting-state FC, the stability of the FC is reflected by the dFC. The findings of this study may provide new insights into the abnormal brain activity of children with ADHD. Previous studies that analyzed the amygdala as a whole failed to recognize its structural complexity. Instead, research demonstrated that different subregions of the amygdala perform different functions . PrimariIn this study, the right SFA of the ADHD group showed a significantly higher FC variability in the right PFC, the left precuneus, and the left post-central gyrus. Previous studies suggested that the PFC is fundamentally involved in mechanisms underlying anxiety . In the Generally, the precuneus belongs to the parietal lobe, which is involved in a variety of complex functions and is critical for emotion processing , mediatiThis study also finds a relationship between the dFC of the amygdala subregions and the cognitive functions of patients with ADHD. Specifically, for patients with ADHD, the dFC between the right SFA and the right PFC showed a negative correlation with the 2-back scores and a positive correlation with the IS (error). This means that the more unstable the functional connection between SFA and PFC, the worse the cognitive function of patients with ADHD. This study’s outcomes should be interpreted with caution because of the following limitations. First, the scanning time was relatively short, which might reduce the reliability of the rs-fMRI data. Each participant underwent an rs-fMRI scan for 260 s, whereas similar studies were typically performed for 5 to 8 min . Second,Despite these limitations, the following two advantages enhance the reliability of the results. Previous studies have outlined that stimulants can change the brain structure and function of patients with ADHD  and the In summary, we investigated the dynamic variability of amygdala-based FC and its association with anxiety symptoms and the cognitive function of children with ADHD. The results of this study suggest that the dFC of the amygdala subregion of children with ADHD is significantly different from that of healthy children, and higher dFCs are negatively associated with the cognitive functions of children with ADHD. In demonstrating an association between the variability of amygdala FC and cognitive functions, this study may contribute by providing a new direction for studying the internal mechanism of ADHD.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical Research Ethics Committee of Shenzhen Children’s Hospital. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.YY and BY: conceptualization. LZ and DF: methodology and investigation. YY, BY, and GP: validation. YY and GP: formal analysis. BY and GP: resources and writing—review and editing. YY and DF: data curation. YY, LZ, and GP: writing—original draft preparation. BY: project administration and funding acquisition. All authors discussed the results and reviewed the manuscript.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. The reviewer LS declared a past collaboration with one of the author BY to the handling editor.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. 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