Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset, neurodevelopmental disorder, whereas major depressive disorder (MDD) is a mood disorder that typically emerges in adulthood. Accumulating evidence suggests that these seemingly unrelated psychiatric disorders, whose symptoms even appear antithetical , are in fact associated with each other. Thus, individuals with ADHD exhibit high comorbidity with MDD later in life. Moreover, genetic studies have shown substantial overlaps of susceptibility genes between ADHD and MDD. Here, we propose a novel and testable hypothesis that the habenula, the epithalamic brain region important for the regulation of monoamine transmission, may be involved in both ADHD and MDD. The hypothesis suggests that an initially hypoactive habenula during childhood in individuals with ADHD may undergo compensatory changes during development, priming the habenula to be hyperactive in response to stress exposure and thereby increasing vulnerability to MDD in adulthood. Moreover, we propose a new perspective on habenular deficits in psychiatric disorders that consider the habenula a neural substrate that could explain multiple psychiatric disorders. The current diagnostic manuals of psychiatric disorders, such as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)  and InteAttention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder . In contIn this article, we first briefly summarize the literature demonstrating correlations between ADHD and MDD, followed by a discussion of the effects of habenular deficits in these disorders based primarily on animal models. Then, we further propose that investigations examining habenular dysfunction not in the context of a unitary, categorized disorder but as a common factor underlying multiple psychiatric conditions would be a thriving future direction.ADHD comprises the core symptoms of hyperactivity, impulsivity, and attention deficit that is classified into three types, depending on which symptoms are prominent: inattentive, hyperactive/impulsive, and combined types . MDD is Some MDD symptoms could be antithetical to those of ADHD. For instance, psychomotor retardation  in MDD cThere are other interesting coincidences between ADHD and MDD. Both disorders involve sleep disturbances, such as insomnia , althougSubjects with ADHD are frequently diagnosed with other comorbid disorders, such as autism spectrum disorder, mood and anxiety disorder, drug addiction, and personality disorder . EpidemiVarious mediators have been suggested regarding the comorbidity of ADHD and MDD. These include psychosocial factors, such as parent management , peer prRecent genetic studies have substantiated associations between ADHD and MDD. In a genome-wide association study (GWAS) with ADHD subjects, g = 0.42) (g = 0.42)  . A simil = 0.42) . Thus, s = 0.42) , 2019. Ag = 0.52 .Collectively, these GWASs have demonstrated modest, but highly consistent, SNP-based genetic correlations between ADHD and MDD, consolidating the associations between these disorders.Extensive research has been conducted to reveal the molecular and cellular mechanisms in the habenula that influence cognitive and affective functions as well as dysfunction implicated in psychiatric disorders. There are many comprehensive reviews that have summarized these studies , such thUsing animal models of MDD, hyperactivity in the lateral nucleus of the habenula has consistently been demonstrated . SpecifiCompared with MDD and other psychiatric disorders, such as schizophrenia and drug addiction , researcNHLs also cause an assortment of neural alterations, such as a smaller PFC volume  and abnoAlthough a neonatal “lesion” gives an impression of damage in the habenula, NHLs result in smaller nuclear sizes of both medial and lateral habenula than those of normal rats, which could be due to the manipulation during early brain development. This raises a couple of issues to be further examined. First, since both medial and lateral nuclei of the habenula are affected by NHL, it has remained elusive whether and in what way neonatal manipulations of either the medial or lateral nucleus alone would yield distinct alterations. For instance, ADHD symptoms are grouped into hyperactive-impulsive dominant, inattention dominant, and mixed types . NHLs afTaken together, a hypothesis has emerged that may explain the pathophysiology of comorbid ADHD and MDD . In partIn addition to ADHD and MDD, habenular deficits have been implicated in other psychiatric disorders. As is the case with MDD, although a relatively large number of animal model studies have provided support for habenular deficits in schizophrenia  and drugImplications of habenular deficits in such an assortment of psychiatric disorders are not surprising, given the function of the habenula . Thus, tA current diagnosis of psychiatric disorders is based on the categorical model . In thisAs an alternative to the categorical model, the dimensional model has been considered, especially in childhood psychiatry . In thisAlthough it has been suggested that patients are more likely to have comorbidities of psychiatric disorders within the same dimension, correlations have also been observed between externalizing and internalizing symptoms , which cFuture investigations that clarify the impacts of habenula deficits in psychiatric disorders may be fertile in the context of general psychopathological factors, such as how habenular deficits can explain the comorbidity of multiple disorders, rather than being associated with deficits in a particular psychiatric disorder.We have proposed a hypothesis that habenular hypoactivity early in development may produce ADHD-like behaviors. The habenula may subsequently go through compensatory changes across development that leads to hyperactivity with an increased vulnerability to stress and MDD. Thus, the habenula may be a crucial brain region linking ADHD and MDD. Moreover, the roles of the habenula could be generalized across multiple psychiatric disorders beyond ADHD and MDD as a neural substrate of the p-factor.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.YAL and YG conceived the idea and wrote the article. Both authors contributed to the article and approved the submitted version.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 dopamine D4 receptor gene (DRD4) has been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). Recent studies have linked DRD4 to functional connectivity among specific brain regions. The current study aimed to compare the effects of the DRD4 genotype on functional integrity in drug-naïve ADHD children and healthy children. Resting-state functional MRI images were acquired from 49 children with ADHD and 37 healthy controls (HCs). We investigated the effects of the 2-repeat allele of DRD4 on brain network connectivity in both groups using a parameter called the degree of centrality (DC), which indexes local functional relationships across the entire brain connectome. A voxel-wise two-way ANCOVA was performed to examine the diagnosis-by-genotype interactions on DC maps. Significant diagnosis-by-genotype interactions with DC were found in the temporal lobe, including the left inferior temporal gyrus (ITG) and bilateral middle temporal gyrus (MTG) . With the further subdivision of the DC network according to anatomical distance, additional brain regions with significant interactions were found in the long-range DC network, including the left superior parietal gyrus (SPG) and right middle frontal gyrus (MFG). The post-hoc pairwise analysis found that altered network centrality related to DRD4 differed according to diagnostic status (p < 0.05). This genetic imaging study suggests that the DRD4 genotype regulates the functional integration of brain networks in children with ADHD and HCs differently. This may have important implications for our understanding of the role of DRD4 in altering functional connectivity in ADHD subjects. Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and highly heritable childhood-onset neurodevelopmental disorder characterized by age-inappropriate levels of inattention, hyperactivity, and/or impulsivity Apa, . The etiMost of the candidate genes associated with ADHD belong to the dopaminergic system  studies have been conducted to bridge the gap between genotypical and behavioral correlates. However, genetic imaging studies related to the genotype DRD4 2R allele are scarce. Previous task-based fMRI studies have shown that the DRD4 gene can also influence brain activity in areas involved in executive function  is a measure used in graph theory to investigate global connectivity by measuring the number of instantaneous functional connections (or correlations) between a given voxel (node) and the rest of the brain, rather than with specific nodes or networks  Using Reverse Transcription-Polymerase Chain Reaction (RT-PCR) technology, it has been found that DRD4 is relatively highly expressed in the above brain regions . The final analysis included 47 children with ADHD (15 2R and 32 non-2R) and 37 HC participants (16 2R and 21 non-2R). All participants were Han Chinese and right-handed.Fifty-nine children with ADHD were recruited from the Mental Health Center of the First Affiliated Hospital of Wenzhou Medical University. Also, 38 healthy controls (HCs) were recruited from a local primary school and were matched for handedness and intelligence quotient (IQ). All participants were recruited between March 2012 and November 2014. Among them, 12 children with ADHD and 1 HC participant were excluded because of unqualified head movement  criteria according to two experienced clinical psychiatrists, C.Y. and Q.L., based on a semi-structured diagnostic interview and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime Versions (K-SADS-PL)  were excluded. Other exclusion criteria were similar to those used in our previous study . The R-fMRI lasted eight minutes in total, and 240 volumes were obtained for each participant. Children were accompanied by a guardian to ensure their safety during the scanning process.All imaging data were acquired at the Department of Radiology. All participants were scanned on a GE Signa HDx 3.0 T scanner with an eight-channel phased-array head coil. During resting-state fMRI, the subjects were instructed to keep their eyes closed, relax their mind, and remain as still as possible without falling asleep. Plastic foam pads were used to minimize noise and the head movements of the subjects. Firstly, all subjects underwent a T2 weighted sequence scan to exclude any structural lesions in the brain. Then, resting-state functional MR images were obtained via an echo-planar imaging sequence  = 2000 ms, echo time (TE) = 30 ms, flip angle = 90°, matrix size = 64 × 64, and field of view (FOV) = 192 × 192 mmhttp://www.rfmri.org/dpabi) in Matlab 7.12.0 software  to eliminate differences in the brain spatial structure of each subject. Further preprocessing included spatial smoothing with a 4-mm full width at half-maximum (FWHM) Gaussian kernel. Removal of linear trends and a temporal filter  were then applied. Finally, several sources of spurious variance, including 24 head motion parameters, white matter signal intensity, and cerebrospinal fluid signal intensity, were extracted and regressed from the data.The resting-state data were preprocessed using the toolbox for Data Processing and Analysis for Brain Imaging  and healthy control (n = 37) groups.During preprocessing, four children with ADHD were excluded for having head motion > 3 mm (displacement) or 3° (rotation). In-scanner head motion during EPI acquisition was indexed by mean frame-wise displacement (FD) derived from Jenkinson’s relative root mean square algorithm  in a voxel-wise manner with a threshold of r > 0.2, as previously described  were computed for all possible pairs of voxels, which resulted in an individual whole-brain functional connectivity matrix  toolbox  and short-range (< 75 mm) categories according to their anatomical distance.For genotyping, DNA was extracted from 10 mL of peripheral venous blood followed by cell lysis and heme/protein precipitation. Genomic DNA was analyzed using TIANGEN (NO. DP304). Then, we genotyped the 48 bp VNTR in the Exon-3 DRD4 gene of each subject using polymerase chain reaction (PCR) and short tandem repeat (STR) methods. The primers used in this protocol are as follows: forward: 5’- GCG ACT ACG TGG TCT ACT CG-3’, reverse: 5’-AGG ACC CTC ATG GCC TTG-3’. PCR reactions were prepared in 25 μL volumes, each containing 12.5 μL KAPA2G Fast Multiplex Mix, 1 μL Forward primer (10 μm), 1 μL Reverse primer (10 μm), 1 μL Template DNA and 9.5 μL ddH2O. The samples were heated at 95◦C for 10 min and then cycled 40 times at 94◦C for 30 s, 55◦C for 30 s and 72◦C for 1 min, followed by 72◦C for 3 min with a final extension at 4◦C.Then, the GS500LIZ standard sample and PCR products were mixed. Next, the atlas of STR was obtained using HIDI for electrophoresis. All participants were genotyped for the DRD4 48-bp repeat VNTR polymorphism.t-test was used for normally distributed variables. Non-normally distributed data were evaluated by Mann–Whitney U tests. Two-tailed p-values < 0.05 were considered statistically significant.SPSS 22.0 software  was used to conduct non-neuroimaging data analyses. A two-tailed independent-sample p < 0.05, corrected for multiple comparisons using the Gaussian random field (GRF) theory . Once regions showed the significant diagnosis-by-genotype interactions, two-sample t-test were performed to examine the connectivity differences between the genotype DRD4 2R and non-2R subjects in the ADHD and HC groups separately, with nuisance covariates including age, gender, IQ and mean FD.A voxel-wise two-way ANCOVA was performed separately to examine the main effects of diagnosis (ADHD vs. HC) and DRD4 genotype (2R vs. non-2R) and diagnosis-by-genotype interactions on DC maps, using age, gender and mean FD as covariates. The significance level was set at genotype × diagnosis interaction effects, with the Z-scores of neuropsychological tests or clinical symptoms. These analyses were conducted separately for each subgroup and included the nuisance covariates of age, gender, IQand mean FD. Bonferroni corrections were performed, setting the significant p-value at 0.002 (= 0.05/(8 × 3), where 8 represents the number of neuropsychological tests and 3 represents the significant clusters of DC analyzed).Partial correlations were calculated to associate the DC of clusters, which showed significant n = 15, twelve with the 2R/4R genotype and one each with 2R/2R, 2R/5R, or 2R/3R genotypes; HC: n = 16, fourteen with the 2R/4R genotype and two with 2R/2R) or the non-2R group . The genotypes were in Hardy–Weinberg equilibrium (p > 0.05).The remaining eligible participants were classified as being in the DRD4 2R group (ADHD: p < 0.05). Additionally, the ADHD group showing worse impulsivity or hyperactivity performance than the HC group (p < 0.05).As shown in Table genotype × diagnosis interactions on DC were found in the left inferior temporal gyrus (ITG) and bilateral middle temporal gyrus . The DC values in the bilateral MTG were negatively correlated with full-scale response control quotient (FRCQ) in the ADHD non-2R group (p = 0.009 and p = 0.033). We also found correlations between the DC values in the left ITG and psychosomatic problems in the healthy controls 2R group (p = 0.03). However, these above correlational analyses did not pass the multiple corrections process.diagnosis-by-genotype on the brain functional architecture of the ITG and MTG. We found that, in the ADHD group, DC revealed genotype DRD4 2R-related increases in network centrality within the left ITG and bilateral MTG, and decreased long-range network centrality within the left SPG and right MFG. However, these genetic effects were opposite in healthy controls, although some of the results are not statistically significant. Despite, there was still have a certain trend. Our results reveal a divergent effect of the DRD4 genotype on functional connectivity in brain regions with relatively abundant DRD4 expression. As a result, the neuro-functional mechanisms underlying ADHD may differ according to the effect of the VNTR of the DAT1 gene.Using resting-state fMRI and a network centrality approach, we found the first evidence of a significant interaction of DRD4 genotype × diagnosis in children with ADHD. A recent genetic imaging study examined the effect of DRD4 7R allele and ADHD interaction on brain structure. It found that prefrontal gyrification, which is associated with executive function, is reduced in ADHD subjects with the risk allele  and right middle frontal gyrus (MFG) in ADHD children but not in healthy children. This suggests a less prominent role of the MFG and SPG in coordinating the long-range functional brain network in ADHD subjects with the 2R allele. The prefrontal and parietal cortices possibly mediate more general meta-motor executive control functions, such as motor attention, conflict monitoring, and response selection. The prefrontal and parietal cortices are intricately connected to provide unified and tightly regulated attention functions  and the non-2R group ) was relatively small, which restrict the statistical power. Larger sample size and multicenter studies will help us to fully understand the mechanisms of genetic risk underlying ADHD. Second, the interactive analyses revealed no significant main effect of diagnosis on brain network centrality. In contrast, previous neuroimaging studies have observed much abnormal activity in certain brain regions of ADHD subjects, such as the right inferior frontal gyrus (rIFG), sensorimotor cortex, and anterior cingulate cortex (Alonso Bde et al., Several limitations in the present study need to be mentioned. First, the sample size of this ANCOVA analysis (DRD4 2R group (ADHD: In the current study, we found that the DRD4 2R allele mainly affects the connectivity of the temporal and frontoparietal lobes, which involved emotional and attentional functions. Our findings also suggested that the DRD4 genotype differently modulates the functional integration of the brain networks of children with ADHD and healthy controls. This helps us to understand how the overall composition of the brain network is reorganized in response to DRD4 variants in ADHD subjects. And the neuroimaging findings associated with the DRD4 provide new insights into the heterogeneity of ADHD.


Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition that globally affects an average of around 5% of children and is associated with several adverse life outcomes. Comorbidity with autism spectrum disorder (ASD) is highly prevalent. Pharmacological treatment for ADHD symptoms has been shown to be effective. However, the prevailing perception is that children with ADHD and concomitant ASD symptoms report poorer efficacy and more side effects. This has been supported by studies on this population, but prospective studies directly comparing children with ADHD and different levels of ASD symptoms are lacking. We aimed to assess if children with ADHD and concomitant ASD symptoms differ regarding effects and side-effects of pharmacological ADHD treatment compared to children with ADHD without ASD traits. This is to our knowledge the second study to directly compare the effect of ADHD medication between ADHD patients with different levels of ASD symptoms.N=71) and one with low level of ASD symptoms . Treatment outcome was measured as ADHD symptoms, and evaluated using the Swanson, Nolan and Pelham Teacher and Parent ADHD rating scale-version IV (SNAP-IV). Side-effects were evaluated using the Pediatric Side Effects Checklist (P-SEC), at 3 months follow-up.In a non-randomized, observational, prospective cohort study, 323 patients aged 6 to 17 years who were diagnosed with ADHD and starting pharmacological treatment were divided into two groups: one with high level of ASD symptoms (ASD group, From baseline to 3 months, there was no significant difference in neither treatment effect nor number of clinically significant adverse events experienced between the ASD group and the non-ASD group.Our results did not implicate that ADHD patients with concomitant ASD symptoms have decreased treatment effect of ADHD medication than patients with ADHD without concomitant ASD symptoms. Neither did the results support that ADHD patients with ASD symptoms experienced significantly more side-effects than ADHD patients without ASD symptoms. Although, we did not analyze different medications separately, this is in line with the only previous study directly comparing methylphenidate treatment in children with or without ASD.NCT02136147, May 12, 2014. Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition that globally affects an average of around 5% of children . There iReichow et al. performed a systematic review and meta-analysis of 7 double-blind randomized placebo-control trials in which they examined the effect of ADHD medication in children with PDD . The autn = 27) and without (n = 25) concomitant ASD diagnosis. No statistically significant differences between the groups were found [Thus, even though studies examining the pharmacological treatment effect of various ADHD medications in children with ASD exist, there is a shortage of clinical trials conducted on children with or without concomitant ASD symptoms comparing treatment effect and side effects. We have identified only one study directly comparing children with ADHD without ASD diagnosis to children with ADHD and concomitant ASD . Santoshre found . In the Research participants in this study constitute a subsample of those enrolled in the ADHD medication and predictors of treatment outcome (ADAPT) study, a prospective observational cohort study conducted in three Swedish Child and Adolescent Psychiatry units: in Stockholm, Gotland, and Umeå. The ADAPT study has enrolled patients from July 2014 and is still running. By January 2020, 548 patients were included. Patient enrolment in Umeå started in March 2020, and thus for the present all study participants were from the Swedish Child and Adolescent Psychiatry units in Stockholm and Gotland. Inclusion criteria for the ADAPT study were (1) age 6 to 17 years, (2) established clinical ADHD diagnosis, and (3) initiating pharmacological ADHD treatment. Patients who had been on any ADHD medication within the last 3 months prior to study start were not eligible. Participating units were instructed to ask all eligible patients on participation and to report numbers declining and accepting to the study. However, only the numbers of accepting participants were reported. For the present study, participants lacking baseline rating of ASD-symptoms, baseline rating of ADHD-symptoms, or rating of ADHD-symptoms at 3 months were excluded. Forty-three patients did not complete the Autism Spectrum Screening Questionnaire (ASSQ) at baseline, 40 patients did not complete SNAP-IV at baseline, and 208 patients did not complete SNAP-IV at 3 months, leaving the cohort with 323 patients. 295 patients in the cohort had complete information on ADHD medication at 3 months; information was missing for 28 participants. One 5-year old was accepted in the cohort.Participant flowchart is presented in Fig. To estimate the effect of medication and assess the ADHD symptoms, we used parent’s ratings of the validated Swanson, Nolan and Pelham Teacher and Parent ADHD rating scale-version IV (SNAP-IV) , 35 at bTo answer our main research question, we compared the total SNAP-IV points at baseline and at 3 months follow-up, although we also performed analyses on the subscales. Further, we introduced a prerequisite, a cutoff at 40% reduction in total SNAP-IV score from follow up at 3 months compared to baseline. This resulted in two groups: responders, defined as a SNAP-IV score reduction ≥ 40 %, and non-responders, defined as a SNAP-IV score reduction < 40%. According to previous studies, a 40% threshold has shown good coherence with the degree of change in the SNAP-IV rating scale score that predominantly correspond to a substantial clinical effect in regards of ADHD characteristic symptoms , 23.To distinguish children in our cohort with high level of ASD symptoms, we used the validated Autism Spectrum Screening Questionnaire (ASSQ) , 37. TheThe Pediatric Side Effects Checklist (P-SEC) , containInitiating ADHD medication was an inclusion criterion for enrollment in the study. Consequently, all patients were assumed to have started ADHD medication at baseline. At 3 months, data on ADHD medication was obtained and noted as binary yes or no answers. ADHD medication was defined as at least one of either methylphenidate (MPH), dexamphetamine (DEX), lisdexamphetamine (LDX), atomoxetine (ATX), or guanfacine (GXR). In Sweden, MPH is the first drug of choice and accordingly was prescribed to the vast majority of patients. Thus, hereafter when we refer to ADHD medication, it indicates the use of MPH, LDX, ATX, or GXR alone or in combination with others, though the medication used was predominantly MPH. The distribution of ADHD medication  is presented in Table To examine whether patients in the ASD group had inferior treatment effect and augmented adverse effects of ADHD medication compared to patients in the non-ASD group, we analyzed the differences between the ASD group and the non-ASD group concerning total SNAP-IV score reduction from baseline to 3 months as well as a number of side effects for each group.A multivariable linear regression model was conducted to assess the relationship between the dependent outcome variable, SNAP-IV score at 3 months, and the independent variables (ASD group vs. non-ASD group), adjusting for age, gender, and baseline SNAP-IV score.In addition, we also performed logistic regressions to assess if the interaction between variables would change if we set the primary outcome to a binary variable, responder or non-responder, using the same independent variables: ADHD medication, ASD or non-ASD group, age, gender, and SNAP-IV score at baseline.The sum of the number of adverse events in each of the 11 categories from the P-SEC scale was calculated and compared between the non-ASD group and the ASD group using chi-square tests with continuity correction.P-.05.All statistical analyses were conducted using IBS SPSS Statistics software version 26. Comparisons were 2-tailed with statistical significance set at n = 87 datapoints). The number of random lacking data points were distributed according to SNAP-IV at baseline (n = 31), SNAP-IV at 3 months (n = 43), and ASSQ at baseline (n = 36). Mis generates 5 imputations and thereof a merged pooled result. All analyses were conducted following imputation.Multiple imputations (Mis) technique was used to limit the effect of occasional single missing data in ASSQ and SNAP-IV questionnaires , 44. Misn = 252.4 and the ASD group was n = 70.6. This fact had a negligible effect on our results but did result in somewhat varying composition of the non-ASD and ASD group for dichotomous analyses, precisely examining adverse events, and SNAP-IV responder and non-responder. However, importantly, it did not have any significant impact on our findings.Mis generates a pooled non-integer value, which therefore is not compatible with all analyses in IBS SPSS Statistics software. Since the non-ASD and ASD group were defined by a pooled multiple imputed value of the ASSQ data, the groups were not absolute determined entities. Using pooled data, the non-ASD group was actually Concerning the P-SEC scale, random missing data counts were regarded as 0, since we assumed leaving out answering solitary questions about adverse events almost exclusively could be viewed as having “no side-effect,” which equaled a rating of 0. Multiple imputation method used for the SNAP-IV scale and the ASSQ scale was not considered applicable, since the items on the P-SEC scale represent very different themes, and consequently the imputation model would adventure generating adequate answers. There were on average 2.62 (95% CI 1.57–3.68) missing data points per patient in the P-SEC ratings in the Non-ASD group and 2.16 (95% CI 0.69–3.63) per patient in the ASD group. Consequently, the low number of missing data points on the P-SEC scale did not motivate the risk of bias trying to adjust for missing data.t test established that the non-ASD group scored significantly lower on the SNAP-IV scale than the ASD symptoms group. When comparing total SNAP-IV score, at baseline the mean difference between groups was 13.99 points , and at 3 months, the mean difference was 8.72 points . Both groups, as expected, decreased in scores from baseline to 3 months. Accordingly, the same pharmacological treatment effect between the two groups remained when adjusted for higher scores for the ASD symptoms group. When analyzing each SNAP-IV subscales separately—inattention, hyperactivity/impulsivity, and ODD—the same pattern with lower scores for the non-ASD group compared to the ASD group, including both at baseline and at 3 months, as well as the sum of scores overall deceasing from baseline to 3 months for both groups, were exhibited. A slight difference between subscales was observed, where the change in inattention scores (mean difference at baseline 2.38 (P = 0.01) and 1.84 (P = .015) at 3 months) was less pronounced between the groups than for hyperactivity/impulsivity (mean difference at baseline 5.34 (P < .001) and 2.79 (P = .001) at 3 months) and ODD (mean difference at baseline 4.31 (P < .001) and 2.81 (P < .001) at 3 months). The divergence between the non-ASD and the ASD group was significant throughout all subscales except for inattention score at 3 months (Table Independent n = 19) registered as having no ADHD medication and 91.61% (n = 207.4) registered as having ADHD medication at 3 months. In the ASD group, 16.03% of participants (n = 11) were noted as having no ADHD medication, and 83.97% (n = 52) did have ADHD medication at 3 months (P = .06623). 74.95% (n = 153.2) in the Non-ASD group and 77.39% (n = 43.8) in the ASD group stated treatment with MPH (P = .68). The second most frequent treatment in both groups was LDX, 15.19% (n = 31.2) in the non-ASD group and 15.55% (n = 8.8) in the ASD group (P = .84) . The effect of ADHD medication on SNAP-IV score at 3 months indicated that the medicated group had a lower score, albeit not significant , after controlling for age and gender (Table N = 88.8) were responders and 65% (N = 163.6) were non-responders. In the ASD-group, 30% (N = 21) were responders and 70% (N = 49.6) were non-responders. Pearson chi-square test  with continuity correction did not reveal a significant difference (P = .447). The logistic regression analyses did not show any significant interactions between any of the variables. Chi-square tests with continuity correction, performed to examine the relation between ASD symptoms and adverse events, did not exhibit significant difference of reported adverse events for any of the 11 subcategories between the non-ASD and the ASD group ). We hypothesize ADHD medication would also significantly have affected our original model if the number of study objects had been larger and the rate of missing information on ADHD medication had been smaller.Further, we examined both the absolute reduction in ADHD symptoms from baseline to 3 months follow-up and response rate (defined as 40% reduction from baseline to 3 months) to investigate if the lack of difference between the groups remained introducing a clear cutoff. We also analyzed the SNAP-IV score subdivided in the three subscales: inattention, hyperactivity/impulsivity, and ODD. The results, for both additional examinations, was consistent, with SNAP-IV at baseline being the only significant predictor of SNAP-IV at 3 months, except for when performing linear regression for the subscale inattention, where also ADHD medication significantly improved ADHD symptoms , thereby diminishing the risk of selection bias in data. Occasional missing data points in the P-SEC scale were regarded as zero, which might have underestimated the number of adverse events. However, missing data points in that dataset were low, which implies that the risk of undervaluing the number of adverse events was small.Fourth, like many clinical trials, our study suffered from losses to follow up, especially concerning completion of the ADHD medication form. However, there were no significant difference in the rate of continued pharmacological treatment at 3 months between the ASD group and the non-ASD group. Neither was there a significant difference in the number of patients defined as having ASD symptoms (ASSQ points ≥ 17) between patients lost to follow up (27%) and included patients (21%) ) compared to the non-ASD group (11.75 years (CI: 11.34–12.15, P = .001, Table Ninth, mean age at inclusion was significantly 1.49 years younger in patients in the ASD group (10.26 years (CI: 9.51 to 11.04, Tenth, in our study, we were limited to use only SNAP-IV Parent rating scale as a proxy for ADHD symptoms. Since children may behave different at home compared to in a school environment, having access to the SNAP-IV Teacher rating scale, could have given a more complete picture. However, additional informants also mean greater challenges to carry through data collection with the risk of less participation rate. Including teachers’ ratings in future data collections will be an asset to study any differences between the groups in the school setting.Despite limitations, we believe that our results are an important contribution to research aimed at examining the effect of pharmacological ADHD treatment in children with comorbid ASD or ASD symptoms. For clinicians as well as for experts stipulating medical guidelines, it is crucial that decisions are based on best available evidence, increasing the probability of patients receiving the appropriate treatment. ADHD is associated with lower quality of life . ComorbiOur results indicate the need to reconsider that ASD patients experience more adverse events, which could precipitate preterm pharmacological treatment, for symptoms that are not related to medication but to the characteristics of the diagnosis itself. The need of equal and correct treatment for children suffering from comorbid disorders is essential, and the possibility of customized treatment must be further elucidated. Since our study is the second to directly compare the pharmacological effect of ADHD medication between ADHD patients with different levels of ASD symptoms, more research is needed to shed light on the discrepancy of our results and previous perceptions.In summary, our results indicate that there were no significant differences in pharmacological treatment effect between patients with ADHD and concomitant pronounced ASD symptoms and patients with ADHD without high level of ASD symptoms. There was also no significant difference in the number of reported clinically significant adverse events between the groups. Studies directly comparing the effects of ADHD medication in children with only ADHD and children with comorbid ASD are important to diminish the risk that decisions about medication rely on unconfirmed assumptions. The present results are in line with the results from the only previous prospective study comparing these patient groups.


Childhood cancer patients experience emotional hardship associated with their life-threatening diagnoses. Interdisciplinary team members working in pediatric cancer care can help alleviate physical pain and psychological suffering of children by facilitating collaborative legacy-building activities with patients and families. The contents of this article aim to support legacy building as a medium for emotional healing prior to the end of life. The authors use a case review to contextualize legacy-building projects and provide a comprehensive overview of methods and considerations for these initiatives. When faced with a pediatric cancer diagnosis, children and families experience profound grief and a sudden loss of normalcy. A sense of powerlessness takes over as parents realize they are in a situation they cannot control and “fixing” the child’s illness is out of their hands . ChildreA cancer diagnosis can feel like a home invasion: the dreaded sound of an alarm system warning of an intruder, the shock of coming face-to-face with a potentially deadly threat, and the realization that one’s privacy and home have been assailed and safety has been compromised. Following a home invasion, one might upgrade their alarm system or add a deadbolt to their front door. With childhood cancer, the alarms keep going off and more invaders enter a child’s private space in what feels like a recurring nightmare. Cancer is not cured by upgrading an alarm system; there is no simple fix.Members of the newly diagnosed child’s care team work together with the patient and their family to create a plan for healing. Medical team members address the physiological needs of their patients by creating treatment plans and administering medications and therapeutic agents for healing . OncologInterdisciplinary team members including psychologists, social workers, child life specialists, creative arts therapists, visual arts specialists, and chaplains play an indispensable role in alleviating stress associated with hospitalization and optimizing coping for pediatric cancer patients . These pDespite the establishment of robust psychosocial teams at many pediatric cancer care centers, providers may not know the extent to which these staff members are able to minimize pain and suffering for children with cancer. Cancer care providers may be especially unfamiliar with legacy-building interventions, the processes by which building a legacy for cancer patients can occur, and the benefits for patients’ overall well-being when engaging in these activities during their cancer journeys. The content of this paper includes an overview of the roles some psychosocial team members play in cancer care, a comprehensive discussion of the art of legacy building and meaning making for pediatric cancer patients, and how the combination of support from psychosocial team members and cultivation of legacy-building projects can address emotional pain and suffering experienced by children with cancer. A case review was utilized to contextualize this paper’s contents. All names were changed to respect the privacy of the patient described in the review.Thomas was diagnosed with acute lymphoblastic leukemia (ALL) in May 2016 at the age of twelve, marking the beginning of a period of unequivocal change in Thomas’s life. Following a fairly standard course of chemotherapy treatment from 2016 through 2019, Thomas rang the “remission bell” to celebrate the completion of treatment for his disease. Just months after this triumphal event, though, leukemia cells were spotted during a routine follow-up bone marrow aspiration, signaling a recurrence of his cancer and another devastating blow to the lives of Thomas and his family members. Thomas’s course of treatment in the context of this relapse included CAR-T cell therapy, which he received during a hospital admission that lasted several weeks. Unfortunately, CAR-T therapy was not successful at eradicating the cancer from Thomas’s body as he and his medical team had hoped. Thomas experienced another recurrence of disease toward the end of 2020, within a year of his first relapse.At the time of his second relapse, Thomas was sixteen years old and had spent the better portion of the past four years of his life in hospital rooms, surrounded by members of the healthcare team who had come to be his primary source of psychosocial support. When Thomas was informed of this relapse, following what he thought would be the ticket to his cure (CAR-T therapy), Thomas was blind-sided, asking almost every staff member who entered his hospital room, “Can you believe I relapsed again?”.Despite the devastating realization that his cure was still out of reach, Thomas continued to present with a jovial demeanor, engaging in therapy sessions with a pediatric psychologist, creating art with the hospital’s visual art specialists, and immersing himself in conversations with the oncologists about his treatment options moving forward. However, once Thomas restarted chemotherapy and began feeling the effects, his demeanor changed to one of withdrawal and regression. Thomas’s mood seemed to be directly in tune with his level of pain and discomfort, with more pain causing increasingly flat affect and occasional outbursts of anger and despair . Thomas’Meanwhile, Thomas’s oncologists worked tirelessly to come up with feasible treatment options that had the best chance of a cure. They decided to move forward with a plan that included a stem cell transplant, which he would undergo in early 2021. Thomas’s oncology team explained the prognosis for all patients worsens with each consecutive recurrence of disease, but the stem cell transplant gave him the best chance of eradicating his cancer, despite coming with an onslaught of risks, including death.Despite the risks, Thomas and his mother decided to move forward with the stem cell transplant, and he was admitted just after his seventeenth birthday to begin the transplant process. Given the high-risk nature of Thomas’s transplant, Thomas and his medical team anticipated a long, tumultuous hospital admission.At Thomas’s hospital, child life specialists, school teachers, one music therapist, and two visual arts specialists are employed under a department called “support programs”.With the knowledge that Thomas would be staying inpatient at the hospital for several weeks, members of support programs met to discuss a potential schedule of activities for Thomas during his stay to help promote positive coping strategies and minimize adverse psychological effects of prolonged hospitalization. During this discussion, the child life specialists shared information from Thomas’s team of stem cell transplant physicians including their concerns for high risk of pain associated with transplant side effects and high risk of decompensation and death during the transplant process.Given the challenging nature of Thomas’s cancer and treatment plan, the child life specialist, music therapist, and visual arts specialists working with him decided to introduce the concept of a collaborative living legacy project to Thomas, which would act as a long-term endeavor to be completed gradually throughout his hospital stay. One intent of this initiative would be to combat boredom and add structure to his hospital experience by giving Thomas something to do and work toward completing during his transplant. The therapeutic intent would be to promote meaning making for Thomas through reflection on his cancer process and stem cell transplant journey .When Thomas’s child life specialist introduced the concept of a long-term, reflective legacy-building project during his hospital stay, Thomas was enthusiastic about creating a video journal where he would capture a video clip of himself every day of his stem cell transplant admission. Thomas’s support team of child life specialist, music therapist, and visual arts specialists provided him with the tools needed to complete this project, including an iPad for daily video capturing and apps for video editing and music-making.Thomas’s child life specialist visited Thomas daily during his first weeks of admission to the hospital, often helping record his videos and prompting him during filming to reflect on his day, how he was feeling, and his hopes for the next day. Thomas’s videos at the beginning of his admission were short and simple, usually starting off by saying the date, how many days until his stem cell transplant, and how his pain and anxiety were that day. His child life specialist served as a facilitator of conversation and reflection about his feelings and fears surrounding his transplant process while filming. Thomas’s visual art specialists visited him throughout his admission as well, helping add creative visual elements to his film and teaching him about video editing software. His music therapist encouraged the use of iPad apps for sound effects and music choices to add to his video, as well as providing a therapeutic presence for both Thomas and his mother throughout his admission.Midway through his stem cell transplant, Thomas became very ill with veno-occlusive disease (VOD) and disseminated adenovirus, requiring him to be transferred to the intensive care unit for oxygen support and placement of an intraperitoneal drain. During this time, Thomas continued to engage in his daily video ritual when he was lucid enough to do so, without being prompted by his child life specialist. Thomas would sometimes film himself under his blanket, expressing fears for his life and uncertainty about his resolve to “keep fighting”, all while choking back tears or actively crying during the filming sessions.During Thomas’s stay in the intensive care unit, members of support programs continued visiting him and engaging with him in therapeutic activities and his film-making process. On days when Thomas was experiencing extreme pain and discomfort in his abdomen due to the VOD, he would often still choose to engage in filming, which would offer a reprieve from the pain through the distraction offered by filming and processing his emotions. Thomas’s child life specialist and music therapist facilitated many conversations with Thomas during this critical period of his admission surrounding his mortality and his hopes for his future, in life and in death.Thomas recovered from his VOD and adenovirus and eventually was transferred out of the critical care unit and returned to routine stem cell transplant care on the regular oncology unit. Thomas continued filming, and by the end of his two-month admission, he had filmed over thirty video clips and edited them into a 36-min-long video montage of his transplant. The video ends with him filming his cleaned-out hospital room and stating, despite periods of considerable stress and pain during his transplant, “It’s been a fun journey. Keep on keeping on”.Thomas relapsed again four months after his discharge from the hospital at the end of his transplant. Thomas was placed on concurrent hospice care with palliative chemotherapy, and he and his mom tearfully watched this video together before going home on hospice.Psychosocial distress in pediatric cancer patients and their caregivers is often present from diagnosis through the end of treatment. Children with cancer experience separation from peers and siblings, changes in physical appearance that can lead to lowered self-esteem, and severely reduced autonomy and control . PhysicaCultivating positive coping skills is of utmost importance for the reduction of pain and emotional distress for pediatric cancer patients. When children are given the tools to learn to cope with stressful and painful experiences in the healthcare setting, they are more likely to experience emotional and physical healing ,11. PsycWhile children with cancer experience emotional distress and suffering, their parents and caregivers simultaneously encounter the greatest of psychological distress of their lifetimes as they grapple with how to comfort their children while feeling a total sense of powerlessness. Interventions that address the psychological needs of both the patients and their family members should be utilized to decrease emotional suffering for the family unit as a whole . One sucMany consider a legacy to be what is left behind or how one is remembered after death. However, a legacy cannot be produced outside of the context of a life that has been lived. Building one’s legacy is a continual process of meaning making through creation of a narrative surrounding one’s lived experiences. Child life specialist Jessika Boles describes legacies as “universal human experiences... personal and relational summations of our unique histories, current activities, and hopes for the future” . In 2021All children (and adults) cultivate their legacies incidentally as they live their lives despite their diagnoses and develop personal characteristics that define who they are. Incidental legacy building is a process that happens naturally, without intervention or encouragement . Legacy Children living with cancer often experience existential suffering associated with concerns about death and dying . Even foIntentional legacy-building activities often naturally lend themselves to discussions of life review and remembrance . Having Several members of the interdisciplinary cancer care team are skilled in facilitating legacy-building activities with patients, with child life specialists often being the first point of contact. As legacy-building projects often involve creative approaches to life review, creative arts therapists and visual arts specialists are key parts of this process as well. In Thomas’s case, his support team included one music therapist, one child life specialist, and two visual arts specialists. The following section of this paper will describe the roles of each of these interdisciplinary team members.Certified child life specialists are closely involved in legacy-building projects with patients, often introducing legacy-building projects and helping to facilitate supportive conversation and positive coping throughout the process. Child life specialists are specially trained healthcare professionals with expertise in child development and the developmental phases of grief for children ,19,20. AAdditionally, music therapists can help facilitate legacy projects. Pediatric medical music therapy is the use of music and therapeutic relationships to promote healthy coping and safeguard the child’s psychosocial well-being during medical treatment ,24,25. MThomas’s hospital does not employ an art therapist, but instead employs two visual artists who worked with Thomas closely to humanize his hospital experience by promoting wellness through normative art-making. Visual artists offer a multitude of normative, educational, sensory, social, and emotional benefits to hospitalized individuals, particularly those experiencing pain and distress as a result of illness ,30. VisuChild life specialists, creative arts therapists, and visual arts specialists are aligned in their common goal of reducing the stress of hospitalization for patients through normalization and promotion of autonomy, choice, and control . Child lJust as their roles in general supportive care of patients with cancer are complementary to one another, child life specialists, creative arts therapists, and visual arts specialists present with unique skillsets that can be utilized through collaborative efforts in legacy building. Legacy building projects prioritize the unique needs and interests of the patients in the process . CollaboThomas’s video project ended up being a wonderful example of collaborative efforts between multiple disciplines, the patient, and his family. Bedside nursing and physicians were also able to passively partake in his video process by making cameo appearances and by planning care around his video clip times. Rehabilitation services such as physical and occupational therapy were able to use his video-making as motivation for mobility, encouraging him to take a walk and film as he went.Legacy building takes on many forms . Thomas It is common practice for child life specialists to offer to create keepsake items for patients’ families, including plaster hand molds, handprint art pieces, and customized fingerprint jewelry ,18. MusiThe overall perception of legacy building by pediatric healthcare workers is that it is a process of memory-making that occurs at the end of life . In pediThomas’s child life specialist offered to create a family plaster hand mold with him, his mother, and his brother when he was very ill during his most recent relapse hospitalization. While Thomas was lucid and able to participate in the project to some extent, he primarily participated as a passive member of the activity, holding hands with his brother for the mold process while nodding off to sleep.When given the final hand mold product a few days later, Thomas was excited to see the results and his mother was happy with the final product as well. However, Thomas’s mother endorsed that Thomas’s video legacy project would be “treasured more”, as Thomas had more of an active role in the creation of the video than in the creation of the hand mold.Legacy building is an ongoing process, something that happens over time, rather than an isolated event . Even thWhile many healthcare workers perceive legacy building as something that happens at the end of life or after death, legacy work can be more meaningful for the child and family when the living child takes an active role in the experience, as Thomas’s mother endorsed. When engaging in legacy building with the living child, the patient is able to exercise autonomy and control through the creation of a legacy project, which can lead to alleviation of some of the physical and emotional burden of the cancer process ,36.Despite insurmountable pain and emotional suffering associated with pediatric cancer, especially for those patients approaching the end of life, children with cancer still have the innate, unique human ability to find and create meaning out of their misfortunes, and that creation of meaning is the centerpiece of intentional legacy building interventions ,37. CultLiving legacy projects often involve a creative outlet through which a patient can tell their story . This miNarrative legacy projects in the age of technology can also involve the use of photography and videography as a means of storytelling. In Thomas’s case, he engaged in narrative legacy building through a video documenting his daily life in the hospital. Orally narrating his experiences each day led to a profound experience of emotional expression for Thomas. The child life specialist was intentional about the questions she prompted Thomas to reflect upon, often asking him how he was feeling physically and emotionally, which allowed Thomas to make a connection between his mind and body and reflect upon those feelings. Over time, Thomas was able to create those connections without being prompted by his child life specialist.When Thomas’s video was finished, Thomas was asked if he wanted to show the video to his mom. Thomas stated, “Yeah, it’s for her.” Prior to this point, Thomas had not discussed who the video was for or what he intended to do with the video after its completion. His statement at the end of his narrative legacy project process reflects the idea that narrating one’s life in this manner can promote bonding between the child and their family prior to and after death ,37.Video and digital media enable their users to visually represent otherwise spoken or written words to create space for the exploration of lived experiences. This can be used as a tool for empowerment, social engagement, and honoring one’s culture, and can serve as an avenue for therapeutic work . DigitalVirtual engagement with digital media also offers a level of distance not found in traditional in-person engagement. Malchiodi  argues tIn Thomas’s case, video engagement allowed him to speak more freely about his emotions, fears, and hopes for the future. Oftentimes, when asked by his healthcare team members how he was doing on any given day, he would simply say “I’m okay” or “I’m fine”. However, through the third space of his iPad videos, he expressed his emotions with much greater detail and more organic emotions.Thomas chose not to share his video project on social media, but some pediatric cancer patients turn to social media as another way of cultivating their legacies and sharing their stories. The lives of children and young adults growing up in the 21st century have been mediatized and globalized through the 24-h news cycle and easy access to multiple social media platforms. Social media sites are used as a platform for ill children and teens to communicate about loss and find like-minded individuals going through similar experiences . Social Being mindful of the psychosocial needs of pediatric cancer patients’ family members is of utmost importance to the overall well-being and coping of the family unit as a whole. Parents and siblings of children with cancer often experience high levels of psychological distress, which can lead to family conflict and challenges with emotional regulation . DespiteLegacy building can be used as a meaning-making activity to encourage family bonding and communication. Research shows that parents of children who have participated in legacy-building activities had positive experiences, noting the benefits of emotional expression and increased communication about their child’s cancer experience through the process of cultivating legacy projects . ParentsSome pediatric cancer patients choose to include their family members in the legacy-building process, asking for their involvement in creating tangible products or narrating their stories. Family bonding occurs in these cases through intentional communication about the child’s story and illness that may not have otherwise been discussed. However, some children choose to engage in legacy-building processes independently. In Thomas’s case, although he ultimately stated that he created his video for his mother to see, he did not include his mother in the narrative process of his video-making, despite her constant presence at bedside during his hospital admission. However, Thomas’s mother was able to engage in the legacy-building process with Thomas passively by watching him create his daily videos and listening as he expressed himself emotionally. At the conclusion of the project, she was then able to watch the video in full and experience Thomas’s emotional expression through thirty-six minutes of his narration. Thomas’s mother was tearful while watching the final product and expressed gratitude to both Thomas and the support programs team members for helping facilitate Thomas’s legacy project.Pediatric cancer patients and their families experience physical pain and emotional suffering, and their interdisciplinary medical teams have an ethical imperative to address these issues in order to promote adequate healing. Members of the interdisciplinary team, including child life specialists, creative arts therapists, and visual arts specialists share the common goal of minimizing emotional suffering endured during healthcare encounters by promoting positive coping through normalization of the hospital environment. These same team members, through extensive rapport building, also form bonds with patients that make them well-suited to facilitate legacy-building exercises. In healthcare systems with less resources and staff availability, legacy building still happens organically as patients carry on with their lives during cancer treatment and continue to evolve into who they are as people. However, hospitals employing and utilizing trained professionals that are skilled at providing creative outlets for children with cancer allow patients to be more intentional about expressing their legacies. This intentionality promotes positive coping and can lessen existential and emotional suffering and pain. Through collaboration amongst interdisciplinary team members, patients, and families, children with cancer can create a product of their own fruition and unique creation that can be cherished by their family members throughout their lifetimes or after death. Future research into the benefits of these collaborative legacy-building interventions could help to expand upon the empirical framework of legacy building. Media-based legacy building is a promising medium for cultivating legacy projects in the 21st century as social media and technology-based interventions are now woven into the fabric of childhood and personhood, and more research and exploration into the benefits of media-based interventions is needed.


Obstructive sleep apnea (OSA) is a form of sleep-disordered breathing that affects up to 9.5% of the pediatric population. Untreated OSA is associated with several complications, including neurobehavioral sequelae, growth and developmental delay, cardiovascular dysfunction, and insulin resistance. Attention-deficit/hyperactivity disorder (ADHD) is among the neurobehavioral sequelae associated with OSA. This review aims to summarize the research on the relationship between OSA and ADHD and investigate the impacts of OSA treatment on ADHD symptoms. A literature search was conducted on electronic databases with the key terms: “attention deficit hyperactivity disorder” or “ADHD”, “obstructive sleep apnea” or “OSA”, “sleep disordered breathing”, and “pediatric” or “children”. Review of relevant studies showed adenotonsillectomy to be effective in the short-term treatment of ADHD symptoms. The success of other treatment options, including continuous positive airway pressure (CPAP), in treating ADHD symptoms in pediatric OSA patients has not been adequately evaluated. Further studies are needed to evaluate the long-term benefits of surgical intervention, patient factors that may influence treatment success, and the potential benefits of other OSA treatment methods for pediatric ADHD patients. Obstructive sleep apnea (OSA) is a form of sleep-disordered breathing (SDB) caused by a complete or partial obstruction of the upper airway, resulting in altered gas exchange and/or sleep disruption. Major risk factors for the development of OSA in children are adenotonsillar hypertrophy and obesity. Other risk factors that have been identified include prematurity, asthma, low socioeconomic status, and abnormal craniofacial features ,2. ManifPhenotypic presentation of OSA exists on a wide spectrum and is influenced by multiple factors such as age, ethnicity, and socioeconomic status. For this reason, diagnosis and treatment thresholds and outcomes vary for each child . The AmeADHD is characterized by a pattern of inattention, hyperactivity, and impulsivity that interferes with daily functioning in more than one setting . The gloCurrent literature shows bidirectional associations between OSA and ADHD. This review aims to summarize the most recent and available literature on the relationship between OSA and ADHD and investigate the impacts of OSA treatment on ADHD symptoms.A PubMed, EBSCO, and Google Scholar database search was conducted using the terms: attention deficit hyperactivity disorder or ADHD, obstructive sleep apnea or OSA, sleep disordered breathing, and pediatric or children. References cited in selected articles were reviewed. Literature on OSA and ADHD, individually, was reviewed as well for supplemental purposes. Articles referenced for the purpose of this review were published between March 2002 and August 2021. The authors reviewed eligible articles that met criteria and excluded articles with no relevance, case reports, and non-English language studies.The relationship between ADHD and OSA appears to be reciprocal, each exacerbating the symptoms of the other. ADHD symptoms overlap with the diagnosis of OSA, with attention deficits reported in up to 95% of pediatric OSA patients . A 2018 Wu et al. (2017) investigated the relationship between allergic rhinitis, ADHD, OSA, and age. ADHD was significantly more common in children aged four to five years old with severe adenoid hypertrophy as compared to those without. Allergic rhinitis was positively associated with OSA and ADHD in this age group. In children aged six to 11 years old, ADHD was observed more in children with severe tonsillar hypertrophy as compared to those without. It is difficult to know whether systemic inflammation is causing the resulting adenotonsillar hypertrophy and thus resulting in ADHD-type symptoms or underlying genetic or environmental factors are exacerbating both ADHD and OSA symptoms. The incidence of ADHD also increased with age, which may be linked to the effects of OSA-induced hypoxia on brain development and function . This suSeveral studies have sought to explore the relationship between the two conditions. Khadra et al. 2008) demonstrated a complex relationship between regional oxygen saturation (rSO2), apnea–hypopnea index (AHI), and mean arterial blood pressure (MAP) in children with SDB. rSO2 and AHI were negatively associated with SDB, rSO2 and MAP were positively associated with SDB, and AHI and MAP were positively associated with SDB. rSO2 levels increased with age and were higher in females as compared to males. This suggests that males are affected more by ADHD than females. All three variables were strongly associated with SDB severity. The implications of this study suggest that SDB variably affects individuals, and neurocognitive deficits should be expected to vary as well . The sev08 demonsA 2006 study by Gozal et al. observed elevated levels of high-sensitivity CRP (hsCRP) in children with OSA, indicating that hsCRP testing may be useful for monitoring the development of neurocognitive deficits in children with OSA . AnotherStudies which have linked ADHD and OSA do share other common mitigating factors that may contribute to both conditions. Sleep deprivation, either as fragmented sleep or as reduced total sleep time has also been linked to worse OSA symptoms as well as more severe ADHD behaviors. In addition, stimulant medications also can worsen sleep quality and in turn worsen ADHD behaviors. The elevation in CRP, other inflammatory cytokines and markers are presumed to result in end-organ dysfunction that manifests as ADHD behaviors, OSA symptoms, or comorbid disease .Treatment approaches for pediatric OSA include adenotonsillectomy, positive airway pressure therapy, orthodontic measures such as rapid maxillary expansion, and weight reduction for obese patients . MedicalAdenotonsillectomy is the most common treatment for pediatric OSA . SurgeryIn 2013, the Childhood Adenotonsillectomy Trial (CHAT) study performed a multicenter, single-blind, randomized, controlled trial to evaluate the differences between early adenotonsillectomy versus watchful waiting on neurocognitive and behavioral outcomes in children five to nine years old with OSA. A total of 464 children with OSA confirmed by PSG were randomized into the two groups. Children’s attention and executive function were evaluated using the Developmental Neuropsychological Assessment (NEPSY) at the onset of the study and after seven months. Average NEPSY scores prior to intervention were similar to that of the general population and increased in both groups by the end of the study. This trial did not show any difference in the two main outcomes between groups. The increase was greater in children who underwent adenotonsillectomy but was not significant. However, both caregivers and teachers reported significantly greater improvement in observed behavior on the Conners’ Rating Scale in children who received surgery. Additionally, symptoms of OSA were measured using the Pediatric Sleep Questionnaire Sleep-Related Breathing Disorder scale (PSQ-SRBD) and Epworth Sleepiness Scale (ESS) and were shown to significantly decrease in patients who underwent adenotonsillectomy as compared to watchful waiting. Similarly, quality of life was shown to significantly improve when measured on the PedsQL and OSA-18 scales in children who underwent surgery .Since the CHAT trial, additional randomized clinical trials have sought to evaluate the effect of early adenotonsillectomy in children under the age of five, the age of the youngest patient included in the initial CHAT trial. The 2020 Preschool Obstructive Sleep Apnea Tonsillectomy and Adenoidectomy (POSTA) study by Waters et al. evaluated the effect of early adenotonsillectomy on cognition in children aged three to five years old. They performed a multicenter, randomized, controlled clinical trial in which 190 children with primary snoring or mild to moderate OSA were randomized into two groups. The Woodcock Johnson III (WJ-III) Test of Cognitive Abilities and the Brief Intellectual Ability (BIA) score were used to evaluate intellectual ability at baseline and after 12 months. They found that there was no significant difference in intellectual ability between those undergoing early adenotonsillectomy versus those who did not receive surgery. However, like the CHAT trial, parents reported improvements in sleep, dietary habits, snoring, difficulty breathing during sleep, and daytime sleepiness in children who underwent surgery .While the CHAT trial showed perceived improvement in behavior by caregivers, it did not show statistically significant improvements in cognitive/behavioral scoring. However, there are numerous, smaller albeit non-randomized other studies that have examined the effect of adenotonsillectomy on children with SDB and ADHD which have shown more significant resultssuch as reduced inattention and hyperactivity.A study done by Al-Zaabi et al. (2018) aimed to evaluate cognitive and behavioral changes among children aged nine to 14 with OSA after adenotonsillectomy. The results of the study showed a 33% improvement in neurocognitive function and general intellectual ability, as well as a 21% reduction in inattention and hyperactivity scores, thus showing evidence of the effectiveness of adenotonsillectomy in improving ADHD-like symptoms among children .A study performed by Ahmadi et al. (2016) evaluated children with ADHD and observed the clinical symptoms before and after adenotonsillectomy. Results showed a 69% improvement in ADHD symptoms one month after surgery and an 86% improvement in ADHD symptoms three months after the procedure . AnotherDadgarnia et al. (2012) found a significant improvement in ADHD symptoms, especially hyperactivity, six months post-adenotonsillectomy . A 2008 In a study done by Wei et al. (2007), SDB-diagnosed children scheduled for adenotonsillectomy were evaluated before and after surgery using the Conners’ Parent Rating Scale-Revised Short Form (CPRS-RS), behavior categories, hyperactivity, and Conners’ ADHD index. ADHD index, cognitive problems, and oppositional behavior all showed significant improvement following surgery . Dillon Huang et al. (2007) compared different treatment options for school-age children diagnosed with ADHD and mild OSA. The subjects were divided into three treatment options: methylphenidate (MPH) therapy, adenotonsillectomy, or no treatment. Clinical interviews, ADHD rating scale, CBCL TOVA, and OSA-18 were completed prior to initiation of therapy and 6 months later. Results showed that the surgical and MPH groups improved more than the non-treatment group. The surgical group displayed higher improvements in PSG, questionnaire sleep variables, daytime symptoms, and TOVA subscales  as compared to the MPH group. This was found to be significantly different between the two groups as well. Hence, researchers suggest that surgical treatment of children with SDB and ADHD may prevent unnecessary long-term MPH use .Weber et al. (2006) investigated ADHD symptoms in children with obstructive ventilatory disorders (OVDs) for improvement in inattention, impulsivity, and hyperactivity after adenotonsillectomy. As some subjects were unable to complete PSG to diagnose OSA, the authors chose to use the diagnosis of OVD instead. The 30 subjects were divided into three groups according to age . Attention, impulsivity, and hyperactivity were assessed preoperatively and six months post-surgery using 30 questions based on DSM-IV criteria. Children aged 8 to 10 displayed the highest improvement in behavior post-surgery. Results were not deemed to be statistically significant due to small sample size, as noted by the authors. In addition, PSG was not used as the basis for diagnosis, and, rather, diagnosis was based on history and physical examination .Chervin et al. (2006), compared children who underwent adenotonsillectomy for indications apart from sleep disorders, including those who tested negative by PSG. Children scheduled for adenotonsillectomy displayed higher baseline ADHD scores as compared to the control subjects. Post-surgery, 50% of the children scheduled for adenotonsillectomy showed improvement in symptoms, no longer meeting the criteria for ADHD . This stAnother prospective study done by Avior et al. (2004) assessed attention deficit disorder (ADD) in children with OSA scheduled for adenotonsillectomy. Investigators used the test of variables of attention (TOVA) as opposed to the DSM-IV criteria for ADHD diagnosis. Nineteen children were selected for evaluation. TOVA scores, OSA-18, and CBCL/4–8 questionnaires were taken before surgery and two months postoperatively. Results showed significant improvement in TOVA and CBCL/4–8 scores in all children except one . In thisWhile there is strong evidence for the short-term benefits of adenotonsillectomy on ADHD symptoms in pediatric OSA patients, the long-term benefits of the surgery require further evaluation. Studies focused on the long-term benefits of adenotonsillectomy are few, often consisting of small sample sizes. One of these studies is Song et al., which sought to investigate the long-term benefits of adenotonsillectomy on behavioral changes in pediatric patients. Twenty children with PSG-documented OSA completed a KOSA-18, the Korean translation of the OSA-18, and ADHD-RS preoperatively and postoperatively. In contrast to the previously discussed studies, the average interval for follow-up was 54.5 months (range 27–98 months). Upon follow-up, the children displayed significantly decreased KOSA-18 and ADHD-RS scores from baseline. While some patients were lost to follow-up, and the small sample size of the study affects its statistical significance, this study provides evidence of the potential long-term benefits of adenotonsillectomy on ADHD symptoms . It is nCollectively, these multiple studies support the role of adenotonsillectomy for OSA as improving ADHD symptoms and cognitive problems . The stuResearch on the benefits of other OSA therapeutic interventions on ADHD symptoms has not been adequately established. One study using continuous positive airway pressure (CPAP) demonstrated significant improvement in attention, working memory, and depressive symptoms in OSA patients . EscobarThe studies have shown the association of ADHD and OSA in children and adolescents. There are reported improvements post-surgery. It is not clear whether there is complete resolution of either disorder into adulthood. One study evaluated the relationship between ADHD and OSA in adults. They evaluated 194 adults, including 62% males, and found OSA in 83% of patients, with 60% having moderate to severe OSA. The screen for ADHD was positive in 19% of patients, and there was no association between the presence of ADHD symptoms and the severity of OSA. Despite the selection bias, this study suggests that there continues to be an association between OSA and ADHD even in adulthood. The study did not evaluate the onset of symptoms of either disorder nor reported how many patients had adenotonsillectomy in childhood .The studies referenced show how adenotonsillectomy may significantly improve the quality of life, learning, and behavioral problems of children with OSA. All levels of SDB from primary snoring to OSA have shown significant short-term improvement in quality of sleep and behavioral disturbance after adenotonsillectomy. Studies evaluating the long-term benefits of adenotonsillectomy have demonstrated its benefits up to 98 months after treatment, but these studies are few and often with small sample sizes. Despite the fact that the large randomized controlled trials showed no neurocognitive differences in children with OSA post-adenotonsillectomy versus watchful waiting in different age groups, clinical practice still favours surgery in children based on favorable parent reports and outcomes. Due to the clinically significant relationship between adenotonsillar hypertrophy, OSA, and ADHD, adenotonsillectomy should be considered as a treatment option for ADHD in pediatric OSA patients. However, it is not yet possible at this stage to predict which populations will benefit from surgery and which will not. Further research must first be conducted to determine if there are any predictors that will help identify those who might benefit from surgery. More research is needed to determine if other OSA treatments such as CPAP use and orthodontics can improve ADHD symptoms. In addition, future research should include larger sample sizes and l For this reason, future research can include larger sample sizes and longer intervals to better understand the long-term benefits of adenotonsillectomy. Finally, research also needs to focus on the childhood origins of adult ADHD and adult OSA.


Introduction: A substantial proportion of college students experience challenges transitioning from pediatrics to the adult healthcare system. Combined internal medicine and pediatrics (Med-Peds) providers are frequently tasked with facilitating this transition and promoting the health and well-being of this population. There is an increasing proportion of college students with Attention Deficit Hyperactivity Disorder (ADHD) in the U.S. This population experiences particularly pronounced challenges navigating the healthcare system and, as a result, often contends with fragmented healthcare. These issues are due to a range of factors, including lack of physician training, education, and resources, as well as a dearth of available research that can inform Med-Peds providers' efforts to support college students with ADHD.Methods: The current study compared a nationally representative sample of U.S. college freshmen with ADHD to those without ADHD on health, academic, and non-academic capacities. This study analyzed population-weighted data from the Cooperative Institutional Research Program’s Freshman Survey.th percentile. Although they reported lower overall academic aspirations, they were more likely to rate themselves in the highest 10th percentile on a range of non-academic capacities.Results: Students with ADHD were more likely to report co-occurring conditions and feelings of depression and overwhelm. They were less likely to report emotional health that was above average or in the highest 10Conclusion: The results from this study can inform efforts among Med-Peds providers seeking to promote the health and well-being of college students with ADHD. Emerging adulthood (ages 18 to 30 years) coincides with the transition from pediatrics to adult healthcare. Combined internal medicine and pediatrics (Med-Peds) providers are tasked with promoting the health and well-being of this population during this transition. Given their role in supporting emerging adults, Med-Peds providers are often confronted with the need to support college students.There is an increasing proportion of college students with attention deficit hyperactivity disorder (ADHD), a developmental condition characterized by inattention, hyperactivity, and/or impulsivity and experienced by at least 4% of the U.S. adult population . The majThe unmet needs of college students with ADHDThe available research on college students with ADHD suggests that they have a range of unmet needs ,4. Of paThis heightened vulnerability is exacerbated by the unmet academic needs of college students with ADHD. Indeed, they experience lower overall achievement , includiThe majority of previous research focuses on these challenges. Individuals with ADHD, however, may possess exceptional skills related to problem-solving, entrepreneurial endeavors, and other areas ,20. As aThe current studyA lack of robust research on college students with ADHD perpetuates shortcomings in healthcare practice and policy for this population ,22. It iThe data for this cross-sectional study come from five separate administrations of the Cooperative Institutional Research Program (CIRP) Freshman Survey, which collects snapshot data on a nationally representative sample of incoming first-year college students in the U.S. Most campuses conduct the survey during orientation, wherein about one hour for survey administration is allowed. Since its inaugural administration in 1966, more than 15 million students attending more than 1100 institutions have completed the survey. The current study is approved by the Higher Education Research Institute, UCLA Graduate School of Education Institutional Review Board (#10-001293).SampleThe analytic sample included first-year, full-time students enrolled at four-year non-profit colleges and universities who completed the CIRP Freshman Survey in 2012, 2014, 2016, 2018, or 2019. Students with ADHD were identified by self-identification through the question, “Do you have any of the following disabilities or medical conditions?” There were seven response options, including ADHD. Population weights were calculated for each survey cohort by considering representation by students’ sex, race or ethnicity, and several characteristics of the institutions they attended, including control , type , and selectivity level  . When apData analysisThe analyses compared first-year full-time self-identified students with ADHD with their peers who did not report ADHD on a select set of demographic characteristics , emotional and mental health indicators , measures of academic achievement , and items related to confidence in their academics  and social skills .Many of the survey items appear as Likert scales, and the analyses for those items typically relied on chi-square statistics to determine whether the ADHD sample significantly differed from the comparison group in the proportion of respondents choosing the same value . For other categorical variables , the analyses compared the proportions in each category between the two samples and relied on chi-square statistics to indicate statistically significant differences. Continuous measures  relied upon t-tests to determine significant differences between the sample means for each group. Of note, because of changes in the SAT scoring system in 2016, we have presented the SAT Math and SAT Reading scores in all years and did not include the SAT Writing scores in our analyses.Several latent constructs were calculated from individual items using item response theory (IRT), which represents a model-based approach for psychometric data analysis. It offers several advantages over traditional factor analysis, which is based on classical test theory. A full discussion of IRT and the corresponding item weights for all latent constructs have been published previously in a technical report . AdditioThe analyses used list-wise deletion for cases with missing data. Due to the high probability of obtaining significant p-values in analyses with large samples, percentage differences of 3% or greater were considered practically significant. All tests were performed at a two-tailed alpha level of 0.01. All analyses were completed in IBM Corp. Released 2021. IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp.With the population weights applied, the total sample was 7,73,1640, with 435,234 students with ADHD (5.6%) and 7,296,405 students without ADHD. ADHD subtypes were not assessed in the current study.Demographic differences are displayed in Table Health differences are displayed in Table Differences in academic aspirations and achievement are displayed in Table Differences in academic and non-academic capacities are displayed in Table The current study represents one of the only nationally representative studies to report the characteristics, strengths, and challenges of freshmen with ADHD entering four-year colleges and universities in the U.S. This research identified several key differences between college students with ADHD and their counterparts on demographic characteristics, health outcomes, and a range of academic and non-academic strengths and challenges. Findings from this research have the potential to inform Med-Peds providers’ efforts to support their diverse emerging adult patients.First, 5.6% of U.S. college students reported having ADHD. This is slightly higher than the reported U.S. prevalence of 4%. This discrepancy may be due to differences between college students and the general adult population and/or differences between ADHD self-identification and diagnosis . It may Consistent with childhood data reported in the National Survey of Children’s Health and the Early Childhood Longitudinal Study ,30, studAlso consistent with previous research , signifiThe mental health challenges identified in this research may be partially attributed to findings from previous research that suggest that college students with disabilities experience discrimination, stigma, and/or marginalization . Given tWe also found significant differences concerning academic characteristics. A higher proportion of students with ADHD reported that obtaining a bachelor’s degree was their career aspiration, and a lower proportion rated themselves in the highest 10 percent on academic ability and drive to achieve. In addition to these findings, fewer students with ADHD reported aspirations for a medical or health-related degree. These findings suggest that higher education is not sufficiently promoting student motivation and drive to achieve among diverse learners upon college entry. Research shows that "growth-oriented" classrooms may be beneficial for enhancing the motivation and success of students with ADHD . In pracFinally, students with ADHD reported several strengths. Significantly more students with ADHD rated themselves in the highest 10 percentile on artistic ability, computer skills, creativity, public-speaking ability, social self-confidence, self-understanding, understanding of others, compassion, and risk-taking relative to their counterparts. This is consistent with previous research that has found college students with ADHD to be more likely to have entrepreneurial intentions .The finding that college students with ADHD have different strengths relative to their counterparts without ADHD suggests several next steps for higher education and healthcare. In education, the findings lend support to the importance of integrating principles of Universal Design in college classrooms. Universal Design is an educational approach that ensures that all types of learners with different strengths have opportunities to display their abilities and knowledge. Concerning healthcare, it would be beneficial for Med-Peds providers to support their college student patients in cultivating self-determination and self-advocacy. During appointments, this might involve empowering patients to engage with support networks in college  through both virtual and in-person settings; providing suggestions for them to employ a range of studying and learning skills, and supporting them in pursuing opportunities that can leverage their unique strengths.The current study had several limitations. First, we relied on self-identification to determine ADHD status. Future research should seek to integrate more robust diagnostic measures that include ADHD subtypes. Second, our study was cross-sectional. Research is needed to investigate students with ADHD over time. Finally, this study reported data from a large, national survey. Future studies with qualitative methodologies can add additional insight and depth to these findings.Findings from the current study provide key insights into college students with ADHD in the U.S. In describing the characteristics, strengths, and challenges of this population, these findings illuminate opportunities for Med-Peds providers to more effectively promote their health and well-being during and after college. In particular, the current study sheds light on targeted areas that require support  and can be further cultivated  to promote the overall health and well-being of college students with ADHD. These next steps are particularly important in the aftermath of the COVID-19 pandemic, which resulted in myriad challenges for college students. Future studies should continue to investigate opportunities to support college students with ADHD.


Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental brain disorders in childhood. Despite extensive researches, the neurobiological mechanism underlying ADHD is still left unveiled. Since the deficit functions, such as attention, have been demonstrated in ADHD, in our present study, based on the oddball P3 task, the corresponding electroencephalogram (EEG) of both healthy controls (HCs) and ADHD children was first collected. And we then not only focused on the event-related potential (ERP) evoked during tasks but also investigated related brain networks. Although an insignificant difference in behavior was found between the HCs and ADHD children, significant electrophysiological differences were found in both ERPs and brain networks. In detail, the dysfunctional attention occurred during the early stage of the designed task; as compared to HCs, the reduced P2 and N2 amplitudes in ADHD children were found, and the atypical information interaction might further underpin such a deficit. On the one hand, when investigating the cortical activity, HCs recruited much stronger brain activity mainly in the temporal and frontal regions, compared to ADHD children; on the other hand, the brain network showed atypical enhanced long-range connectivity between the frontal and occipital lobes but attenuated connectivity among frontal, parietal, and temporal lobes in ADHD children. We hope that the findings in this study may be instructive for the understanding of cognitive processing in children with ADHD. Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders, characterized by age-inappropriate symptoms of inattention, hyperactivity, and impulsivity . It arisThe brain is not only a dynamic system but also a complex network . Of noteIn this study, we hypothesized that the differences in ERP components could reflect on which stage the cognitive deficits in ADHD occurred, and brain network analysis might further uncover the potential network mechanism underlying the task behaviors of ADHD during the designed P3 tasks. Therefore, to better understand how ADHD children recruit cognitive resources to complete the tasks, the ERP and complex network analyses were adopted to investigate the potential differences between HCs and ADHD children.Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria of ADHD diagnosis. Two psychiatrists made these diagnoses independently based on DSM-5 and needed to assess the children in two or more situations. For the control group, age-matched children did not have ADHD or any other psychiatric disorders. Exclusion criteria were neurological disorder, a history of brain injury, mental retardation, comorbid current psychiatric diagnosis, and other neurodevelopmental disorders.A total of 71 children, including 40 ADHD children  = 2.11 years) and 31 HCs  were recruited from Shenzhen Luohu District Maternity and Child Healthcare Hospital, China. ADHD children needed to meet the Our experiment complied with a standard oddball paradigm, as shown in Ω.The EEG data were recorded with a 16-channel Ag/AgCl  electrode cap . All electrodes were positioned according to the 10-20 international system. During online data recording, electrode AFz served as the reference. EEG signals were sampled at 1000 Hz and online bandpass filtered at 0.05-100 Hz. During recording, the impedances of all electrodes were kept below 5 kt-test.Reaction accuracy (RA) was the ratio of the number of correct responses to the total number of stimuli. Reaction time (RT) was measured from the onset of the stimulus to the time for response (pressing the “1” key) as indicated in the recordings. Any potential differences in RA and RT between the HCs and ADHD children were investigated by an independent μV were implemented to preprocess the EEG datasets. In fact, to evoke the clear P3, subjects have to pay all of their attention to the target stimuli, by mentally counting the target number or physically pressing the required button [Multiple preprocessing procedures, including References Electrode Standardization Technique (REST) referencing –29, [1, d button , which wd button . After cd button .t-test.After preprocessing, all artifact-free trials were trial-averaged for each subject. Then, according to previous studies , 33, theThe phase lock value (PLV) was proposed to estimate the phase synchronization among each pair of signals  and has ϕx(t) and ϕy(t), of two given signals, x(t) and y(t), the analytical signal H(t) is defined by the Hilbert transform (HT) as follows:t) and t) are the HT of x(t) and y(t), which are defined as follows:ϕx(t) and ϕy(t), can be computed as follows:To estimate the corresponding instantaneous phases, wplv is the connection weight estimated by PLV, Δt is the sampling interval, and N denotes the sample number.Finally, the PLV value can be estimated as follows:t-test was used to investigate the potential difference in brain architecture between the two groups.Based on the PLV, the adjacency matrix per trial per subject was first calculated. Afterwards, for each subject, the final weighted network, a 16 × 16 adjacency matrix, was acquired by averaging matrices across all trials. Based on these constructed brain networks, an independent t-test.In our present study, when estimating the cortical current density of P2 and N2, the sLORETA (v20171101) was adopted. The cortex has been modeled as a collection of volume elements (voxels) in the digitized atlas provided by the Brain Imaging Center, Montreal Neurological Institute (MNI) . The sLONo significant differences in RA and RT between the two groups were first found in this study, as shown in p < 0.05), as displayed in Thereafter, when investigating the concerned ERP components on electrodes P3 and P4, similar results on both electrodes were found. In detail, no significant difference in P3 was found between the HCs and ADHD children. On the contrary, the amplitudes of both P2 and N2 were reduced in ADHD children, when compared to HCs (p < 0.01) and in temporal, frontal, and occipital regions for N2 (p < 0.01), whose MNI coordinates, T-value, and voxel number are listed in Tables Given the differences in N2 and P2, the differences corresponding to the cortical activity between the two groups were statistically investigated, which are shown in p < 0.05) between the two groups. In detail, relatively stronger functional connectivity  among frontal and occipital lobes but weaker linkages  among frontal, parietal, and temporal regions were found for ADHD children, when compared to HCs.As previously illustrated, ADHD patients usually showed the task deficits in varied substage information processing, such as information integration and neuronal response stages, rather than the whole task period . HoweverBeing exposed to external stimuli, to achieve satisfying task performance, the brain has to receive, integrate, process, and respond to their perceived target stimuli. P3 is the neuronal response to target stimuli after the decision process . Li et aP2 is regarded as the exogenous response, as it is automatically produced regardless of the task or attention variables but is amenable to attentive manipulations, and its latency and amplitude may covary with aspects of selective attention or stimulus encoding processes . TherefoMore evidence underlying these differences would be acquired, when considering the cortical N2 and P2 activity. On the one hand, compared to ADHD children, HCs showed much stronger activity in frontal, cingulate, and central areas for P2. And these cortexes involved in the generation of P2  and abnoGiven that only EEG datasets of several ADHD girls were collected, one possible limitation was that our present study did not take the gender effect into consideration; in the future, the gender-matched ADHD children will be recruited to validate if the gender could affect our present findings. Another might be that the task behaviors were not taken into consideration when selecting reliable task trials; in our future, more detailed individual behaviors would be recorded and then analyzed during preprocessing to further validate our current findings.Although no significant differences in task behavior between the HCs and ADHD children were found, electrophysiological ERP and functional network did uncover the potential cognitive deficits in ADHD children, especially in the early task stage. In particular, significant differences in both N2 and P2 amplitudes and cortical activity, but not in P3, between the two groups were first found. And further, the topological differences showed the attenuated functional connectivity among frontal, parietal, and temporal lobes in ADHD children, which might be compensated by the enhanced long-range frontal-occipital connectivity to accomplish the required tasks.