Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high prevalence, heritability, and heterogeneity. Children with a positive family history of ADHD have a heightened risk of ADHD emergence, persistence, and executive function deficits, with the neural mechanisms having been under investigated. The objective of this study was to investigate working memory-related functional brain activation patterns in children with ADHD (with vs. without positive family histories (ADHD-F vs. ADHD-NF)) and matched typically developing children (TDC). Voxel-based and region of interest analyses were conducted on two-back task-based fMRI data of 362 subjects, including 186, 96, and 80 children in groups of TDC, ADHD-NF, and ADHD-F, respectively. Relative to TDC, both ADHD groups had significantly reduced activation in the left inferior frontal gyrus (IFG). And the ADHD-F group demonstrated a significant positive association of left IFG activation with task reaction time, a negative association of the right IFG with ADHD symptomatology, and a negative association of the IFG activation laterality index with the inattention symptom score. These results suggest that working memory-related functional alterations in bilateral IFGs may play distinct roles in ADHD-F, with the functional underdevelopment of the left IFG significantly informing the onset of ADHD symptoms. Our findings have the potential to assist in tailored diagnoses and targeted interventions in children with ADHD-F. Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a high prevalence rate, ranging between 5.29% and 9.4% for children worldwide ,2,3. CliSeveral studies have associated ADHD with impaired cognitive development and deficits in EF, especially working memory ,18. EF iFamilial risk has been suggested to be an important contributor to impaired EF in ADHD children ,34,35. TPrevious multimodal neuroimaging studies in siblings and parent–child pairs have implicated alterations in prefrontal cortical (PFC) regions associated with familial ADHD. Among these, a voxel-based structural MRI (sMRI) study reported medial and orbito-frontal cortex grey matter volume reductions in ADHD children and their unaffected siblings compared to TDC . A multiThe current study aimed to investigate working memory-related functional brain mechanisms associated with familial vs. nonfamilial ADHD in three matched and independent groups of ADHD-F, ADHD-NF, and TDC from the baseline pool of the Adolescent Brain Cognitive Development (ABCD) study. The ABCD study recruitment replicated the demographic characteristics of the general population, with similar rates of familial vs. non-familial ADHD as shown in other large-scale community-based studies ,14,45,46The participants in the current study were enrolled from the baseline pool of the ABCD study, taking advantage of the large  neuroimaging dataset of this prospective study on brain development and behavior in children and adolescents, recruited from 21 sites across the US ,49. ThisADHD symptomatology in the ABCD study was assessed using the recently validated and computerized Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-5), an interview designed to assess symptomatology across a wide range of psychiatric disorders ,52,53. KAmong those with ADHD, the biological parent history of ADHD was assessed based on the parents’ medical history questionnaire and the Conners Adult ADHD Rating Scale (CAARS) that was administered to parents during the baseline study visit . A childAmong 588 children with ADHD who met the general and group-specific inclusion and exclusion criteria described above, 412 were excluded due to insufficient parental history information; missing sMRI data; neuroimaging artifacts; heavy head motion in fMRI scans; an n-back task (both 0-back and 2-back) performance accuracy of less than 65%; missing fMRI scans, or missing task performance data. Thus, a total of 176 children with ADHD (80 ADHD-F and 96 ADHD-NF) participated in further analyses.A total of 186 children without a diagnosis of ADHD comprised the TDC group. The groups of TDC and ADHD were well matched for age, sex, race, handedness (using the short version of the Edinburgh handedness inventory ), IQ, puBriefly, the participants of this study were obtained from the ABCD study baseline pool. The general inclusion/exclusion criteria were first applied to all the baseline subjects with or without ADHD. The imaging and task performance data quality were examined to further exclude unqualified subjects. Then, among candidates in the group of ADHD, the medical histories of their biological parents were assessed to form the sub-groups of ADHD-F and ADHD-NF and remove subjects with unclear family risk information. Participants in the TDC group were chosen to best match with the group of ADHD for age, sex, race, handedness, IQ, pubertal developmental scale, parental education, and combined income. Further information on the participant characteristics can be found in The CBCL attention problem T-scores are the normalized scores from the attention CBCL syndrome scale, and CBCL ADHD T-scores are the normalized scores from the ADHD CBCL DSM-5 scale . Both thA modified n-back task with a block-based design was used in the ABCD study’s fMRI protocol, which has been detailed previously . The n-bThis block-based design spanned over a set of 2 runs of 8 blocks each, with an equal number of blocks for each condition , as shown in The protocols and parameters of the ABCD study neuroimaging data acquisition have been previously described in detail . BrieflyThree-dimensional T1-weighted sMRI data of each of the 362 subjects were acquired on a 3T scanner  with a 32-channel head coil. The sMRI data were acquired using inversion-prepared RF-spoiled gradient echo pulse sequences, with the following parameters: a voxel size of 1.0 mm isotropic; flip angle = 8°; a TR/TE of 2500/2.88 for Siemens, 6.31/2.9 for Philips, and 2500/2 for GE scanners; FOV = 256 × 256 for the Siemens and GE scanners and 256 × 240 for the Philips scanner.p-values from 0.01 to 0.001, and was therefore considered to be standard in the fMRI studies [For each subject, the fMRI data were preprocessed using the fMRI Expert Analysis Tool (FEAT) from the fMRI Software Library (FSL). Eight initial volumes were excluded for the 4D volumes collected using the Siemens Prisma Fit and Philips scanner machines. Five and sixteen initial volumes were excluded for those collected using the GE–DV25 and GE–DV26, respectively, because these initial volumes made up the pre-scan reference for the 4D images . The fMR studies .The PFC is one of the core components of the brain pathways for working memory processing, and has been frequently reported to be involved in the neurophysiology of ADHD . Voxel-bThe ROI masks were then created by overlapping the activation maps of the TDC group with the automated anatomical labeling atlas version 3 ,72. ThenL and R are the ROI-specific activation t-values in the left and right hemispheres, respectively. The LI is used to study hemispherical patterns of brain activation for a given brain region, where a positive LI value indicates a left-hemisphere-dominated activation pattern, and negative LI value indicates a right-hemisphere-dominated activation pattern.Lateralized activation patterns for cognitive information processes have been frequently observed in fMRI studies in human subjects ,74,75,76Descriptive statistics were performed in SPSS  using an independent samples t-test (for continuous variables) and chi-square analysis (for discrete variables) to study the group differences between TDC vs. ADHD and between ADHD-NF vs. ADHD-F for demographic measures, the pubertal developmental scale, behavioral measures, and task performance , and 2-back mean RT). Levene’s test was used to check for equality of variance.ROI-based activations and the LI were analyzed for group differences among TDC, ADHD-F, and ADHD-NF using a one-way analysis of variance (ANOVA). Aiming to balance the sample sizes of the groups of TDC, ADHD-F, and ADHD-NF, as well as cross-validate the group comparison results, subjects in the TDC group were randomly split into two sub-samples for testing and validation . A post hoc analysis was conducted using an independent samples t-test between each group pair.Understanding the brain–behavioral relationship is critical for searching the neural mechanisms that are associated with cognitive impairments and clinical symptoms in brain disorders . In our There were no significant group differences in demographic variables between TDC and ADHD groups and between ADHD-F and ADHD-NF, as shown in p = 0.027, d = 0.261) compared to ADHD-NF. Group comparisons between ADHD-F and ADHD-NF did not show significant differences in the 0-back and 2-back mean RT and 0-back percentage accuracy.Group comparisons between the TDC and ADHD groups based on task performance measures did not show significant differences . ADHD-F Within the PFC, the SFG medial, middle frontal gyrus (MFG), and IFG triangular showed significant group differences (ADHD vs. TDC and/or ADHD-F vs. ADHD-NF) in the intermediate voxel-based analyses  and the bilateral SFGs , whereas children with ADHD-NF showed significantly reduced mean activation in the bilateral IFGs  and the right SFG   . Althougp = 0.003), the mean activation in the right IFG was significantly negatively correlated with the CBCL ADHD T-score (p = 0.021), and the LI in the IFG was significantly negatively correlated with the KSADS-5 inattention raw score (p = 0.001). In children with ADHD-NF, the LI of the IFG showed a significant positive correlation with the KSADS-5 hyperactivity raw score (p = 0.037); the mean activation in the left SFG showed a significant negative correlation with the CBCL attention problem T-score (p = 0.025)  .The present study examined working memory-related PFC activation and laterality patterns in children with familial vs. non-familial ADHD, in three matched and independent groups of children with ADHD-F, ADHD-NF, and TDC. Relative to TDC, children with ADHD-F showed significantly reduced working memory-related activation in the left IFG, and this reduced left IFG activation was significantly correlated with a longer RT for 2-back task performance in ADHD-F. Relative to the groups of TDC and ADHD-NF, children with ADHD-F also had the trend of a right-hemisphere-shifted LI, which was caused by the significant dysfunction of the left IFG during working memory processing. Bounded superiorly by the inferior frontal sulcus and inferiorly by the lateral sulcus, the IFG forms an integral component of the ventrolateral PFC (VLPFC) . StudiesFurthermore, we found that the mean activation of the right IFG in children with ADHD-F was significantly negatively correlated with their CBCL ADHD T-score with a small effect size, suggesting that the robust right IFG activation in this group links to reduced ADHD symptoms. Meanwhile, the LI of the IFG in the group of ADHD-F was significantly negatively correlated with the KSADS-5 inattention raw score, with a magnitude of small to medium size. The LI is a measure of the spherical weight of brain activation. The lower IFG LI in the group of ADHD-F resulted from a reduced left-side activation, relative to the right-side activation. Therefore, the negative correlation of a lower IFG LI with a higher KSADS-5 inattention score can further suggest a linkage of the left IFG hypoactivation to elevated inattentive symptoms in ADHD-F. In addition, the LI of the IFG showed an unique asymmetrical, right-higher-than-left pattern in the group of ADHD-F. Although the group differences of the LI of the IFG were not significant after Bonferroni corrections, future studies in different samples can further test if such a pattern exists in ADHD-F. Over the decades, the IFG has been implicated in attention processes by being a part of cingulo-frontal–parietal cognitive-attention network, the abnormalities in which have been widely suggested to be responsible factors in childhood ADHD . Our resWhen the family history risk factor was not present, our results indicate that children with ADHD  have distinct patterns of IFG activation, laterality, and their linkages with the cognitive impairment and clinical manifestations of ADHD. Compared to TDC, children with ADHD-NF showed significantly reduced IFG activation of a medium magnitude in both hemispheres, while ADHD-F only showed reduced IFG activation in the left hemisphere, also with a medium magnitude. Existing meta-analyses of task-based fMRIs showing robust hypoactivation in the left IFG in ADHD is consistent with our results from both ADHD groups, but do not show right IFG hypoactivation, as seen in our sample of ADHD-NF ,97. Due In addition, we observed that the ADHD-NF group showed very similar non-negative LIs of IFG activation to those in TDC, and a higher IFG LI was significantly correlated with an increased KSADS-5 hyperactivity raw score in ADHD-NF with a small effect. Given that the activations in the bilateral IFGs were both significantly decreased in ADHD-NF, the maintenance of a non-negative IFG LI and its association with increased KSADS-5 hyperactivity may both be directly contributed to by the significantly reduced right IFG activation. Again, further research is needed to identify if this is a critical neural marker of all types of ADHD-NF. Putting together all the results of the IFG, the distinct patterns of working memory-related IFG activation and laterality in children with ADHD-F vs. ADHD-NF may significantly imply the unique family heritage risk factor-related neural substrate of ADHD in children. These findings therefore have the potential to serve as biomarkers for more tailored diagnoses and targeted treatments and interventions.Compared to TDC, children with ADHD-F also showed significantly reduced activation in the bilateral SFGs, whereas children with ADHD-NF only showed significantly reduced activation in the right SFG. In contrast to the significant differences in the IFG, these differences had small effect size. And in children with ADHD-NF, the mean activation in the left SFG showed a significant negative correlation with the CBCL attention problem T-score, also with small magnitude. The SFG is involved in various EFs of planning, inhibition, abstract reasoning, and working memory by being a part of the dorsolateral PFC and its connections to a multitude of subcortical and cortical brain regions, such as the basal ganglia, hippocampus, thalamus, parietal, and temporal areas ,99. ConsThere are certain limitations to the current study that need to be considered. Our study included both male and female subjects. Although it is unestablished yet whether the neurofunctional basis of familial ADHD has sex differences, differences in symptomatic and comorbidity profiles have previously been observed in clinical studies . To partOn the basis of our findings, another future study direction can focus on testing treatment efficacy on left IFG functional improvement in children with ADHD-F. Previous fMRI studies have reported the normalization of IFG activation during a range of EF tasks in youth with ADHD after the administration of methylphenidate (MPH) . One stuOur study on matched and independent groups of ADHD-F, ADHD-NF, and TDC found that children with ADHD-F have some unique working memory processing-related activation and laterality patterns in the IFG, when compared to the cohorts of TDC and ADHD-NF. Specifically, children with ADHD-F had significantly reduced working memory-related activation in the left IFG, which was significantly correlated with longer RTs for 2-back task performance. Children with ADHD-F also had a trend of right-hemisphere-shifted LIs, caused by the significant dysfunction of the left IFG during working memory processing. Meanwhile, the activation of the right IFG in children with ADHD-F was significantly negatively correlated with their CBCL ADHD T-scores, and the LI of the IFG was significantly negatively correlated with their KSADS-5 inattention raw scores. These unique patterns suggest that functional underdevelopment associated with the left IFG may serve as a distinct role in working memory impairment and symptom onset in ADHD-F. These findings have the potential to indicate critical biomarkers of ADHD-F and aid in the development of more tailored diagnostic and treatment strategies in children with ADHD.


Hyperfocus symptom is the intense concentration on a certain object. It is a common but often overlooked symptom in those with attention-deficit/hyperactivity disorder (ADHD). Hyperfocus disrupts attention control and results in a focus on inappropriate behaviors. It allows individuals to focus on internet use and make them use internet excessively. This excessive internet use can lead to an addiction. This study investigated the status of IA and hyperfocus, the mediation effect of hyperfocus in relation to IA, and the relationship between ADHD subtypes and hyperfocus in those with ADHD symptoms.This web-based cross-sectional study included 3,500 Japanese adults who completed internet-based questionnaires, which included the Adult ADHD Self-Report Scale (ASRS), Internet Addiction Test (IAT), and Hyperfocus Scale (HFS) to assess ADHD symptoms, internet dependence, and hyperfocus symptoms, respectively. The mediating role of HFS in the relationship between ASRS and IAT was assessed by mediation analysis. To analyze the relationship between hyperfocus symptoms and ADHD subtypes, we compared the correlation of HFS with the Inattention and Hyperactive Scores of ASRS.p < 0.001) and higher HFS scores (p < 0.001). Mediation analysis and bootstrap testing showed that HFS significantly mediated the association between ASRS and IAT. Analyses of ADHD subtypes demonstrated that HFS was significantly correlated with the Inattention  and Hyperactive  Scores. The correlation between HFS and the Inattention Score was significantly higher than that between HFS and the Hyperactive Score (p < 0.001).ADHD traits were associated with higher IAT scores (Our findings suggest that hyperfocus may play an important role in addictive behavior in ADHD as a manifestation of attentional control malfunction. Attention-deficit/hyperactivity disorder (ADHD) is a chronic lifelong condition that is mainly characterized by symptoms such as inattention, hyperactivity, and impulsivity . ADHD isAmong the comorbid conditions of ADHD, “hyperfocus” symptom, an experience of very intense concentration or “overconcentration”, has been recognized by clinical practitioners . This coAlthough hyperfocus may sometimes improve abilities in ADHD individuals, such as productivity , it can These features, from concentration on inadequate behavior to social dysfunction, are similar to those in people with behavioral addiction , which iN = 3,500) to investigate the (1) status of IA and hyperfocus in people with ADHD symptoms, (2) mediation effect of hyperfocus in relation to IA in people with ADHD symptoms, and (3) relationship between the subtype of ADHD and hyperfocus.Despite the findings on hyperfocus symptom and IA in ADHD, there are still no reports, to the best of our knowledge, on the relationship between hyperfocus symptoms and IA in people with ADHD. In this study, we conducted a web-based questionnaire survey of a large sample of Japanese adults  to evaluate ADHD symptoms, the Internet Addiction Test (IAT) to measure the degree of dependence on the Internet, and the Hyperfocus Scale (HFS) to estimate the tendency to hyperfocus.Participants provided answers related to their gender, age, and birthplace.In this study, we used the ASRS to screen for possible ADHD and determine the severity of the ADHD trait. ASRS was developed by the World Health Organization and has been widely used in epidemiological studies on ADHD –29. The IAT is a questionnaire based on the Internet Addiction Diagnostic Questionnaire, which is a list of eight addiction criteria to diagnose problematic internet use developed by Young . IAT conHFS is a questionnaire to measure the tendency to hyperfocus , 17. It t-tests for continuous variables and chi-square tests for categorical variables. Regarding the normality of the continuous data, if the sample size is large enough, the distribution of differences estimated by the central limit theorem approaches a normal distribution even if the population is not normally distributed. Therefore, it was determined that there would be no problem to perform the parametric test . The correlation comparisons were performed using R , with thThe average IAT score was significantly higher in the possible ADHD group than in the non-ADHD group. In addition, the percentage of those with ≥40 points, indicating possible IA, was 85.3% in the possible ADHD group and 34.3% in the non-ADHD group. Furthermore, the percentage of those with a score of ≥70, indicating severe addictive behaviors, was 28.4% in the possible ADHD group and 1.9% in the non-ADHD group.p < 0.001). The regression analysis also indicated a significant relationship between the ASRS and HFS scores . Furthermore, we added the mediating variable HFS to the equation and performed regression to examine whether HFS mediates the relationship between ASRS and IAT. In this multiple regression analysis, the path between Hyperfocus and internet addiction, examined by regressing the IAT trend on HFS, indicated a significant positive association between these two variables . This indicated that the association between ASRS and IAT was significantly mediated by HFS. The direct effect of the regression analysis, with HFS as a mediating variable, remained significant, indicating that this was a partially mediated model. A bootstrap test showed that the indirect effect was significant. These results indicated that the relationship between ASRS and IAT was partially mediated by HFS.The model tested in this study and its results are shown in p < 0.001; 4.40, p < 0.001, respectively) and with HFS scores . The mediating effect of HFS to these relationships were also shown significant .The regression analysis and mediation analysis were also applied to the Inattention Score and the Hyperactive Score as the ASRS to IAT and HFS. Both the Inattention Score and the Hyperactive Score were shown to have significant relationship with IAT scores  and between HFS and the Hyperactive Score , with the relationship between HFS and Inattention Score showing a significantly higher correlation coefficient , suggesting that the hyperfocus symptom is more highly correlated with the inattention symptom than with the hyperactive symptom.Pearson correlation showed significant linear relationships between HFS and the Inattention Score (The present study showed that the (1) ADHD group was significantly more likely to have IA and hyperfocus tendencies, consistent with previous studies , 16, (2)This study included a large sample through an internet survey. Generally, the prevalence of possible ADHD in this study (5.4%) did not deviate from the ADHD prevalence in previous studies . In addiOur findings suggest that hyperfocus plays a significant role in the mechanism of progression from ADHD to IA. This study confirmed a high incidence of IA among people with ADHD as previously reported –44. A stOur findings suggest that hyperfocus is associated with IA in individuals with ADHD, while inattention has been shown to be related to IA , 46. HypThere are some limitations to this study. First, possible ADHD was determined by the cutoff score of the ASRS without structured clinical interviews. Second, ASRS was used for people aged < 18 years in this study, although the questionnaire is designed for people aged ≥18 years. Third, because of the nature of an internet survey, the response rate could not be calculated . Fourth,The present study revealed that hyperfocus, along with ADHD tendencies, was significantly associated with IA. Although hyperfocus is often overlooked as one of the symptoms of ADHD, it may play an important role in the development of IA. Furthermore, hyperfocus symptoms were more common in inattentive types of ADHD as a manifestation of malfunctioning attentional control. Our findings shed light on the relationships between hyperfocus symptoms and addictive behaviors in ADHD.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethical Committee of Tokyo Medical and Dental University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas, took part in drafting, revising or critically reviewing the article, gave final approval of the version to be published, have agreed on the journal to which the article has been submitted, and agree to be accountable for all aspects of the work.


What percentage of children with parent-reported attention-deficit/hyperactivity disorder (ADHD) receive treatment?In this cross-sectional study of 11 723 children aged 9 and 10 years, 12.9% of children with parent-reported ADHD were currently receiving ADHD medications, including 15.7% of boys, 7.0% of girls, 14.8% of White children, 9.4% of Black children, 32.3% of children of parents without a high school education, and 11.5% of children whose parents had a bachelor’s degree. Approximately 26.2% of children with parent-reported ADHD had ever received outpatient mental health care.This study suggests that pervasive gaps exist in the treatment of children, especially girls, with parent-reported ADHD. Characterizing the extent and pattern of unmet needs for treatment of children with attention-deficit/hyperactivity disorder (ADHD) could help target efforts to improve access to ADHD medications and outpatient mental health care.To describe current ADHD medication use and lifetime outpatient mental health care among a large national sample of children with ADHD.Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for current ADHD. Statistical analysis was performed from March 23, 2022, to March 10, 2023.This study uses cross-sectional survey data from the first wave of the Adolescent Brain and Cognitive Development Study (n = 11 723), conducted from June 1, 2016, to October 15, 2018, among 1206 school children aged 9 and 10 years who met parent-reported Current ADHD medications including stimulants and nonstimulants, lifetime outpatient mental health care, or either treatment. Weighted results are reported.Among a sample of 11 723 children, 1206 had parent-reported ADHD , 149 (12.9%) were currently receiving ADHD medications. Children receiving ADHD medications included a significantly higher percentage of boys (15.7% [121 of 826]) than girls (7.0% [28 of 108]), White children (14.8% [104 of 759]) than Black children (9.4% [22 of 206]), children of parents without a high school education (32.2% [9 of 36]) than of parents with a bachelor’s degree or higher (11.5% [84 of 715]), and children with the combined subtype of ADHD (17.0% [83 of 505]) than with the inattentive subtype (9.5% [49 of 523]). Approximately 26.2% of children (301 of 1206) with parent-reported ADHD had ever received outpatient mental health care. Children receiving outpatient mental health care included a significantly higher percentage of children whose parents had a high school education (36.2% [29 of 90]) or some college (31.0% [109 of 364]) than a bachelor’s degree or higher (21.3% [153 of 715]), children with family incomes of less than $25 000 (36.5% [66 of 176]) or $25 000 to $49 999 (27.7% [47 of 174]) than $75 000 or more (20.1% [125 of 599]), and children with the combined subtype of ADHD (33.6% [166 of 505]) than with the predominantly inattentive subtype (20.0% [101 of 523]) or the hyperactive-impulsive subtype (22.4% [34 of 178]) of ADHD.This cross-sectional study of children with parent-reported ADHD suggests that most were not receiving ADHD medications and had never received outpatient mental health care. Gaps in treatment, which were not directly associated with socioeconomic disadvantage, underscore the challenges of improving communication and access to outpatient mental health care for children with ADHD. This cross-sectional study uses data from the Adolescent Brain and Cognitive Development Study to describe current attention-deficit/hyperactivity disorder (ADHD) medication use and lifetime outpatient mental health care among a large national sample of children with ADHD. However, a focus on the increasing numbers of children treated for ADHD does not give a sense of what fraction of children in the population with ADHD receive treatment. To estimate the unmet need for ADHD treatment, it is necessary to ascertain children from outside of clinical settings, evaluate them for ADHD, and assess their treatment use.Reports of increasing rates of children treated with medications for ADHD have fueled public17 to receive ADHD medications, as are children from ethnic and racial minority groups compared with non-Hispanic White  children.19 Although some research further suggests that children with ADHD who are from lower-income families compared with higher-income families are less likely to receive ADHD medications,22 other studies have reported the reverse.24 In a school-based sample, children with the combined subtype of ADHD were more likely than those with either the inattentive or hyperactive-impulsive subtype of ADHD to receive stimulants.25 One study found that hyperactive symptoms were associated with ADHD medication use,26 while another found that severity of inattention and hyperactivity-impulsivity symptoms had similar correlations with ADHD medication treatment.27Beyond estimating the overall proportion of children with ADHD who receive treatment, it is important to understand which children with ADHD are more or less likely to receive treatment. Characterizing treatment patterns could guide efforts to improve mental health care access for underserved groups. Prior studies have reported that, among children with ADHD, girls are less likely than boysDiagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) ADHD criteria. We estimate the percentages of these children who were currently treated with ADHD medications, had ever received outpatient mental health care, or both. We hypothesized that most children with parent-reported ADHD would not be currently receiving ADHD medications or have never received outpatient mental health care and that treatment gaps would be greater for girls than boys and for children from families of lower socioeconomic status.We characterize treatment patterns among a cohort of US school children aged 9 and 10 years whose parents reported that their children met 28 A stratified probability sample of schools was selected from each site to approximate national representativeness with respect to sex, race and ethnicity, and socioeconomic status. Survey weights were developed to further balance the sample with respect to basic sociodemographic characteristics, including child age, sex, and race and ethnicity, as well as household family income, family type (married parents or single parent), household size, parent’s work status, and US Census region.29 Parent and child recruitment within schools was voluntary and therefore self-selected, and response rates were not available to incorporate into the sampling weights. As a consequence, the sample is not representative of the selected school systems or the nation.30 The institutional review board of the University of California, San Diego gave centralized approval for data collection, and each individual study site obtained approval from their local institutional review board. All parents and caregivers provided written informed consent, and the children provided verbal assent. This report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for reporting cross-sectional studies.Analyses were performed with baseline data from the Adolescent Brain Cognitive Development (ABCD) Study of 11 723 children ages 9 and 10 recruited from primary schools and public school systems at 21 sites nationwide from June 1, 2016, to October 15, 2018. By recruiting from demographically, geographically, and socioeconomically diverse school systems, the ABCD Study sought a sample reflecting the US demographic composition.Inclusion criteria were age 9.00 to 10.99 years and attendance at the sampled school. In brief, exclusion criteria included not being fluent in English; neither parent being fluent in English or Spanish; a major medical or neurologic condition; gestational age less than 28 weeks or birth weight less than 1200 g; a contraindication to magnetic resonance image scanning; a history of traumatic brain injury; a diagnosis of moderate or severe autism spectrum disorder, intellectual disability, or schizophrenia; or a substance use disorder.31 Family income was assessed with General Social Survey items,32 and the language predominantly spoken to the child by their parent or guardian was coded as English vs other.Sociodemographic characteristics including age, birth sex, parent-reported race and ethnicity, parental marital status, and highest parental educational level were derived from the PhenX toolkit.DSM-5 (KSADS).34 Following DSM-5 criteria, respondents were classified by current ADHD symptoms as combined, predominantly inattentive, or predominantly hyperactive or impulsive presentations. Prior research demonstrates 90% agreement between parent and clinician ADHD current diagnoses from the computerized KSADS (Cohen κ = 0.79).34Current mental health disorders were assessed with the parent version of the self-administered computerized Kiddie Schedule for Affective Disorders and Schizophrenia for Some analysis involved comparing treatment of children with ADHD with or without the following comorbid conditions: disruptive behavior disorders ; anxiety  or mood  disorders; and obsessive-compulsive disorder.35 Children with psychotic disorders, bipolar disorder, and IQ less than 70 36 were also excluded. Requirement of teacher ratings follows the DSM-5 criteria of symptoms in 2 or more settings.37In a secondary analysis (n = 4594), the ADHD definition was narrowed to require parent-reported ADHD and a T score of 65 or more on the Brief Problem Monitor teacher-version attention scale.Parents were asked what medications their children had taken in the past 2 weeks. Medications for ADHD included stimulants  and nonstimulants . Parents were also asked whether their child had ever received outpatient mental health care. Three nonmutually exclusive groups were considered: ADHD medications, any outpatient mental health care, or either (“any treatment”).Statistical analysis was performed from March 23, 2022, to March 10, 2023. First, the background characteristics of children with or without parent-reported ADHD were evaluated. Second, among children with parent-reported ADHD, the percentages of children with any treatment were determined overall and stratified by sociodemographic and diagnostic characteristics. A series of unadjusted logistic regressions was performed with each treatment measure as dependent variables to generate odds ratios (ORs) with 95% CIs. Corresponding logistic regressions were adjusted for ADHD subtype and comorbid psychiatric disorders. Third, the percentages of children with ADHD currently receiving stimulant medications or other ADHD medications were determined stratified by background characteristics. Fourth, among children who met the more restricted ADHD criteria involving parent and teacher ratings, ADHD treatment rates were determined overall. For these analyses, nonresponse inverse probability weights were created using logistic regression of the Brief Problem Monitor teacher response (present or absent) as the dependent variable associated with child sociodemographic variables (eTable in Compared with children without parent-reported ADHD (n = 10 517), children with parent-reported ADHD (n = 1206) included a larger percentage of boys (68.2% [826 of 1206] vs 49.4% [5295 of 10 517]), White children (62.2% [759 of 1206] vs 55.3% [6234 of 10 517]), Black children (15.2% [206 of 1206] vs 13.6% [1614 of 10 517]), and children whose parents had never married (16.8% [175 of 1206] vs 14.2% [1261 of 10 517]) . ChildreApproximately 10.1% (n = 1206) of children had parent-reported ADHD. Among this group, 149 (12.9%) were currently receiving ADHD medications, 301 (26.2%) had ever received outpatient mental health care, and 400 (34.8%) had received either . Among cChildren receiving ADHD medications included a significantly higher percentage of boys (15.7% [121 of 826]) than girls (7.0% [28 of 108]), White children (14.8% [104 of 759]) than Black children (9.4% [22 of 206]), children of parents without a high school education (9 of 36 [32.2%]) than of parents with a bachelor’s degree or higher (11.5% [84 of 715]) , and chiAmong those meeting the more stringent criteria of both parent-reported and teacher-reported ADHD , 15 (12.3%) were currently receiving ADHD medications, 35 (33.7%) had ever received outpatient mental health care, and 44 (39.4%) had received either service.In the parent-reported ADHD sample, the odds of any mental health care did not significantly vary by child sex or race and ethnicity or by parental marital status . HoweverIn unadjusted analyses, current ADHD medication use was significantly more common among boys than girls  and among children whose parents did not have a high school education than children of parents with a bachelor’s degree , but it was less common among Black than White children  . Lower pChildren with parented-reported inattentive ADHD were significantly less likely than those with the combined subtype to have received all 3 treatment outcomes . ChildreApproximately 8.0% of children (n = 97) with parent-reported ADHD were receiving stimulants, and 5.1% (n = 53) were receiving atomoxetine, guanfacine, or clonidine . StimulaIn this cohort of children with parent-reported ADHD, 26.2% had ever received outpatient mental health care, 12.9% were currently receiving ADHD medications, and 34.8% had received either treatment. Contrary to our expectations, children whose parents had higher incomes and a higher educational level tended to be less likely than those whose parents had lower incomes and a lower educational level to have received outpatient mental health care. Medication treatment for children with parent-reported ADHD was also more common among children whose parents had a lower rather than higher educational level. Use of ADHD medications was more common among boys than girls, White children than Black children, and children with combined rather than inattentive ADHD.38 Because most US children receive an annual well-child visit,39 opportunities exist to improve ADHD detection in primary care. However, because no screening tool has sufficient accuracy for stand-alone use,40 primary care clinicians should consider multiple informants when evaluating children for ADHD. Local shortages of child mental health clinicians also hinder care access in many communities.41Low treatment rates among children with parent-reported ADHD suggest a need to increase mental health service availability; enhance knowledge of ADHD symptoms among parents, teachers, and primary care clinicians; and develop accessible care pathways.44 This discrepancy is likely associated with ascertainment bias. Unlike the current analysis, the CDC reports were based on parent-reported treatment of children who had received a clinical ADHD diagnosis. By contrast, the current treatment rates in our study more closely align with earlier epidemiologic studies.45These ADHD treatment rates contrast with CDC reports that most children with ADHD receive treatment.17 boys were more likely than girls to receive ADHD medications. A common explanation for this sex-based difference is that, because boys tend to have more disruptive clinical presentations than girls, they have a higher likelihood of referral for evaluation.46 However, we found that boys compared with girls had more than twice the odds of receiving ADHD medications after adjustment for ADHD subtype, comorbid disruptive behavior disorders, and other common psychiatric comorbid conditions. Other factors, such as diagnostic biases favoring boys vs girls,47 greater prevalence of educational problems in boys compared with girls,14 or higher levels of physical aggression in boys than in girls with ADHD48 might be associated with greater ADHD medication use among boys than girls.In keeping with prior research,49 or have greater apprehension concerning the stigma of receiving treatment or the long-term effects of stimulant therapy.50Children with parent-reported ADHD from families with the highest income level were less likely than those from families with the lowest income level to receive outpatient mental health care. It is unclear what inhibited highly resourced families from seeking treatment. Compared with families with lower income, those with higher income might more frequently rely on nontraditional strategies, such as tutoring, exercise, sports programs, and healthy eating,51 Black children were specifically less likely than White children to receive stimulants, while this difference was less pronounced for nonstimulants. Because nonstimulant medications tend to yield smaller therapeutic effects than stimulants,53 all parents should be provided with relevant clinical information to make informed ADHD medication choices. Prescriber implicit bias might be associated with disparities in stimulant prescribing.54 Strong population-based racial and ethnic gradients exist in prescriptions for stimulants and other controlled substances, with the highest rates in majority-White areas.55 As a result of structural racism,56 Black parents’ perspectives might further influence ADHD management decisions through mistrust in clinicians and concerns over safety and efficacy of stimulants.57 Physician efforts to recognize and manage their own implicit biases,58 together with patient-centered clinical approaches that promote shared decision-making, including open explorations of Black parents’ knowledge, attitudes, and beliefs concerning ADHD and its management, might help reduce these treatment disparities.Black children compared with White children with parent-reported ADHD were significantly less likely to receive ADHD medications. This finding is broadly consistent with prior research.60 In a discrete choice study of parents of young children with medication-naive ADHD, medication-avoidant parents had a significantly higher educational level than more outcome-oriented parents who favored the use of ADHD medication.61 As a group, parents with a lower educational level may be more focused on improving their child’s functioning than parents with a higher educational level who may be more concerned with medication-associated risks and might therefore be more motivated to implement parent-based interventions.Children whose parents had the lowest educational level were most likely to receive ADHD medications. Earlier research has reported an association between low parental educational level and ADHD medication prescription.26 but it supports the hypothesis that children with more severe or complex presentations are more likely to receive ADHD medications. Common psychiatric comorbid conditions were not significantly associated with increased likelihood of ADHD medication use. This finding suggests that community ADHD medication prescribing practices are appropriately and specifically focused on ADHD symptoms. In evaluating the finding that 57.0% of all children who received ADHD medications did not have parent-reported ADHD, it is important to consider the possibility of symptom response.Children with parent-reported combined ADHD tended to be more likely than those with either inattentive or hyperactive-impulsive ADHD to receive ADHD medications. This pattern contrasts with a previous report that hyperactivity is specifically associated with ADHD medication treatment,62Among children with parent-reported ADHD, nonstimulant ADHD medications were significantly more commonly prescribed to children with combined ADHD than inattentive ADHD and were more commonly prescribed to those with than without comorbid disruptive behavior disorders. Although there is some evidence to support the use of guanfacine and atomoxetine for disruptive behavior disorders, psychostimulants have more evidence for effectiveness, and there is little evidence of the effectiveness of clonidine.30 and stimulant prescriptions have demonstrated substantial regional variation.23 Second, treatment and medication assessments were based on parent reports without confirmatory administrative or prescription data, and no information was available concerning medication dose, duration, or prescriber. Because many children with ADHD stop and start stimulants,63 measuring medication use in the past 2 weeks will miss children who recently stopped medications. Third, information was also not available concerning the clinical focus of the lifetime child mental health care, whether it occurred before or after the onset of ADHD, or whether it included evidence-based treatments, such as parent training in child behavioral management62 for ADHD. Parents may also vary in how they define what constitutes outpatient mental health care. Fourth, the study was limited to a narrow age range, and treatment patterns vary by patient age. Fifth, eligibility criteria for the ABCD Study, which include English fluency, gestational age, birth weight, major medical conditions, and other factors, as well as imperfections in the survey weights, limit the generalizability of the study findings. Sixth, parent-reported ADHD may have excluded children who, due to active interventions, did not meet ADHD criteria.This study has several limitations. First, although the ABCD Study involved multistage probability sampling of schools and survey weights were applied, the study did not involve nationally representative sampling,44 Contrary to our expectations, children with ADHD from families with a lower educational level and lower incomes tended to be more likely than those with a higher educational level and higher incomes to have received outpatient mental health treatment. These patterns suggest that attitudinal rather than socioeconomic factors often impede the flow of children with ADHD into treatment.In this cross-sectional study of children with parent-reported ADHD, 26.2% had ever received outpatient mental health care, and 15.7% of boys and 7.0% of girls were currently receiving ADHD medications. These findings contrast with the view that most children with ADHD receive treatment for their symptoms.It would be naive to assume that all children with parent-reported ADHD need or would benefit from treatment. Parent reports from research diagnostic interviews do not substitute for a thorough clinical assessment involving a patient history, clinical child interview and observation, physical examination, teacher reports, and validated rating scales. Nevertheless, the findings provide a sense of the scale and distribution of children with parent-reported ADHD not receiving treatment. As such, they highlight the importance of developing strategies to increase clinical recognition of children with ADHD, especially girls, and increasing access to acceptable treatments.


Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental polygenic disorder that affects more than 5% of children and adolescents around the world. Genetic and environmental factors play important roles in ADHD etiology, which leads to a wide range of clinical outcomes and biological phenotypes across the population. Brain maturation delays of a 4-year lag are commonly found in patients, when compared to controls of the same age. Possible differences in cellular growth rates might reflect the clinical observations in ADHD patients. However, the cellular mechanisms are still not elucidated. To test this hypothesis, we analysed the proliferation of induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs) derived from male children and adolescents diagnosed with ADHD and with genetic predisposition to it (assessed using polygenic risk scores), as well as their respective matched controls. In the current pilot study, it was noticeable that NSCs from the ADHD group proliferate less than controls, while no differences were seen at the iPSC developmental stage. Our results from two distinct proliferation methods indicate that the functional and structural delays found in patients might be associated with these in vitro phenotypic differences, but start at a distinct neurodevelopmental stage. These findings are the first ones in the field of disease modelling of ADHD and might be crucial to better understand the pathophysiology of this disorder.The online version contains supplementary material available at 10.1007/s00702-023-02600-1. Inclusion and exclusion criteria were described in previous publications of our group  from ADHD patients and healthy controls were collected and reprogrammed into iPSCs using Sendai virus transduction. Quality control (QC) from generated iPSCs was performed as reported in previous publications  was investigated, using ACTB and C5orf18 (REEP5) as reference genes. The technical procedure was performed as described in Grossmann et al. and Yde Ohki et al., and the primers used are available in Supplementary Table 2 . Details about the primary and secondary antibodies used in this protocol may be found in Supplementary Table 3.™ X-100, 1% BSA in PBS) was added to the wells, which were incubated for 30 min at RT.Once the NSCs reached around 90–100% of confluence in 96 wells, the media was removed, and the cells were carefully washed with PBS 1X. Paraformaldehyde (PFA) at 4% was added and cells were incubated for 20 min at room temperature (RT). After incubation, PFA was aspirated properly discarded in special waste and the wells were rinsed 3 times with PBS 1X for 5 min each. After the last washing step, blocking buffer  was added to each well. Images were subsequently acquired using an IX81 microscope (Olympus) and the cellSens Dimension software (version 3.1) (Olympus).® real-time cell analysis (RTCA) system (ACEA Biosciences).Human iPSCs that were generated and checked for QC in our study were tested in xCELLigence. Real-time impedance-based cell proliferation of generated iPSCs and NSC was measured using the xCELLigence® BIO) coated with Vitronectin 5 μg/mL (Gibco™) beforehand and stored overnight at 4 °C. Baseline was measured during 1 min after temperature equilibration with Essential 8™ Flex medium  for 30 min at 37 °C and 5% CO2. iPSCs were counted using Countess™ II FL Automated Cell Counter (Thermo Fisher Scientific™) and seeded at a concentration of 25′000 cells/well. For NSCs, 15′000 cells/well were seeded onto Geltrex (Gibco™) -coated E-96 plates, diluted 1:100 in DMEM/F12 (Gibco™), and cultivated in Neural Expansion Media .Each iPSC line was seeded in 12 replicates onto E-96 plates  and the graph was generated using the GraphPad Prism software (version 9.0).Growth rate was determined according to a Malthusian growth model using a least squares method to fit the non-linear regression curve on the cell index (CI) data during the exponential growth period defined from 24 h to CImax set as the first peak followed by 5 steps decline . Outliers between the replicates were removed according to the interquartile range (IQR) method. For iPSCs, at least 9 replicates per experiment were analysed, while for NSCs, at least 3 replicates were analysed in two independent experiments each. Mean of the wells were plotted per experiment.™)). On the other hand, NSCs were seeded at a final concentration of 15′000 cells/well onto Geltrex-coated 96 wells (1:100 dilution in DMEM/F12). Cells were seeded in triplicates on 8 different plates for each time point  in E8 Flex or NEM. For both iPSCs and NSCs, the media were completely refreshed every other day.Using the same cell concentrations per well as in xCELLigence, 25′000 iPSCs /well were seeded onto Vitronectin-coated 96-well plates  considered as blank. Each experiment was performed in triplicates, which were verified for outliers at each time-point by the z-score cleaning method. For iPSCs, three independent experiments were performed, in which the slope of the log2 transformed curve generated from 24 h to maximal absorbance was considered after applying a linear regression model . For NSCs, two independent experiments were performed and growth rates were computed using a linear regression from 24 h to maximal absorbance (GraphPad Prism software (version 9.0)).At each time-point 10 µL of WST-1 tetrazolium salt (Sigma) was added in each well and the plate was incubated for 4 h in a humidified atmosphere at 37 °C, 5% COFor cell viability analysis, the mean of absorbance values from 96 and 114 h post-seeding (hps) per experiment were plotted.t tests with Welch’s correction were applied. On the other hand, two-tailed unpaired nonparametric Mann–Whitney tests were applied for data that were not normally distributed. A p value of at least 0.05 was considered significant.Statistical tests and graphs were performed using the GraphPad Prism software (version 9.0). When data were normally distributed but with unequal standard deviations, two-tailed unpaired In the current pilot study, we investigated only cell lines derived from males, in which the patients were those with positive PRS z-score for ADHD, while the controls had negative PRS for ADHD genetic predisposition (See Supplementary Table 1). Individual growth rates for each iPSC line are depicted in Fig. t test with Welch’s correction, t(18.23) = 0.2514, p = 0.8043), while WST-1 assays have confirmed the non-significant finding . On the other hand, growth rates from ADHD NSCs were significantly lower than controls in the real-time impedance method xCELLigence  = 2.187, p = 0.0495), as well as for the WST-1 method  = 2.846, p = 0.0113).In the results for iPSC proliferation, we observed no significant differences in growth rates between ADHD and control groups measured using the xCELLigence  = 2.755, p = 0.0123) and 114 h post-seeding . At both time-points, ADHD NSCs seem to show lower metabolic rates than controls. Individual absorbance values are presented in Fig. When NSC WST-1 experiments were analysed at each time-point separately, differences in the measurements were found for the latest time-points: 96 . Papes et al. have shown reduced proliferation of iPSC-derived PTHS NSCs, while no differences were seen between the proliferation of PTHS and control iPSCs  patients were previously assessed. In this case, NSC from patients were proliferating more than controls, which might be contributing to the macrocephaly clinically observed in ASD . However, the use of iPSC-derived 3D brain organoids would be helpful to study in the future the ADHD pathophysiology in a more complex and heterogeneous scenario.Here, we report a preliminary novel finding that might be of interest to the ADHD field. Using iPSC-derived neural cell lines allows us to maintain the genetic background of ADHD patients, while reproducing ex vivo cellular phenotypes. Despite the validity and strong contribution of animal models to ADHD research, the iPSC technology offers an advantageous alternative to the use of these models, which would not be able to represent the human polygenic profile of ADHD and its symptoms in a high fidelity manner, as well as human commercially available neural cell lines  for more gender balanced and highly powered study.Regarding age differences, participants from ADHD and control groups were not perfectly age matched, which could be considered a limitation. Up to this date, as multiple studies have shown, the irreversibility of age-related epigenetic identity from somatic cells through the reprogramming process is still debatable, as reviewed by  are being assessed in the current preliminary study. Considering the fact that this disorder is a spectrum, patients with low genetic liability to ADHD must also be investigated, as well as respective controls with high genetic predisposition. Balancing ADHD and control groups in this context would also be essential to understand the interplay between genetic and environmental risk factors in this disorder.Regarding techniques, here we used two different methodologies to assess proliferation. Although WST-1 assays can be performed in distinct time-points to analyse how metabolically active cells are over time based on metabolism  in viable cells, indirectly measuring mitochondrial activity Below is the link to the electronic supplementary material.


This study was performed to provide an updated systematic review of herbal medicines and phytochemicals used for treatment of the pediatric patients with attention- deficit/hyperactivity disorder (ADHD). International electronic databases, including Scopus, PubMed, ScienceDirect, and Google Scholar were investigated from 1st January 2000 to late October 2021. Interventional studies published in English language, including randomized controlled trials (RCTs) or open-label clinical studies, which evaluated the effect of herbal medicines and phytochemicals on pediatric ADHD were included in this review.Ginkgo biloba L. and Pycnogenol; mainly inconclusive evidence could be found for Valeriana officinalis L., Melissa officinalis L., and ginseng. The results showed that while Hypericum perforatum L. was ineffective for ADHD, Passiflora incarnata L., Crocus sativus L, and Prunus dulcis (Mill.) D.A.Webb had similar efficacy compared to methylphenidate (MPH).Fifteen studies met the inclusion criteria. Several pieces of evidence support the efficacy of  A number of herbal medicines appear to be relatively safe and provide potential efficacy in amelioration of ADHD. However, due to lack of adequate reports of RCTs, no definitely specific recommendations could been made so far. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders among the children and adolescents. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), ADHD is characterized by inattention, impulsivity, and hyperactivity . This psychiatric disorder begins in childhood and is an important issue in mental health . About 5-7% of school-aged children and 2-5% of adults are estimated to suffer from ADHD worldwide . Current treatment options principally include a pharmaceutical component, a behavioral component, and a psychosocial component separately or in combination . However, some of children and adolescents with ADHD could not tolerate the side effects of psychostimulant medications . Furthermore, concerns about risks of long- term exposure to these medications, such as dependence, diversion, and abuse discourage parents to continue the use of them . In recent years, the use of medicinal herbs has been considered an adjuvant to conventional pharmaceuticals in the management and amelioration of ADHD symptoms . In order to evaluate the effectiveness and tolerability of herbal medicines for the management of ADHD, three systematic reviews have been published so far by Sarris et al. (2011), Wong et al. (2012), and Anheyer et al. (2017) . Sarris et al. (2011) focused mainly on studies on the effect of nutritional interventions on ADHD rather than herbal interventions. Wong et al. (2012) have also only reviewed traditional oriental herbal medicines studies such as the Korean, Chinese and Japanese Pharmacopoeia on ADHD. Anheyer et al. (2017) reviewed evidence in herbal therapy in the treatment of pediatric ADHD, which were published up to July 2016. In the current update, we used more new studies based on a broader search to combine evidence in this scope to provide a basis for discussing the findings, and to identify areas that need further study. In addition, the results of studies on the efficacy of saffron, ginseng and sweet almond in the treatment of pediatric ADHD have been reviewed for the first time. Due to the importance of effective treatment with fewer side effects, this study was performed to evaluate current evidence related to safety and efficacy of the herbal medicines and phytochemicals on ADHD in an updated systematic review.The current systematic review was performed according to the standard of Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) .Search strategyThis systematic review of randomized clinical trials (RCTs) and open-label clinical studies was accomplished to determine the effect of herbal medicines and phytochemicals on the management and amelioration of ADHD in children and adolescents. Studies published in English language were investigated in electronic databases, including Scopus, PubMed, ScienceDirect and Google Scholar. The search was done using the following keywords: "attention deficit disorder with hyperactivity" [Title/Abstract] OR "ADHD" [Title/Abstract] OR impulsivity [Title/Abstract] AND child [Title/Abstract] OR children [Title/Abstract] OR adolescent [Title/Abstract] OR pediatric [Title/Abstract] OR paediatric [Title/Abstract] AND "Herbal Medicine" [Title/Abstract] OR "Plant Extracts" [Title/Abstract] OR "Herbal therapy" [Title/Abstract] OR "Safety" [Title/Abstract] OR "Efficacy" [Title/Abstract]. The search was performed independently by two researchers and the dispute was resolved by a third person. Reference lists of related review articles also were assessed for potential relevant studies.Study selection and data extractionAll clinical trials or open-label (pilot) studies with a minimum of a 3-week duration that were published from 1st January 2000 to late October 2021, which assessed the effect of herbal medicines and phytochemicals on pediatric ADHD were included in the current review. The articles that studied ADHD participants under 18 years old were included (without any limitations on the diagnosis of ADHD). Combined type of ADHD as well as predominantly inattentive, and predominantly hyperactive/impulsive were considered ADHD. Therefore, all the participants in these clinical trials were pure ADHD. Other comorbidities, especially seizure/epilepsy were not included. Only studies that evaluated ADHD symptoms as a primary or secondary outcome were considered eligible. The cohort, case- control, case reports, duplicates, and unrelated studies as well as studies that did not provide required data were excluded. Chinese herbal medicines were not included in this study. Two review authors independently performed the screening of studies, and extracted the first author's name, study design, date of publication, sample size, age of participants, gender, intervention/comparison drug, outcomes, and data on the results and conclusion.Risk of bias analysisThe Cochrane Collaboration Risk of bias tools , which asses the sequence generation, the concealment of the allocation, blinding, and other biases were used for risk of bias analysis. The overall quality of each study was considered low risk of bias, some concerns of bias, or high-risk of bias. Therefore, if a domain with a high risk of bias is rated, the study is considered to have a high risk of bias. Disagreements between reviewers were discussed until consensus was reached. The risk of selection bias, reporting bias, attrition bias, performance bias and detection bias was assessed by the mentioned tool. According to the results of risk of bias analysis, the manuscripts were divided into three subgroups that include low, unclear, or high risk of bias.Study characteristics and risk of bias among the included studiesThe search in all scientific databases resulted in finding 8311 related studies in the field of herbal medicines and ADHD, 3233 of which were duplicates, and 5062 of which were excluded for reasons such as irrelevance, lack of required data, and not found full text. Finally, fifteen eligible articles were included in this study . The chaOutcomesL.Ginkgo biloba Ginkgo biloba L. is an ancient medicinal species native to China, which is mostly known as ginkgo and maidenhair tree. Due to its antioxidant, neurotransmitter/receptor modulatory, and inhibition of platelet activation, this plant has the potential to improve conditions such as impairments in memory and cognitive speed, Alzheimer's dementia, stroke, and aging . Lyon et al. (2001) conducted an open-label clinical study to determine the efficacy of a herbal product containing G. biloba extract (200 mg Panax quinquefolium L. extract and 50 mg G. biloba extract) in the treatment of ADHD. They reported that this herbal product could relieve the symptoms of ADHD. However, due to the lack of a comparison group in this study, the results are inconclusive .G. biloba special extract on ADHD symptoms in 20 children. The initial dose was 40 mg twice daily and based on persistence of symptoms increased to 60 and 120 mg twice daily. After 3–5 weeks of treatment, an amelioration in ADHD symptoms as well as Continuous Performance Test (CPT) performance and quality of life were reported in children given G. biloba (240 mg/daily). No serious adverse events described in this study .Uebel-von Sandersleben et al. (2014) conducted an open-label clinical study to evaluate the effect of G. biloba and placebo on 60 children and adolescents with ADHD who were receiving methylphenidate (MPH). They assessed ADHD symptoms by parents and teachers using the ADHD Rating Scale IV (ADHD RS-IV). After six weeks of treatment, more reduction was observed regarding parent rating inattention score and total score as well as teacher rating inattention score in the G. biloba group. The response rate was also significantly higher with G. biloba based on parent rating compared with placebo .Shakibaei et al. (2015) compared the effect of a herbal preparation of G. biloba compared to a standard MPH therapy over 6 weeks on 50 ADHD children. At the end of the study, it was found that G. biloba in the dosage range of 80–120 mg/day had a lower efficacy compared with MPH. Salehi et al. reported significant changes over time in the assessed ADHD symptoms for the MPH group. Whereas among the G. biloba group changes over time were reported to be non- significant . Both studies of Salehi et al. (2010) and Shakibaei et al. (2015) reported only mild to moderate side effects .The study by Salehi et al. (2010) evaluated the effect of Pine bark extractPycnogenol (French maritime pine bark extract) contains polyphenolic compounds with free radical-scavenging activity against reactive oxygen and nitrogen species, and it is able to create a variety of potential protective effects against chronic and degenerative diseases such as neurodegenerative and neurodevelopmental disorders. Treatment with Pycnogenol reduced hyperactivity of children and catecholamine excretion and improved the antioxidant status of ADHD children . There were 3 studies with 165 participants included in this review using Pycnogenol on ADHD.Trebaticka et al. (2006) evaluated the effects of treatment with Pycnogenol (1 mg/kg/day) for 1 month on 61 participants (aged 6–14 years) compared to a placebo. They reported that Pycnogenol was able to improve ADHD symptoms as well as visual-motor coordination. After discontinuing the use of pycnogenol, a relapse of symptoms was observed in patients. The placebo group showed no amelioration during the study period. The authors did not report any serious side effects. Only an increase in slowness and gastric discomfort in two patients in the intervention group was reported . Due to the lack of determination of primary and secondary results, there is a risk of selective reporting bias in this report. Furthermore, this clinical trial was supported by Horphag Res. Ltd, the manufacturer of Pycnogenol, the risk of other biases is also expected.In summary, minimal side effects as well as the significant effects of Pycnogenol might confirm that it could be considered an alternative treatment for ADHD, however, more research is needed before a definitive judgment can be made about the overall application of the findings. GinsengPanax ginseng C.A. Meyer) and American ginseng (Panax quinquefolius L.) are the main sources of ginseng. It is a herbal medication with diverse pharmacologic activities, including anti- stress effect, improvement on cognitive function, prevention of memory impairment, and antioxidant effect . The therapeutic benefits of ginseng in pediatrics ADHD have been studied previously.The roots and rhizomes of Korean ginseng (G. biloba extract (200 mg Panax quinquefolium L. extract and 50 mg G. biloba extract) could relieve the symptoms of ADHD. This study did not have a comparison group .Lyon et al. (2001) reported that a herbal product containing In another included study, the effects of ginseng compared to a placebo were evaluated on 70 ADHD patients aged 6–15 years old. In the intervention group, 33 patients were given 40 ml of Korean red ginseng (KRG) twice per day. After 8 weeks, a decrease in inattention and hyperactivity scores was recorded in treatment group compared with the control group. Moreover, a decreased electroencephalography theta/beta ratio was observed in comparison with the control group. The two groups did not differ significantly in terms of the frequency of adverse events. There were no serious adverse reactions .Prunus dulcisPrunus dulcis (Mill.) D.A.Webb or sweet almond is a nutraceutical and therapeutic agent, which can improve all neurological functions . Motaharifard et al. (2019) evaluated the efficacy and safety of sweet almond compared with the standard treatment through a randomized controlled trial on 50 children aged between 6 to14 years. Symptoms were evaluated via ADHD RS-IV. The results of the study showed that sweet almond is as effective as MPH in the treatment of ADHD. Regarding both the parents and teachers ADHD RS- IV, the results showed a significant treatment effect. At the end of the trial, no significant difference was observed between the two groups. The two treatment groups were similar in trend over time and the difference was not statistically significant. However, more studies are needed with larger sample sizes as well as with different doses of the medication and longer follow-up. All observed adverse effects were transient and were not serious. The frequency of reported adverse events was more in patients receiving MPH .L.Melissa officinalis Melissa officinalis L. or lemon balm is a plant that is native to Iran, southwestern Europe, and Asia . Katz et al. (2010) tested an herbal compound  to treat ADHD symptoms in 120 participants. The score of the test of variables of attention was the primary outcome. A high rate of attrition among the placebo group could indicate the high risk of incomplete outcome data in this study. All subtests of the test of variables of attention score for the intervention group between baseline and post-intervention measurement were significantly improved. No significant changes over time were observed in the placebo group. No serious adverse events occurred during the study. Minor side effects happened within both arms of the study .L.Crocus sativus Crocus sativus L., also recognized as saffron, has traditionally been used for its antispasmodic, anticancer, anticancer, and anticonvulsant properties . The efficacy of saffron as an ADHD treatment has been studied in two studies. Baziar et al. (2019) in a pilot study reported that treatment with saffron showed the same efﬁcacy as MPH . Fifty-four ADHD children were randomlyallocated to either MPH or saffron groups. Symptoms were assessed by both teacher and parents via the ADHD-RS-IV at baseline and then the third and sixth weeks of the study. This study showed that changes in ADHD-RS-IV scores during the study period were not signiﬁcantly different between the two groups . Another study aimed to evaluate the effectiveness of saffron in the treatment of children suffering from ADHD who were receiving MPH. This showed that after four weeks, the average score assigned by the parents and teachers in the MPH with saffron group was lower than the average total score in the MPH group (p<0.05) .Bacopa monnieriB. monnieri -also known as Herpestis monnieri, water hyssop, or Brahmi- has been used in the traditional medicine as a tonic for learning, memory, and concentration. This plant has antioxidant activity and protective effects against dopaminergic degeneration. Treatment with 225 mg Bacopa extract per day for 24 weeks showed a significant alleviation of the symptoms of ADHD in children. In this study, the score for restlessness was improved among more than 90% of participants. Also, the score for self-control as well as attention-deficit symptoms was improved in 89% and 85% of participants, respectively. Furthermore, impulsivity, learning and psychiatric problems were improved .L.Valeriana officinalis Valeriana officinalis L. or valerian is a medicinal herb with known sedative and antispasmodic effects. The efficacy of this plant in the treatment of ADHD has been evaluated in a pilot study . The study included 30 children aged 5 to 11 years who were given valerian for two weeks and three times a day. The authors reported an improvement in ADHD symptoms which were measured via Children's checking task (CCT), Conner's parent symptom questionnaire (PSQ), and the Barkley and DuPaul teacher rating scale. Because the authors did not mention randomization or blinding in the article, there is a possibility of bias in the results of this study, so further studies are needed to confirm the results of such a study and to decide on the effectiveness of valerian in treatment. No serious adverse events or side effects were reported by the authors.L.Passiflora incarnata Passiflora incarnata L. or passion flower on anxiety, insomnia and ADHD . The effect of passion flower on ADHD symptoms has been investigated in 34 children with ADHD; the treatment group received passion flower twice a day. The control group received MPH twice a day. No significant difference was reported based on parent and teacher rating scores. Moreover, the side effects were less common among the passion flower group compared with placebo group. Although anxiety and loss of appetite were recorded in the control group more than the intervention group, the authors reported no serious side effects . The blinding of participants and assessors remained unclear in this study.Recent preclinical studies have displayed potential effects of L.Hypericum perforatum Hypericum perforatum L., also known as St John's wort, is a plant in the Hypericaceae family that has an influence on certain CNS neurotransmitters . A preliminary study by Niederhofer (2010) reported an improvement in ADHD symptoms in 14-16 years old patients who were administered St. John’s wort . However, a randomized trial by Weber et al. (2008) aimed to study the safety and efﬁcacy of a H. perforatum in the treatment of ADHD found that 8 weeks of H. perforatum treatment (300 mg/day) did not reduce ADHD symptoms in 54 ADHD children . The ADHD RS-IV was used to evaluate symptoms rated by parents. The severity of symptoms was also measured via the Clinical Global Impression Improvement Scale (CGI). The frequency of adverse events as well as side effects was equal between the two groups.H. perforatum in the treatment of ADHD. Although the above studies did not report adverse effects of H. perforatum, investigation on the safety of this herbal remedy is still required.Based on these findings, further studies are needed to assess the efficacy of In summary, the results of included reports showed that most of the mentioned herbal remedies had positive effects in alleviating the symptoms among the children and adolescents with ADHD. Another point was about the side effects of the studied herbal medicines. According to the results, they had minimal side effects, which was one of the advantages of using them in combination with current treatment options. In addition to the beneficial therapeutic effects, having ignorable side effects makes them more welcome and increases their tolerability, which can be seen in the case of herbal medicines and phytochemicals.The findings of the current systematic review show positive but inconclusive evidence of herbal remedies in the treatment of ADHD. Seven of the fifteen included studies had a high-risk bias domain. Thus, despite the positive findings, it is difficult to conclude that herbal medicines and phytochemicals are effective treatments for ADHD in children and adolescents, and the seemingly promising results should be interpreted with caution. The findings of this study are relatively consistent with previous systematic reviews of herbal and nutritional products in the treatment of ADHD . Except for St. John’s wort which does not show positive results, almost all other herbal medicines revealed mainly positive evidence and may provide a beneﬁcial effect on reducing ADHD symptoms.G. biloba and Pycnogenol were based on multiple studies but not conclusive. While Pycnogenol and G. biloba are promising herbal medicines in the management of ADHD symptoms, more investigation with a longer duration is essential to prove the worth of these medicines as an option in the treatment of ADHD. However, in each case, based on only one study, the result for M. officinalis and ginseng were positive but, it is difficult to make any decision about the efficacy, and more studies are required to assess the efficacy of these medicines in treating ADHD. Further studies also are required to confirm the safety and efficacy of Bacopa as an ADHD treatment.The results for The potential effect of ginseng can be considered an alternative to ADHD treatment, due to its low side effects and high efficacy. The neuroprotective as well as the antioxidant effects of ginseng, which could increase the dopamine and norepinephrine levels have been shown . The efficacy of treatment by Passion flower, saffron, and sweet almond in pediatrics ADHD was similar to that reported for MPH. The safety and lower side effects of these herbal medicines compared to MPH could be considered the main advantage. Passion flower has neuroprotective effects and could alter the serotonergic neurotransmission in the brain . Boron is a trace element found in sweet almonds; some studies have shown that boron plays a key role in improving cognitive performance . Saffron affects glutamatergic and monoaminergic systems  and is generally a safe medication .G biloba, St. John's wort, M. ofﬁcinalis, P. incarnata, and the V. ofﬁcinalis . In the present study, the evidence for saffron, ginseng, Bacopa monnieri, and sweet almond was furthermore examined.All the studies reported no serious adverse events or severe side effects. Seven of the fifteen studies assessed in this review, including Akhondzadeh et al. (2005), Trebatická, et al. (2006), Weber et al. (2008), Katz et al. (2010), Salehi et al. (2010), Razlog et al. (2011), and Shakibaei et al. (2015) were also included in the review of Anheyer et al. (2017) were consistent with our findings regarding the The limitation of this systematic review was about the rarity of eligible clinical trials. For some herbal medicines, only one eligible study could be identified, and despite a comprehensive search, we eventually included only a small number of randomized, controlled clinical trials. Also, further randomized, controlled clinical trials are required to confirm the effectiveness of herbal treatment on ADHD in children and adolescents. In addition, it seems that researchers in this field need to pay special attention to the Consolidated Standards of Reporting Trials (CONSORT) in presenting the results of primary studies. Despite the acceptable methodological quality of most studies, the small sample size needs to be taken into consideration as a limitation. Moreover, the unclear randomization and allocation concealment methods, incomplete reporting of outcome data in some studies were among other limitations.A higher frequency of male participants was found in all of the included studies. In addition, it should be noted that the countries in which different studies have been conducted are culturally different and largely heterogeneous. Finally, we have included only the published studies in English language in the review.In summary, the studies included in the current systematic review show that herbal medicines appear to be relatively safe and with limited side effects and providing potential efficacy in amelioration of ADHD. Because there are not yet enough RCTs of herbal remedies on ADHD, no specific recommendations would be possible. We hope that the results of the present study, in addition to assisting physicians in evidence-based decision- making, will be useful both in providing clinical evidence-based guidelines and in encouraging researchers to conduct new, high-quality randomized trials in this field.The authors have declared that there is no conflict of interest.


Introduction: Patients with attention-deficit/hyperactivity disorder (ADHD) often show abnormalities related to cognitive activities, especially related to working memory and inhibitory control. Functional near-infrared spectroscopy (fNIRS) is a non-invasive brain imaging technique based on the changes in cerebral hemodynamics to measure the response of brain activities to cognitive tasks.Methods: In this review, we collected all clinical experiments that evaluated the changes of oxyhemoglobin levels in relevant brain regions of patients with ADHD through cognitive tasks by fNIRS to determine the abnormalities of brain regions related to working memory and inhibitory control activities in patients with ADHD.Results: From the beginning of November 2021, PubMed, PsycINFO, Scopus, EMBASE, CINAHL, web of science and Cochrane library were searched, and ROBINS-I was a tool to evaluate the quality and risk bias of the articles included. Sixteen eligible clinical trials or randomized controlled trials were included, of which six measured working memory and eleven measured inhibitory control.Conclusion: We found that compared with healthy people, the activation scope of working memory and inhibition control in the frontal cortex in ADHD patients was smaller than that in healthy people, and the activation degree was weak or even inactive, which can provide new ideas for the direction of research on ADHD. ADHDCognitive activity is the most common activity in daily human life, which leads to an increase in neuronal activity. In the brain, the increased neuronal activity causes increased energy expenditure . Our comVarious imaging techniques can measure brain activities by measuring cerebral haemodynamic changes, such as functional magnetic resonance imaging (fMRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). Functional near-infrared spectroscopy (fNIRS) has advantages over these imaging techniques because fNIRS is quiet, portable, low-cost, and has a high temporal resolution, especially for children. It can wear on the head to participate in activities in a normal environment instead of lying quietly in a cramped environment . MoreovefNIRS is a non-invasive brain imaging technique and a useful tool for measuring brain activities based on the cerebral haemodynamic changes in response to a cognitive task . fNIRS dWorking memory (WM) is a cognitive capacity responsible for concurrently retaining and processing information . And inhth steps earlier in a sequence of stimuli. The memory load factor n can be adjusted to make the task more or less challenging [Several tasks measure working memory, such as n-back task, digit span recall tasks, and visuospatial working memory task -23. N-ballenging . The digllenging . A Visuoe.g., the word ‘GREEN’ appears in red) within the given time [e.g., press a button) and withhold the response for nogo stimuli  [Color Stroop task and Go/Nogo task are the two commonly used tasks to measure the different inhibitory skills -26. Coloven time , 26. The button) . The tesThis is currently the first review to summarize the corresponding brain region activation in ADHD patients measuring working memory and inhibitory control under fNIRS. We aim to provide evidential support to all those engaged in ADHD research.22.1Electronic databases were systematically searched until November 2021: PubMed, PsycINFO, Scopus, Embase, CINAHL, Web of Science, and Cochrane-Library. The main keywords used were (NIRS OR fNIRS OR near-infrared spectroscopy) AND (ADHD OR Attention deficit OR hyperactivity disorder) AND (working memory OR n-back OR digit span OR block OR inhibitory* OR inhibition* OR Stroop OR Nogo OR go). The review author screened the titles and the abstracts, and the full text of potentially eligible studies was also retrieved and assessed by the Lihao HOU. We have registered our review on the PROSPERO with ID CRD42021289851.2.21). The population contains all patients with ADHD symptoms. There are no gender, age, and nationality restrictions on the population.The search keywords were operationalized using a Population, Intervention, Comparison, Outcome (PICO) chart (Table 1).Inclusion criteria were defined by PICO: (1) were clinical trials (CTs), including randomized controlled trials (RCTs) and non-RCTs that included ADHD patients; (2) contained the working memory or inhibitory control tasks; (3) used fNIRS to measure for the outcome; (4) were published in English. Studies were excluded if: (1) patients had the medication; (2) combined with the Autistic Spectrum Disorder (ASD); (3) no oxy-hb data; (4) not in English. The process was carried out in line with the guidelines for systematic reviews and meta-analyses (PRISMA) flow diagram  first author, year, and country; (2) article type (3) number and characteristics of the participants; (3) mean age (4) details of fNIRS devices, (5) region of brain activation and (6) evaluation of scales. For this review, our outcome was the change of oxy-hb level before and after intervention evaluated by fNIRS measures to determine the difference between working memory and inhibitory control activity-related brain region changes in ADHD patients.2.42). Each domain was rated as “high” (seriously weakens confidence in the results), “unclear”, or “low” . Studies that met at least four domains with no severe flaws were considered a low risk of bias. This assessment was processed in Review Manager 5 software .The quality of reporting for the trials was evaluated by ROBINS-I (A CochraneRisk Of Bias Assessment Tool: for Non-Randomized Studies of Interventions) . ROBINS-33.11), 981 titles and abstracts were retrieved from 7 databases. After adjusting for repetitive and retrospective titles and abstracts, 895 studies were deleted. Then screening for eligibility, 86 abstracts and titles were screened against the inclusion and exclusion criteria. The reasons for the exclusion of 55 studies were as follows: (1) participants not with ADHD (2) not CTs or RCTs (3) not focusing on working memory or inhibitory control. Moreover, 31 full-text articles were further screened, then 15 studies were continued to be excluded for the following reasons: (1) articles are not in English (2) Participants with ADHD combined with ASD (3) Participants with ADHD took medication in the trial (4) fNIRS measurement results had no oxy-hb activation data (5) not referred cognitive activity tasks. Finally, five studies on working memory, ten studies on inhibitory control, and one study on both cognitive activities met the inclusion criteria of this review.According to Fig. (3.22). 11 studies were described as having a low risk of confounding, while five studies had no detailed confounding information [The risk of bias was assessed and summarized in Fig. , especially on the right dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC), while for the visuospatial working memory (VSWM), the activation region is distributed in the rightPFC, frontal pole, left superior frontal cortex (SFS). According to the inhibitory control, the activation region for the capacity to inhibit cognitive interference focused on bilateral PFC, while for the inhibitory control skill, the activation region is widely distributed in bilateral PFC, parietal and frontal regions, left temporal and superior temporal cortex, and right inferior frontal gyrus (IFG) and middle frontal gyrus (MFG).4fNIRS is a portable and potential device for detecting brain activities, which can be widely used in ADHD research. This review aims to summarize the activation of brain regions associated with working memory and inhibitory control in ADHD patients and the differences between ADHD patients and healthy individuals. To our knowledge, no similar systematic review focuses on the association between fNIRS and working memory or inhibitory control in patients with ADHD. A recent systematic review  analyzedOn the one hand, the deviation is related to the number of channels used in fNIRS. The more channels used in fNIRS, the more regions of the brain can be detected , 33. On In 16 articles, there are five articles refer to the method to solve the motion artifacts in oxy-hb data, such as the empirical mode decomposition method , a low-pThere are several limitations to this review. Due to the language limitations of the researchers, we excluded non-English articles, and these exclusions may result in publication bias. In addition, due to the limited number of such articles, only one RCT was found, and the rest were all CTs with small to medium sample sizes. RCTs provide the highest level of evidence required for confirmation practice, and if there are more randomized controlled trials and large sample experiments, the evidence will be more reliable and effective. Nevertheless, this review has identified brain activation regions for different types of working memory tasks and inhibitory control tasks, which may help explore working memory and inhibitory control mechanisms in patients with ADHD. Future studies could use RCTs with better design quality to provide strong evidence for more ADHD studies in the future.In healthy people, the activation regions of verbal working memory (VWM) were mainly in the right prefrontal cortex (PFC), especially in the right ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC), while the activation regions of visuospatial working memory (VSWM) were mainly in the right PFC, frontal pole and left upper frontal cortex. Moreover, the activation regions of inhibition of cognitive interference were mainly concentrated in bilateral PFC, while the activation regions of inhibitory control skills were widely distributed in bilateral PFC, parietal, and frontal lobe, left temporal and superior temporal cortex, right inferior frontal gyrus (IFG) and middle frontal gyrus (MFG). While in participants with ADHD, the activation regions are smaller than that of healthy people, and the activation degree is weaker or none in working memory and inhibitory control.


ABCA4) gene. STGD1 is the most common form of juvenile macular degeneration with onset in late childhood to early or middle adulthood and causes progressive, irreversible visual impairment and blindness. No effective treatment is currently available. In the present article, we review the most recent updates in clinical trials targeting the management of STGD1, including gene therapy, small molecule therapy, and stem cell therapy. In gene therapy, dual adeno-associated virus and non-viral vectors have been successful in delivering the human ABCA4 gene in preclinical studies. For pharmaceutical therapies ALK-001, deuterated vitamin A shows promise with preliminary data for phase 2 trial, demonstrating a decreased atrophy growth rate after two years. Stem cell therapy using human pluripotent stem cell-derived retinal pigment epithelium cells demonstrated long-term safety three years after implantation and visual acuity improvements in the first two years after initiation of therapy. Many other treatment options have ongoing investigations and clinical trials. While multiple potential interventions have shown promise in attenuating disease progression, further exploration is necessary to demonstrate treatment safety and efficacy.Autosomal recessive Stargardt disease (STGD1) is an inherited retinal degenerative disease associated with a mutated ATP-binding cassette, subfamily A, member 4 ( ABCA4) gene . T. T39]. TCA4 gene . The comABCA4 gene mutations found in STGD1, a nonfunctional ABCA4 protein hinders this removal of all-trans-retinal from photoreceptors, which leads to the production of A2PE within outer segments and buildup of A2E, a major component of toxic lipofuscin, in the RPE cells. This leads to degeneration of RPE cells and subsequent photoreceptor loss . Ac. Ac52]. function . Dietaryhenotype .Given these positive preclinical results, a phase I clinical trial (NCT02230228) was completed with 40 healthy subjects showing safety and tolerability of oral ALK-001. An ongoing multicenter 24-month phase 2 clinical trial  in 50 patients receiving oral ALK-001 in late-stage STGD1 was initiated in 2015 with an open-label extension (NCT04239625) initiated in 2020 B. PrelimRetinol-binding protein 4 (RPB4) antagonists are being explored as potential therapeutic agents for STGD1. RPB4 has been shown to be involved in STGD1 and dry AMD pathophysiology through the toxicity of accumulated lipofuscin in the RPE ,57. RPB4−/− mice, fenretinide caused a dose-dependent reduction in serum retinol and RBP4 with subsequent reductions in visual cycle retinoids and decreased A2E and lipofuscin accumulations in the RPE . C5. C563]. neration . In the neration .Avacincaptad pegol is delivered by intravitreal injection and has been explored as a potential therapy for several disorders including STGD1, dry AMD, neovascular AMD, and idiopathic polypoidal choroidal vasculopathy . A randomized, double-masked phase 2/3 clinical trial (NCT02686658) was completed in 2019 with 286 subjects with geographic atrophy receiving intravitreal avacincaptad pegol. A significant reduction of 27% in geographic atrophy mean growth rate was observed in patients receiving either 2 or 4 mg doses versus sham over 12 months without serious adverse events [ABCA4 retinopathy disease progression by decreasing lipofuscin accumulation, thus slowing RPE and photoreceptor degeneration [−/− mice, oral metformin was shown to decrease lipid and lipofuscin accumulation in the RPE/choroid [ABCA4 retinopathies including STGD1  and eicosapentaenoic acid (EPA), types of omega-3 polyunsaturated fatty acids, have been investigated due to their role as components of photoreceptor cells. These polyunsaturated fatty acids are esterified into phospholipids and help maintain photoreceptor membrane fluidity, retinal integrity, and visual function ,74,75. DA phase I clinical trial (NCT00060749) that ended in 2007 utilized DHA supplementation as a tool for macular function improvement in patients with STGD1. In this double-masked, randomized study with 11 participants, patients received either oral DHA supplementation with the dosing of 2000 mg per day or a placebo. However, unlike in preclinical mice studies, no improvement in macular function was observed . SimilarSeveral stem cell studies in animals and humans have been conducted or are currently being conducted to investigate stem cell therapy for STGD1 in an effort to repair retinal tissue and consequently improve VA. These trials mainly focus on the use of human embryonic stem cells (hESCs) .Preclinical studies that transplanted hESC-derived mature RPE cells into the subretinal space of eyes in the rat model of inherited retinal degeneration, which undergo visual deterioration due to a mutation in Mertk (a c-mer proto-oncogene kinase receptor specific to RPE cells), showed promising results ,84. RatsThe first phase I/II human clinical trials  completed in the United States in 2015 injected hESC-RPE subretinally in late-stage STGD1 patients and atrophic AMD, sponsored by the Astellas Institute for Regenerative Medicine ,85. PatiThe fourth phase I trial was completed in Korea (NCT01625559) and sponsored by CHA Biotech Co. It showed no serious adverse events for three patients with STGD1, 3 years after subretinal implantation of 50,000 hESC-RPE cells, with a similar protocol used in the other Astellas’ trials mentioned above . One patSTGD1 is one of the most common inherited retinal degenerative diseases and is highly genetically heterogeneous . No treaABCA4 gene was previously considered to be too large for AAV vectors [For gene therapy, SAR42259 was shown to have long-term safety and tolerability at 3 years with no significant functional changes, potentially indicating that the lentiviral vector may be limited for retinal transduction ,25. Whil vectors , preclin vectors ,29 and a vectors ,40,41. F vectors , which c vectors , which s vectors . While gIn small molecule therapies, STGD1 intervention focuses on modulating the visual cycle, reducing A2E, and decreasing the effects of lipofuscin toxicity. Clinical trials for these interventions have shown variable results. Emixustat demonstrated suppression of the visual cycle with no significant BCVA changes in a phase 2 trial but failed to decrease the macular atrophy growth rate in STGD1 in the subsequent phase 3 trial with a large sample size ,51. ALK-Stem cell therapy may also be a viable avenue for STGD1 treatment. Numerous clinical trials have been performed with subretinal transplantation of hESC-RPE cells, which have shown long-term safety in STGD1 patients 3 years after implantation with limited BCVA improvement ,89. WhilOverall, STGD1 is a complex, progressive disorder that leads to irreversible vision loss and disability without current treatment. Multiple treatment strategies have shown promise in attenuating disease progression. Further exploration will advance our understanding of underlying disease mechanisms and pave the way for the development of treatment solutions and interventions.