Introduction: Autism Spectrum Disorder (ASD) and Attention Deficit/Hyperactivity Disorder (ADHD) figures among the most common neurodevelopmental disorders. Despite having opposite stereotypes, both ADHD and ASD compromise, though in different ways, skills such as social interactions, communication skills, and social thinking, which may underlie difficulties in romantic relationships.Methods: We evaluated 306 adults about their romantic relationships and the intensity of their love. Participants were from one of four groups:, individuals with ASD-only traits, a group with symptoms of ADHD-only, participants with neither ADHD nor ASD symptoms (control) or from a fourth group of individuals with both ADHD and ASD traits.Results: The ASD traits group had fewer married people and more people who have never been married, while the rate of divorce was higher in the ADHD traits group. Regarding the intensity of love, the mean scores of the ADHD and the ADHD+ASD traits groups were higher in the Passionate Love Scale than the mean score of the control group. Passionate love in the ASD group was no different from the other groups. Small positive correlations were found between passionate love and ADHD and ASD behavioral problems.Conclusion: Marital status was distinct depending on symptoms of a neurodevelopmental disorder in adulthood. Also, ADHD and ASD symptoms were associated with greater passionate love. Therefore, ADHD and ASD behavioral dimensions may impact long-term and short-term experiences of a person's relationship with a significant other in distinct ways. Understanding how people with neurodevelopmental disorders experience love might help us to better clarify the mechanisms associated with their relationship patterns. Neurodevelopmental disorders are childhood-onset conditions that commonly have a major impact on the personal, laboral, academic, and social functioning of individuals and their families. Two of the most frequent disorders diagnosed early in life are Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), with a prevalence of ~1.8 and 5.29% of affected children , 4, and ADHD is a heterogeneous disorder marked by inattentive and/or hyperactive/impulsive behaviors. Its functional impairment includes poor occupational performance, lower level of education, higher rates of delinquent behaviors, traffic accidents, self-reported happiness, marital dissatisfaction and divorce , 10–14. Considering that understanding, developing and maintaining intimate relationships requires social interactions, communication skills and social thinking , 23, indConcerning ASD individuals, data on their love life is inconsistent. Lau and Peterson  found thIndividuals with autism are frequently portrayed as insensitive and cold, that lack the need for love. Some traits, such as dislike being touched and poor comprehension of social signs, contribute to social stereotypes, labeling individuals with autism as asexual or uninterested in romantic relationships , 35–37, Meanwhile, individuals with ADHD are often viewed as more creative, passionate and intense , a portrNevertheless, these characteristics may also contribute to higher rates of divorce and poorer marital adjustment within adults with ADHD . ConsidePrevious studies pointed to an association between marital quality and health, with divorce being correlated with poorer outcomes, as a greater risk for early death, for mental illness and with alterations in endocrine and immune function –45. WherConsidering the impact on mental health and well-being of dysfunctional or unsatisfactory romantic relationships, our study aimed to investigate the characteristics of passionate love among individuals with symptoms of ASD and ADHD.via the internet through a virtual snowball sampling strategy  for a partially online open survey specifically designed to study cognition, behavior, and adaptive functioning depending on ASD traits in adults. The research is under the Helsinki Declaration principles and was approved by the local ethics board (registry: CAAE 56534516.1.0000.5149). Participants were assigned to four distinct groups according to clinical cut-off points on ADHD and ASD screening tools. To assess the ADHD symptoms we used the Adult Self-Report Scale (ASRS-v1.1)  recruited RS-v1.1) , and to Participants voluntarily consented with their participation by clicking a button “I agree” in the electronic questionnaire after reading an invitation explaining the purpose of the study, the duration of the form, data that were being stored, and confidentiality security. No incentives were offered for voluntary participation. No technical issues were reported to our research team during data collection. Data were obtained from July 2016 to July 2017, and all questionnaire items were presented in a fixed order for all participants, independent of their response choices. Responses could be changed before submission, but not after. A second submission was not readily available for participants. Duplicates were identified by participants' full name, which was visible only for one researcher (JJP) before masking (each participant received a numeric ID), and only the first response was kept. Participants took an average of 30 min to respond to the electronic questionnaire.To assess the passionate love intensity we used the short version of the Passionate Love Scale (PLS) , a 15-itThe Brazilian Economic Classification Criteria (CCEB) was used to characterize the participants' socioeconomic status. Scores can vary from 0 to 100 and classified in one of six socioeconomic strata: A (monthly household income estimation of U$ 20888.00), B1 (monthly household income estimation of U$ 9254.00), B2 (average household income of U$ 4852.00), C1 (average household income of U$ 2705.00), C2 (average household income of U$ 1625.00), and DE (average household income of U$ 768.00) .All analyses were performed with SPSS 22.0. Descriptive statistics and Spearman's correlation analyses were conducted within the entire sample to investigate variables distribution and their associations. Comparisons between the groups regarding passionate love, ADHD and ASD traits, instruction, sociodemographic measures and age, were performed by the Kruskal-Wallis test. Then, for further details of the results, we used Mann-Whitney tests (Bonferroni corrected) to specific group comparisons. Differences between groups regarding marital status and sex distribution were performed by chi-square tests.M = 31.8; SD = 8.5) being predominantly female (73.9%). This distribution is in accordance with some results that suggest a gender bias, especially in surveys related to mental health and emotional issues (2 = 4.81 p = 0.186) between groups. The sample was classified according to the participants' scores on ADHD and ASD screening scales. Thus, 30.1%  had negative scores for both ADHD and ASD, 13.8%  had high scores for autism traits, 24.8%  had clinical scores only for ADHD, in which 34.2% were inattentive, 14.5% hyperactive, and 51.6% combined, and 31.4%  had clinical scores for both conditions. The participants' description is shown in Z = 2.44, p = 0.486), education  and sociodemographic measures  between groups. Of the total sample, 45.7% (n = 139) was in a steady relationship (married or living with their partner), while the others 54.3% (n = 165) had never been married, or were widowed, separated or divorced at the time. There were also significant differences in the marital status distribution  between groups  and hyperactivity/impulsivity , assessed by ASRS-18, and with Autism Quotient   and the ADHD + ASD-traits group  when compared with the control group  and in the combined group  when compared to the control group, while the hyperactive/impulsive group showed no significant difference (p = 0.058) in this comparison.Regarding the intensity of passionate love,  < 0.01) . Compariol group . Within Previous studies have suggested that individuals with ADHD and ASD may experience difficulties related to romantic relationships, whether to initiate or maintain it , 25, 40.Here we focused on the potential for any difference regarding the intensity of love feelings between people with high ADHD and autism traits and people without symptoms of any of these diagnoses. Romantic or passionate love is an intense emotional state typical of the beginning of romantic relationships, marked by profound feelings of attraction and commitment, as well as by obsessive characteristics, such as a jealous dependence and intrusive thoughts about the partner , 61. SomOur results suggest that the intensity of passionate love in ADHD-traits and the ADHD+ASD-traits group is greater than in the group with no symptoms, which could be interpreted as a trace of emotion dysregulation, a very common aspect among people with ADHD . EmotionFurther analysis also suggested that the difference found in the ADHD-traits group was probably related to the inattentive dimension of the disorder. In previous studies, the ADHD inattentive presentation was associated with lower romantic satisfaction and less expression of love and affection . Indeed,These results are in accordance with the proposition that the point of difficulty in the interpersonal interaction might be in self-regulation of emotion as it is experienced and expressed . People The ASD-traits group does not differ from the ADHD, control and ADHD+ASD-traits group in the romantic love intensity, suggesting that adults with high autism traits do not experience less or more passionate love in their lives compared to the other groups. Although ASD has a very heterogeneous manifestation, difficulties with social interaction, in general, are a core trait, which includes deficits with verbal and non-verbal communication . They usThe common image of an individual with ASD is a person for whom love has no meaning, no draw, no neurochemical reward related to love, however, nothing of this picture was sustained by our data. Despite this, feeling in love is not a lacking emotion for those who have plenty of symptoms compatible with ASD. Our findings agreed with other reports, that individuals with autism, as well as those with a neurotypical development, also desire to be in an intimate and romantic relationship, even when they lack understanding of them, do not have skills, previous experiences, or knowledge to initiate those interactions , 75.fMRI findings suggest that passionate love recruits brain regions involved in complex cognitive processing, such as social cognition, body image, self-representation and attention . We obseAn important limitation is the fact that we analyzed the relationship effects under the presence of symptoms without a diagnostic interview and evaluated only the romantic love effect without any information about the long-term features of love or less stable relationships. Another limitation was the survey's sex distribution, which was predominantly female. Since both ADHD and ASD are more prevalent among males, this could imply a sampling bias. Furthermore, there was also a difference in the sample distribution within the ADHD group, so the results should be interpreted with caution. A strength of our study was the evaluation of the dimensional effect presented in the individuals.In conclusion, the relationship seems to be impacted by the presence of symptoms of neurodevelopmental disorders, having more impact on individuals with symptoms compatible with ASD. However, the impact apparently is not related to the intensity of love in the individual's point of view. Subjects with higher symptoms of ADHD and with high ADHD and ASD traits described having a higher intensity of romantic love, and nevertheless have less stable relationships. They are more likely to have a divorce, pointing toward a possible gap between feeling and expressing their emotions. Further studies are necessary to understand the mechanisms of differences and mechanisms of the relationship deficits. Improvement in relationships showed a beneficial impact and a universal protective factor, however, preventing bad relationships is a more important goal than getting an average relationship to a more satisfactory level . InterveThe 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 UFMG Ethical Board. The patients/participants provided their written informed consent to participate in this study.Material preparation, data collection, and analysis were performed by LS and AA. The first draft of the manuscript was written by LS. All authors commented on previous versions of the manuscript, contributed to the study conception and design, and read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


ADGRL3, DRD4, and FGF1), with cognitive endophenotypes related to working memory and perceptual organization in 113 nuclear families. These families were ascertained from a geographical area of the Caribbean coast, in the north of Colombia, where the community is characterized by its ethnic diversity and differential gene pool. We found a significant association and linkage of markers ADGRL3-rs1565902, DRD4-rs916457 and FGF1-rs2282794 to neuropsychological tasks outlining working memory and perceptual organization such as performance in the digits forward and backward, arithmetic, similarities, the completion of figures and the assembly of objects. Our results provide strong support to understand ADHD as a combination of working memory and perceptual organization deficits and highlight the importance of the genetic background shaping the neurobiology, clinical complexity, and physiopathology of ADHD. Further, this study supplements new information regarding an ethnically diverse community with a vast African American contribution, where ADHD studies are scarce.Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurobehavioral disorder that affects children worldwide, with detrimental long-term consequences in affected individuals. ADHD-affected patients display visual–motor and visuospatial abilities and skills that depart from those exhibited by non-affected individuals and struggle with perceptual organization, which might partially explain impulsive responses. Endophenotypes  might provide a more powerful and objective framework for dissecting the underlying neurobiology of ADHD than that of categories offered by the syndromic classification. In here, we explore the potential presence of the linkage and association of single-nucleotide polymorphisms (SNPs), harbored in genes implicated in the etiology of ADHD ( Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder that affects 8 to 18% of the population ,3,4. Inaproxy to the actual phenotype as they connect behavioral symptoms with the well-understood illness associated with known genetic causes ..® DNA Pu® SNP variation suite (SVS) 8.4.0 . Golden Helix’s SVS is an integrated collection of analytic tools for managing, analyzing, and visualizing multifaceted genomic and phenotypic data. In this study, only SNPs harbored in genes previously reported to confer susceptibility to ADHD in our sample were selected to explore their association with ADHD endophenotypes of working memory and perceptual organization.Allele and genotype frequencies were estimated using maximum likelihood. Mendelian errors and missing genotypes, common features in SNP-based genotyping, were detected and subsequently corrected with the methods available in Golden Helix’sWe used the family-based association test (FBAT) to assess linkage and association of SNPs with perceptual organization endophenotypes in our cohort, which includes complex family structures with multiple affected individuals and, in some cases, several probands, which introduces complex patterns of ascertainment. The FBAT provides a unified framework to generalize the transmission disequilibrium test ,70 and aP-values from the FBAT were corrected for multiple testing using Bonferroni’s method . F. FFGF1-rithelium , lens foithelium ,164 and ithelium ,165 as withelium ,167, desithelium , which mithelium ,170,171.ithelium ,172. Sucithelium  as well ithelium .DRD4-rs916457 is associated with the total digits and incomplete figures endophenotypes (DRD4 is highly expressed in the fronto-subcortical system in the hypothalamus, thalamus, olfactory bulb and hippocampus, which are part of the limbic system [DRD4 are also associated with perceptual organization [Marker enotypes  and exprenotypes . DRD4 isc system , as wellc system . An imbac system . Variantnization , which inization , suggestnization .Despite our encouraging results, some limitations are to be acknowledged. First, the lack of pupil measurements in individuals of our cohort to determine the pupil diameter and rule out possible eye alterations that may impact perceptual organization is a limitation. Second, genotyped variants are localized in intronic regions. Although variants found to be in linkage and association give important insight into the neurobiological aspects of perceptual organization endophenotypes in our cohort, they may not necessarily be causal variants. In this sense, in silico and animal models may help to elucidate the role of such genetic variation at the protein level and how such changes may impact ADHD susceptibility, severity and long-term outcome. Third, only a few SNPs were available, which restricted the identification of potential associations in other genes of interest. This is a common problem, especially in understudied populations, such as the Caribbean community in Colombia ,51,52.DRD4, ADGLR3 and FGF1 are associated with ADHD endophenotypes related to perceptual organization and, as such, may constitute a new explanatory view of ADHD considering that people with the disorder present alterations in visual and speech perception, which are also determinants of symptom severity [FGF1-rs2282794 with ADHD and ADHD endophenotypes [FGF1 as a potential candidate for ADHD. In neurosciences and neuropsychology, our results could contribute to the design, refinement and establishment of a theoretical construct of perceptual organization as a cognitive dimension in ADHD, supported by neurobiological evidence [In summary, our findings suggest that variants in severity . We alsoenotypes ,52. Findevidence . Howeverevidence ,181. Furevidence ,183,184,evidence ,120,185


N = 279 ADHD, N = 70 BPD, N = 60 ADHD + BPD, N = 61 clinical controls) completed the Emotion Reactivity Scale (ERS), the Cognitive Emotional Regulation Questionnaire (CERQ), the Childhood Trauma Questionnaire (CTQ), and the Relationship Scales Questionnaire (RSQ). Reports of childhood maltreatment experiences were significantly associated with increased levels of emotion reactivity in all our groups and in the whole population, with a greater use of non-adaptive cognitive emotion regulation strategies and insecure attachment patterns. Emotional abuse showed the strongest effect. Further analysis indicated that an anxious attachment style significantly mediated the relationship between CM and the use of non-adaptive cognitive emotion regulation strategies and emotion reactivity. The results of our study suggest an impact of CM on ED and a potentially marked effect of emotional abuse. They also indicate a potentially mediating role of insecure attachment in the relationship between a history of childhood abuse and emotion reactivity and a higher use of non-adaptive cognitive emotion regulation strategies in adulthood.Childhood maltreatment (CM) may have a long-term effect on emotion regulation. This study aimed to explore the relationship between CM and emotion dysregulation (ED) in a heterogeneous population. Four hundred seventy French-speaking outpatients ( Experiencing childhood maltreatment can have a long-term impact on mental health and there is some evidence suggesting its association with several psychiatric disorders in adulthood ,11,12,13One hypothesis concerning how adverse experiences may affect these two disorders is through their impact on emotion regulation. Emotion dysregulation (ED) is a transdiagnostic process known to be involved in several psychological disorders, particularly BPD, of which it is a core component ,33. ReceChildhood maltreatment may also hinder the development of mentalizing capacities ,48,49,50Results from our previous study  suggesteFour hundred and seventy French-speaking outpatients were recruited in a specialized center for diagnosis and treatment of adults suffering from ADHD and BPD at the University Hospitals of Geneva. Patients were initially referred to the center for a diagnostic assessment of these disorders.The patients underwent a clinical evaluation conducted by a psychiatrist or psychologist trained in the assessment of ADHD and personality disorders to ascertain the diagnosis of BPD and/or ADHD and to exclude any organic condition and/or other psychiatric disorder that could better explain the symptoms. The evaluation was based on the Diagnostic Interview for ADHD in adults (DIVA 2.0), a structured diagnostic interview assessing DSM-IV ADHD criteria    and the Two-hundred seventy-nine subjects were categorized as having ADHD, 70 as having BPD, and 60 as having both disorders (BPD + ADHD). Sixty-one patients referred to our specialized center were found, after a careful clinical assessment, not to have either of these disorders and were thus used as a clinical control group in our study. Note that 17 people (27.86%) in the control group reported experiencing symptoms suggestive of an ADHD diagnosis during their childhood but did not present the disorder as adults, in line with the observation that in the general population only roughly 15% of ADHD diagnoses persist in adulthood ,79. In aThe study was approved by the ethics committee of the University Hospitals of Geneva, and all subjects provided informed consent.Emotion Reactivity Scale (ERS) [The le (ERS)  is a queCognitive Emotional Regulation Questionnaire (CERQ) [adaptive strategies, which comprise putting into perspective, positive refocusing, positive reappraisal, acceptance, and refocus on planning; and non-adaptive strategies, which comprise self-blame, blaming others, rumination, and catastrophizing. Each subscale contains four items referring to thoughts after the experience of threatening or stressful life events. The cognitive emotional regulation strategies are measured on a 5-point Likert scale, ranging from 1  to 5 .The e (CERQ)  is a 36-Childhood Trauma Questionnaire (CTQ) [The re (CTQ)  was usedRelationship Scales Questionnaire (RSQ) [The re (RSQ)  was usedre (RSQ) .All analyses were performed using Stata v16 . Univariate comparisons between groups were conducted using the chi-square test (or Fisher’s exact test when the assumption of frequencies for the chi-square test was not met) for qualitative variables and a one-way ANOVA for quantitative variables.p-values < 0.05.Linear regression models with adjustments for age and gender were used to assess the effect of childhood maltreatment on scales assessing emotion reactivity, cognitive emotion regulation strategies, and attachment style in each clinical group separately. For analyses of the whole population, an additional adjustment for diagnostic group as the fixed effect was made. Statistical significance was accepted for p < 0.001. Only total scores were considered. The methods described by Hicks and Tingley [A mediation analysis was used to assess the mediating effect of attachment style on the relationship between CTQ total score and emotion-related scales. Mediation analyses were only done in the whole population with adjustments for age, gender, and diagnostic group considering variables that showed a significant association with CTQ total score at a level of  Tingley  using thp = 0.009; b = 22.33, p < 0.001; and b = 26.12, p < 0.001, for the comparisons of ERS total scores between ADHD, BPD, and BPD + ADHD groups, respectively, vs. Controls). The BPD and BPD + ADHD samples (but not the ADHD group) used non-adaptive cognitive emotion strategies more often than did the Controls  and adaptive cognitive strategies less often . The BPD and BPD + ADHD groups, but not the ADHD group, displayed significantly higher levels of avoidant attachment  than did the Controls.The four groups  differed significantly in several demographic and clinical characteristics: age, gender, occupation, and lifetime comorbidities. Concerning scores on the different scales, the four groups differed significantly in almost all the scales except the CERQ acceptance subscale, the BES cognitive subscale, and the RSQ avoidance and secure subscales. The ADHD, BPD, and BPD + ADHD groups displayed significantly higher ED than did the Control subjects . Considering the whole sample, childhood maltreatment also predicted higher ERS total scores  and higher scores on all three subscales  (p < 0.001)  was significantly associated with higher ERS total scores in all our groups  . In the < 0.001) .p < 0.001; with b = −0.03, p = 0.472 for adaptive strategies) (p < 0.001)   . As with< 0.001) . All fou< 0.001) .Nevertheless, there were some differences between samples: the self-blame and rumination subscales were not significantly associated with childhood maltreatment in the ADHD and BPD + ADHD samples but were significantly associated in the BPD and Control groups, whereas the catastrophizing subscale was not significant in the BPD sample but was significant in the other ones.p < 0.001) in this group. The other significant effect of childhood maltreatment   was on refocusing on planning, which is mainly driven by the ADHD sample in that a higher level of childhood maltreatment was associated with a lower refocusing on planning score .Interestingly, among adaptive strategies, acceptance was significantly associated with childhood maltreatment , with an effect mainly driven by the BPD sample in the sense that a higher level of childhood maltreatment was associated with higher acceptance  and lower RSQ secure scores  (p < 0.001)  was significantly associated with higher RSQ avoidant and anxious scores  . The str< 0.001) .p < 0.001)  .Our study investigated whether childhood abuse could be linked to ED in a heterogenous sample including BPD, ADHD, and BPD + ADHD patients as well as a clinical control population consisting of patients referred for assessment for these disorders. We also wished to explore the use of certain cognitive emotional regulation strategies in relation to past experiences of childhood maltreatment. Finally, we investigated the potentially mediating role of insecure attachment on the relationship between childhood maltreatment and emotional dysregulation in adulthood.The results of this study showed that childhood maltreatment, independent of clinical group, was associated with higher total scores on the scale measuring emotion reactivity. In the whole sample, this relationship also predicted higher values for all the dimensions constituting emotion reactivity, namely sensitivity, intensity, and persistence of the emotion. This observation extended to some degree to all groups individually, including our control group. These results suggest that, regardless of the diagnosis or the existence of a current psychiatric disorder, adverse childhood events may have a long-lasting impact on how individuals experience their emotions. A recent study showed similar results to ours: childhood maltreatment, especially emotional maltreatment, was positively associated with emotional regulation difficulties across different groups, namely healthy controls, individuals with BPD, and clinical controls consisting of individuals with ADHD and/or substance use disorder, without BPD . Our stuRegarding the impact of different types of maltreatment, emotional abuse had the strongest effect on emotional reactivity in the total sample. There is some evidence in the literature supporting a particular association between emotional abuse in childhood and emotion regulation difficulties in adulthood, observed in several studies in different clinical and non-clinical populations, some of which explored features of BPD ,89,90,91As for the different cognitive strategies used to regulate emotions, we found that all four non-adaptive strategy subscales  were significantly associated with childhood maltreatment in the whole population. This result potentially suggests that individuals who have been exposed to adverse childhood experiences, regardless of their diagnosis or the existence of a current diagnosis, may use more non-adaptive cognitive emotion regulation strategies than adaptive ones. There is current evidence in the literature suggesting that exposure to childhood trauma may have a deleterious effect on the strategies used to regulate emotions in different age groups, which may be maladaptive, including greater use of rumination and expressive suppression ,92,93,94Interestingly, in our study, emotional abuse presented the strongest association with the use of non-adaptive cognitive emotion regulation strategies. Similar results were found in a study comparing BPD, major depressive disorder, and healthy control populations, where a history of emotional abuse was associated with dysfunctional emotion regulation strategies, in this case expressive suppression . Past exThe last part of our data analysis focused on exploring the association between total score for childhood maltreatment and attachment patterns in the whole sample. Our results showed that childhood maltreatment predicted higher scores for insecure attachment styles and lower scores for secure attachment. In the literature on the topic, childhood maltreatment is associated with insecure patterns of attachment that may persist in adulthood ,99,100. p < 0.001). There are some data in the literature suggesting a mediating role of insecure attachment in the development of psychopathology after a history of childhood abuse. A previous prospective study observed that insecure attachment style played a mediating role in the relationship between childhood maltreatment and depressive symptoms in young adulthood [When we further explored the strongest and most significant associations with childhood maltreatment total score, which included the CERQ non-adaptive strategies total score, the ERS total score, and the RSQ anxious style score, we found a significant mediating effect of the RSQ anxious style on the association between childhood maltreatment total score and CERQ non-adaptive strategies and ERS total scores: at least 40% of the effect was mediated  * 4  = 0.05/12 = 0.004). Due to the high collinearity between subscales in each scale, only one test was considered for each of the scales. The p-value of 0.004 could then be used as a threshold to only consider the most relevant of our results. We also did not explore individual non-adaptive strategies in relation to abuse types in more detail. One final limitation on the comparison of our results with some of the previously published data may be the choice of measures we used for attachment patterns and emotional difficulties, as they may vary throughout studies. While taking these different observations into account, our results may provide some additional data on the impact of childhood abuse, and specifically emotional abuse, on emotion regulation difficulties later in life.Our study has several limitations. The first relates to the use of a cross-sectional design, with retrospective assessments of childhood abuse through self-report questionnaires, which may induce some bias. Further to this, using a mediation analysis in this setting also limits the possibility to infer any causal effects, and leaves uncertainty on the direction of the mediation. Our analysis can only draw hypotheses that may potentially be explored further in prospective studies. One could also question whether our clinical control group might have been affected by selection bias, as the individuals may have been referred in some cases to the clinical service because of emotion regulation difficulties or have presented sub-threshold BPD or ADHD features. There is evidence supporting the clinical relevance of subthreshold symptoms ,108. BesThe results of our study back up previous data suggesting that childhood maltreatment has an impact on emotion dysregulation, and that the effect of emotional abuse can potentially be marked. Reports of past childhood abuse were associated with increased levels of emotion reactivity in all our groups and higher use of non-adaptive strategies in the whole sample, with emotional abuse having the strongest effect. Our data also suggest that insecure attachment has a mediating role in the relationship between a history of abuse and emotion dysregulation in adulthood. In the future, we intend to explore these observations further and add other dimensions that play a role in emotion regulation, such as reflective functioning. We are also interested in investigating the non-specific impact of childhood abuse on emotion dysregulation in more detail, and determine whether this transdiagnostic process may result from other common underlying difficulties in different patient groups.Our findings also highlight the importance of several considerations that could be useful in clinical practice. The first one is the relevance of enquiring about a history of childhood abuse when conducting clinical assessment of patients presenting with emotion regulation difficulties. The significant impact of emotional abuse emphasizes the importance of exploring a history of emotional abuse when conducting assessments, and not solely taking into consideration experiences of sexual or physical maltreatment. Furthermore, interventions designed to increase the use of adaptive cognitive emotion regulation strategies and reduce non-adaptive ones would be particularly helpful treatment targets to improve emotion regulation in patients with a history of childhood abuse.


Glucokinase activators (GKAs) are a novel family of glucose-lowering agents used for the treatment of type-2 diabetes mellitus. Treatment with different GKAs has been shown to reduce blood glucose levels in these patients. We compared the efficacy/safety of GKAs in patients with type-2 diabetes mellitus through a meta-analysis.We searched the PubMed, Excerpt Medica Database, and Cochrane Central Register of Controlled Trials databases for articles published before December 30, 2020. We computed the weighted mean difference (WMD) and 95% confidence interval (CI) for the change from baseline to the study endpoint for GKA versus placebo treatments.A total of 4 articles (5 studies) were included in the meta-analysis. GKAs were associated with reductions in glycated hemoglobin levels from baseline . No significant difference between GKA and placebo treatment was observed in the results of fasting plasma glucose levels from baseline . A significantly higher change in 2-hour postprandial plasma glucose (2-h PPG) levels  was observed following GKA than placebo treatment. GKAs were associated with a higher prevalence of causing hypoglycemic events than placebo treatment . GKAs had no association with the risk of developing adverse effects  and serious adverse events .GKAs were more effective for postprandial blood glucose control. However, these agents showed a significantly high risk of causing hypoglycemia.CRD42021220364. It has been clinically demonstrated that impaired glucokinase function can cause glucose metabolic diseases, including type 2 diabetes mellitus (T2DM).–5 Glucokinase activators (GKAs) can effectively reduce glycosylated hemoglobin (HbA1c) levels and improve β-cell function in patients with T2DM by improving the function of glucokinase. The low affinity of GKAs to glucose makes them show significant activity only at high glucose concentrations, indicating that these molecules may have a low risk of causing hypoglycemia. However, in some clinical trials, the incidences of hypoglycemia following treatment with piragliatin and MK-0941, novel GKAs, were high.,7 At the same time, in some long-term administration studies, it was found that 2 GKAs, AZD1656 and MK-0941, lost efficacy after several months of therapy.,8 However, the dorzagliatin study of Hualing medicine, which completed a phase III clinical trial of the molecule, showed that HbA1c levels can decrease by up to 1.12% after oral administration of the GKA at a dose of twice daily.,10 In addition, an increase in the dosage showed an increase in the proportion of patients whose HbA1c levels dropped to within the standard range, while the incidence of hypoglycemia did not significantly increase. In order to provide new medical evidence for the management of T2DM, we undertook a meta-analysis to assess the efficacy and safety of GKAs in patients with the disease.Glucokinase activity is associated with glucose-regulated insulin and glucagon secretion in the pancreas, with the enzyme acting as a glucose sensor. In the liver, glucokinase processes glucose after a meal and converts it into glycogen by acting as a glucose sensor in pancreatic β-cells. Therefore, glucokinase has a central role in glucose homoeostasis, with the blood glucose levels being maintained at 4 to 6.5 mmol/L.22.1https://www.crd.york.ac.uk/prospero/#recordDetails).This systematic review and meta-analysis protocol was registered in the International Prospective Register of Systematic Reviews database  in patients with T2DM. The detailed search strategy is shown in Table 2.3Studies were eligible for inclusion if they: were RCTs; compared a GKA with a placebo; treated patients for ≥12 weeks; had at least 1 baseline and post-treatment efficacy and/or safety outcome of interest; included patients with T2DM aged ≥18 years; were published in English.2.41c, fasting plasma glucose, 2-hour postprandial plasma glucose [2-h PPG], hypoglycemic events, adverse events [AEs], serious adverse events [SAE]).Two independent reviewers extracted the following information from articles that met the inclusion criteria: publication information (first author's name and year of publication); baseline characteristics of the study ; outcomes regarding efficacy and safety , double-blinding (0–2 points), and description of withdrawals (1 point).2.6Q-statistic and I2 metric  among trials. A P-value of the Q-statistic < 0.1 and an I2 > 50% represented “substantial variability” and a random-effect model was used, otherwise, a fixed-effect model was applied.,13 If heterogeneity was >50%, we performed subgroup analyses. To estimate a possible publication bias caused by the tendency of published studies to be positive, Egger and Begg tests were used and the level of HbA1c was considered to be the main variable outcome. Sensitivity analyses were undertaken by omitting one study at a time and computing the pooled effect size of the remaining studies to evaluate if the results were markedly affected by a single study. All analyses were done using Stata v11.0 . This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.Continuous data were summarized as the weighted mean difference (WMD) with 95% confidence intervals (CIs) for the change from baseline to the study endpoint for GKAs versus placebos. Dichotomous data were summarized as the risk difference (RD) with a 95% CI. If the 95% CI included a value of 0, we considered the difference between the GKA and placebo not to be significant. Heterogeneity was assessed using the 33.1–8,10 The search results are summarized in Fig. A total of 123 potential articles were extracted and evaluated. Following this, 4 articles (5 studies) presenting RCTs were included in our meta-analysis.Table 3.2According to the evaluation of the methodological quality of the included RCTs, all studies scored >3 points and were considered to be of “high quality.”3.33.3.11c levels from baseline to the end of the study period. We carried out a random-effect meta-analysis that involved 1139 participants assigned to the GKAs group and 264 patients assigned to the placebo group. Analysis of the pooled data showed that GKAs were associated with significant reductions in HbA1c levels from baseline  . To eliminate heterogeneity, we conducted subgroup analyses based on the types of GKAs . Sensitivity analyses showed that exclusion of any study did not significantly change the estimate .All 5 studies reported a change in HbA3.3.2I2 = 0%, P = .768). Sensitivity analyses showed that exclusion of any study did not significantly change the estimate  levels from baseline to the end of the study period. Fixed effects meta-analyses showed no significant differences between GKAs and placebos in fasting plasma glucose levels  Fig. B. There 3.3.3I2 = 0%, P = .476). Sensitivity analyses showed that exclusion of any study did not significantly change the estimate  than that observed with the placebo groups . To eliminate heterogeneity, we conducted subgroup analyses based on the types of GKAs . Sensitivity analyses showed that exclusion of any study did not significantly change the estimate  Fig. D. Mild h3.4.2I2 = 0%, P = .959).A fixed-effects meta-analysis showed that the prevalence of AEs was similar between GKAs and placebos  Fig. E. There 3.4.3I2 = 0%, P = .622).A fixed-effects meta-analysis showed that the prevalence of SAEs was similar between GKAs and placebos   to ensure that the brain, red blood cells, and other glucose dependent cells remain in a healthy state. This condition is called glucose homeostasis. As a glucose sensor, glucokinase can sensitively recognize the change in glucose concentration, timely regulate the secretion of insulin and glucagon, and maintain glucose homeostasis. Impaired function and expression of the enzyme has been observed in patients with T2DM.–5 Activation of glucokinase enhances glucose phosphorylation, increasing glucose-stimulated insulin secretion, and hepatic glucose uptake, as well as decreasing hepatic glucose output. Therefore, this enzyme has been proposed as a therapeutic target as it offers the potential for dual effects in correcting 2 underlying defects in T2DM, viz. impaired insulin secretion and excessive hepatic glucose output.Glucokinase is mainly expressed in pancreatic β-cells and the liver, where it catalyses the phosphorylation of glucose to glucose-6-phosphate. MK-0941, AZD1656, dorzagliatin [HMS5532], PF-04991532, piragliatin [RO4389620], AMG 151 [ARRY-403], AZD6370, globalagliatin [LY2608204], and TTP399) have undergone clinical trial investigations; however, the results from these studies were not consistent. Due to the obvious heterogeneity among the studies, we developed strict inclusion criteria for a meta-analysis. Many studies were excluded because they did not meet the inclusion criteria.–24 In addition, the study involving TTP399, a hepatoselective GKA, was excluded because the results could not be extracted. The GKAs included in the meta-analysis were PF-04937319 (N = 2), MK-0941 (N = 1), AZD1656 (N = 1), and dorzagliatin (N = 1). Our meta-analysis showed that GKAs were associated with significant reductions in HbA1c levels from baseline . In terms of function, GKAs can be divided into 3 categories: liver selective GKAs which can only activate glucokinase of the liver, partial GKAs which act on the liver and pancreas at the same time and reduce the Km value of glucokinase, and full GKAs which act on both the liver and pancreas and can increase the Vmax of glucokinase and decrease its Km. PF-04937319 and AZD1656 are partial activators of glucokinase, while MK-0941 and dorzagliatin are all full GKAs. According to the subgroup analyses involving different types of GKAs, both partial and full GKAs were seen to reduce HbA1c levels  . Our meta-analysis showed that GKAs induced a significantly greater change in 2-h PPG levels  but had no effect on fasting blood glucose  than the placebo. The observed reduction in HbA1c appeared to be the result of changes in postprandial blood glucose levels.To date, 10 GKAs ; however, some limitations are noted. First, most of the studies included in our meta-analysis were of a relatively short duration (longest duration was 30 weeks). Therefore, we could not comment on long-term efficacy and safety. Second, despite the addition of more RCTs, statistical heterogeneity was detected. This heterogeneity may have arisen from the differences in study design, duration of T2DM, and control drug therapy. Third, the number of included studies was relatively small. Fourth, the cut-off of hypoglycemia was not clearly defined in the included studies. Therefore, more “high-quality” RCTs are needed to verify our conclusions.5Among patients with T2DM, GKAs were more effective than placebo treatment for postprandial blood glucose control. In addition, GKAs had a comparably high risk of causing hypoglycemia. However, this new class of hypoglycemic agents needs continued evaluation in RCTs to ascertain long-term efficacy and safety.Conceptualization: Qian Gao.Data curation: Qian Gao, Wenjun Zhang.Investigation: Tingting Li.Methodology: Tingting Li.Resources: Wei Zhu.Software: Naijun Chen.Supervision: Wenjun Zhang, Guojun Yang, Huawei Jin.Writing – original draft: Qian Gao.Writing – review & editing: Qian Gao.


Secondary progressive multiple sclerosis (SPMS) subtype is retrospectively diagnosed, and biomarkers of the SPMS are not available. We aimed to identify possible neurophysiological markers exploring grey matter structures that could be used in clinical practice to better identify SPMS. Fifty-five people with MS and 31 healthy controls underwent a transcranial magnetic stimulation protocol to test intracortical interneuron excitability in the primary motor cortex and somatosensory temporal discrimination threshold (STDT) to test sensory function encoded in cortical and deep grey matter nuclei. A logistic regression model was used to identify a combined neurophysiological index associated with the SP subtype. We observed that short intracortical inhibition (SICI) and STDT were the only variables that differentiated the RR from the SP subtype. The logistic regression model provided a formula to compute the probability of a subject being assigned to an SP subtype based on age and combined SICI and STDT values. While only STDT correlated with disability level at baseline evaluation, both SICI and STDT were associated with disability at follow-up. SICI and STDT abnormalities reflect age-dependent grey matter neurodegenerative processes that likely play a role in SPMS pathophysiology and may represent easily accessible neurophysiological biomarkers for the SPMS subtype. Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) and is one of the leading causes of disability in young adults . MS is cSomatosensory evoked potentials and motor potentials evoked by transcranial motor cortex stimulation reveal demyelinating damage and reduced conduction velocity in the central sensory and motor pathways in early stages of RRMS, but they are less effective in demonstrating changes reflecting grey matter loss ,9. HowevThe aim of the present study was to verify whether TMS parameters and STDT measures of motor and sensory grey matter circuits at the cortical and subcortical level are associated with the SPMS rather than RRMS subtype. To do so, we tested: (1) M1 excitability and intracortical inhibitory and facilitatory circuits using single- and paired-pulse TMS paradigms  and (2) Fifty-five pwMS  and 31 age- and sex-matched healthy controls (HCs) were enrolled . PwMS weSingle- and paired-pulse TMS were delivered using a Magstim Bistim2 magnetic stimulator . Magnetic pulses were delivered through a figure-of-eight coil placed on the M1 motor area of the right hand. The coil was placed tangentially to the scalp, and the tail was directed backward and at 45° to the median line to elicit MEPs from the contralateral first dorsal interosseous (FDI) muscle. Resting motor threshold (RMT) was defined as the minimum intensity able to evoke MEPs of at least 50 µV of amplitude in at least 5 of 10 consecutive trials. Single-pulse intensity was set to obtain MEPs of 1 mV of average amplitude . Paired-With subjects seated comfortably on an armchair in front of a table, STDT was assessed following experimental procedures used in previous studies ,30,31,32Statistical analysis was performed using R, version 4.0.2.t-test was applied to all variables to compare pwMS and HCs. Variances were assumed to be unknown and to differ between groups, so Welch correction was applied to the statistic.T-test: An unpaired p < 0.05), and the final model was estimated. Finally, model predictions were computed and validated with leave-one-out cross-validation.Logistic regression and validation: Logistic regression was used to discriminate SPMS from RRMS pwMS. For computational purposes, pwMS with RRMS were coded as class 0, while an SPMS diagnosis was coded as class 1. EDSS was removed from the list of independent variables in order to focus on neurophysiological parameters. Meanwhile, age and disease duration were clinically considered correction factors for other variables. However, age was chosen since it showed higher between-group differences than disease duration. Firstly, all explanatory variables were corrected for age as a multiplicative effect and an automatic stepwise logistic regression was performed to select the most important variables. This procedure was driven by Akaike Information Criterion (AIC), starting from the empty model, i.e., considering only the intercept. At each step, the system included or excluded a single variable depending on how much this change would have lowered the AIC model. The sequence of steps was interrupted when none of the possible model changes would have caused a decrease in AIC. At the end of this automatic variable selection, only significant variables were kept , disease duration , and baseline EDSS score . Conversely, sex distribution was similar in the two groups . For logistic regression analysis, subjects with RRMS were coded as class 0, while subjects with SPMS were coded as class 1. Logistic regression analysis showed that SICI and STDT were the neurophysiological parameters of the best estimated model (data shown in X) would be assessed as SPMS (class 1), was the following:RRMS and SPMS differed in terms of age , 0.65; sensitivity, 0.588; and specificity, 0.679. For STDT, the evaluation metrics were: AUC, 0.805; sensitivity, 0.944; and specificity, 0.543.p = 0.02) and EDSS score  .In order to identify possible clinical correlates of SICI and STDT in pwMS, we performed an age-corrected partial Spearman’s rank correlation coefficient analysis, which revealed a correlation between STDT values and disease duration  . Howeverp = 0.006). We designed a linear regression model with the follow-up EDSS score as the dependent variable and SICI, STDT, age, and disease duration as independent variables. The model also showed that SICI , STDT  (p = 0.001) were associated with the follow-up EDSS score. The Charlson comorbidity index was similar in RRMS and SPMS and did not correlate with neurophysiological parameters.Finally, we performed a one-year follow-up clinical assessment and observed an increase in EDSS score (= 0.007) , and ageIn the present study, we evaluated possible neurophysiological biomarkers for MS subtypes by testing the activity of neural circuits of both motor and sensory grey matter cortical and subcortical structures. Consistent with the hypothesis that grey matter damage is involved in MS progression , we obseDuring the experimental procedures, we took several precautions to minimize possible confounding factors due to methodological biases. Investigators performing the neurophysiological evaluation were blinded to pwMS clinical features. To avoid our findings being affected by fatigue mechanisms, learning processes, or attention level, all techniques were performed in a pseudo-randomized order. Since TMS responses, including SICI and ICF, are influenced by target muscle voluntary contraction , we askeA growing body of evidence has reported that cortical and subcortical grey matter atrophy, rather than white matter damage, is involved in the pathophysiology of SPMS ,6,7. HisOur finding of an association between SPMS and SICI, but not ICF, deserves a comment. Although ICF, like SICI, is elicited by a paired-pulse TMS protocol, it recruits excitatory intracortical pathways in M1 with glutamatergic mediation ,11. The Previous studies in healthy subjects showed that age influences inhibitory-mediated mechanisms in motor  and sensThe follow-up clinical assessment we performed allowed us to explore the clinical weight of SICI and STDT by investigating neurophysiological–clinical correlations. We found that STDT correlated with both disease duration and disability level, as tested by EDSS scores at baseline and follow-up, whereas SICI did not correlate with clinical variables at baseline but was associated with EDSS score at follow-up. As mentioned above, SICI and STDT both depend on cortical activity, whereas subcortical structures are involved only in STDT generation, with the thalamus playing a crucial role . StudiesThe present study has a number of limitations. First, since we aimed to provide neurophysiological markers that could be applied in routine clinical practice, we enrolled pwMS who were on different symptomatic and disease-modifying therapies. Although this approach reflected the real-world condition of pwMS, it is possible that the presence of medication may have at least partly influenced our results. Although we asked pwMS to undergo a 24 h withdrawal from symptomatic medications, we cannot fully exclude long-term effects. Second, our study had a cross-sectional design and only one year of follow-up. Although EDSS scores were significantly increased at follow-up, thus implying disease progression in at least some of the pwMS we tested, the relationships between neurophysiological parameters and SPMS need to be validated by longitudinal studies with a longer follow-up. In addition, in the present study, we did not specifically assess the possible contribution of fatigue on the neurophysiological measures we tested. Therefore, future studies investigating the relationship between fatigue and grey matter involvement in MS are needed.Finally, in the present study, we did not perform a conventional or advanced magnetic resonance imaging (MRI) assessment, which could have provided further support to the current hypothesis regarding the relationship between SICI and STDT abnormalities and grey matter damage in MS. Conventional MRI techniques are able to detect only 20–30% of cortical lesions and do not discriminate between subtypes . ConversThe observation that abnormalities in two neurophysiological parameters reflecting cortical and subcortical grey matter inhibitory mechanisms of the motor and sensory systems were associated with SPMS suggests that neurodegeneration, particularly loss of inhibition, plays a key role in SPMS. We conclude that SICI and STDT are easily accessible pathophysiological candidate biomarkers that may increase the accuracy and timeliness of SPMS identification. Future multicenter longitudinal studies are needed to verify our proposed neurophysiological index.


This study investigated change detection of central or marginal interest in images using a change-blindness paradigm with eye tracking.Eighty-four drug-naïve adolescents [44 with attention-deficit/hyperactivity disorder (ADHD)/40 controls with typical development] searched for a change in 36 pairs of original and modified images, with an item of central or marginal interest present or absent, presented in rapid alternation. Collected data were detection rate, response time, and gaze fixation duration, latency, and dispersion data.Both groups' change-detection times were similar, with no speed–accuracy trade-off. No between-group differences were found in time to first fixation, fixation duration, or scan paths. Both groups performed better for items of central level of interest. The ADHD group demonstrated greater fixation dispersion in scan paths for central- and marginal-interest items.Results suggest the greater gaze dispersion may lead to greater fatigue in tasks that require longer attention duration. Attention-based mechanisms play an essential role in development, redirecting cognitive resources to new or salient stimuli, and facilitating information processing and adaptive response . AttentiA range of experimental paradigms have been used to study different aspects of change detection. For instance, visual-search tests are perceptual tasks requiring attention and active scanning to detect a feature change in a particular object among other objects . In theChange blindness is a perceptual phenomenon that occurs when a transient change in a visual stimulus is introduced and the observer does not notice it right away  on the changed item , and total fixation duration (TFD) on the changed item . We also compared scan paths and gaze dispersion.We hypothesized that ADHD participants would have longer change-detection times, particularly in detecting marginal interest changes because they require greater attentional control, whereas central interest changes semantically pop out from the picture . AlternaWe also expected that limited attentional resources would cause participants with ADHD to have longer gaze TFD on the marginal interest changed items compared to the group with typical development. We assumed that, because detecting marginal change requires an item-by-item scan of the entire image using comparison strategies and working memory, it gives rise to longer identification times if processing is inefficient or speed is slowed. We hypothesized that first-fixation latency (TFF) would be longer for marginal interest changed items for the same reasons. These in turn, we speculated, might cause the ADHD group to exhibit longer scan paths and greater gaze dispersion because they might need to often backtrack to detect the change.*Power for detecting moderate effects with a statistical power of 95%, with alpha at 0.05 ; the group with typical development (TD group) comprised 40 participants . The groups did not differ with respect to age . AdolescThe ADHD group included 15 children who met the criteria for the ADHD/C subtype (exhibit both inattentiveness and hyperactivity/impulsiveness symptoms), 14 who met the criteria for ADHD/A (show predominantly inattentive symptoms), and 15 who met the criteria for ADHD/B .Adolescents in the comparison (TD) group were selected from a local school and attended a regular classroom setting but were excluded from the study if they had above-cutoff scores on the DBDRS. The study was approved by the [blinded] University's Ethical Review Board and by the Helsinki Committee of the Hospital. A written informed assent and consent was obtained from the participants and their parents signed an informed consent.The experimental stimuli consisted of 36 pairs of real-world scene images, 18 of which were adopted from Rensink et al.  and the central) or of low-level interest . The images were matched on psychometric properties, location of change, size of change, conspicuity of change, and intensity . For each image, we analyzed gaze data on an AOI that circumscribed the changing item with an 0.5-visual degree margin (5 mm) to account for the eye tracker's accuracy error. We computed TFD and TFF based on fixations that fell in this AOI.The images were displayed on a 17-in screen in a “flicker” paradigm from a viewing distance of about 50 cm. Responses were collected The images were presented in counterbalanced trials in two test blocks with a 1–2 min rest period in between. Each trial started with a fixation cross  appearing for 1 s. It was followed by a briefly displayed (360 ms) scene image, followed by a gray blank scene displayed for 120 ms, followed by another image displayed for 360 ms, and a repetition of this sequence . The seqParticipants were tested individually in a silent room. Before they began, they received a brief overview of the experiment and were instructed to click on the mouse as soon as they detected that one object appeared and disappeared, and then to verbally describe the change. Participants were told that a change would occur on every trial and were encouraged to keep searching for differences and not give up before the end of the trial. A 9-point calibration of the eye tracker was applied before each experiment.®. The areas of the convex hulls were then averaged over the trials of each participant in each condition to provide a metric for dispersion. Data was analyzed by using IBM SPSS Statistics for Windows, Version 23.0. When appropriate, post-hoc t-tests were performed using the Bonferroni adjustment.A group  × level of interest  repeated measures analysis of variance (ANOVA) was carried out for change-detection times  and eye-tracking metrics. The ANOVA for percentage of errors included an additional factor for the type of error . Change-detection times and eye-tracking metrics in trials in which participants did not detect the change were not included in the analyses. Eye-tracking metrics included the TFF (the amount of time that it took the respondent to first gaze at the changing item), TFD on the changing item, mean scan path , total scan path , and gaze dispersion. Gaze dispersion was computed by identifying the smallest convex area enclosing all the fixation points. A convex hull was computed for each trial of every participant with MatlabF = 7.03, p ≤ 0.01, η2 = 0.01 . However, the percentage of errors did not differ between groups, F = 0.83, p = 0.36, nor was there an interaction effect between type of error  and group, F = 2.6, p = 0.11.There were no errors for the central level of interest in either the ADHD or TD group; therefore, data analysis was applied only for the marginal level of interest. There was a main effect for type of error, F = 363.9, p ≤ 0.001, η2= 0.82. There was no significant difference between the ADHD and TD groups, F = 0.02, p = 0.26, and no interaction effect between groups and levels of interest, F = 0.73, p = 0.84 (Detection times (time to first mouse click) were longer for marginal items compared with central items, p = 0.84 .F = 236.4, p ≤ 0.001, η2 = 0.75, showing that both groups were slower to look at the marginal items, but no significant difference between groups, F = 0.05, p = 0.83, and no interaction effects, F = 0.08, p = 0.79, were found  = 31.1, p ≤ 0.001, η2 = 0.28, showing that both groups looked longer at the marginal items, but no significant difference between groups, F = 0.01, p = 0.72, and no interaction effects, F = 0.03, p = 0.57 were found  and controls  revealed a main effect for levels of interest, F = 6.21, p ≤ 0.01, η2= 0.07, but no interaction effect, F = 1.6, p = 0.21, or between-group effect F = 1, p = 0.32.Mean scan path  findings for the ADHD group  and controls  revealed a main effect for levels of interest, F = 122, p ≤ 0.001, η2 = 0.6, but no interaction effect, F = 0.001, p = 0.97, or between-group effect, F = 0.57, p = 0.45.Total scan path  findings for the ADHD group  = 40.4, p ≤ 0.001, η2 = 0.32, and a main effect for groups, F = 5.72, p ≤ 0.01, η2 = 0.1, with no interaction effect for these two factors, F = 0.39, p = 0.54 (Gaze dispersion (area of the convex hull of fixation points) analysis revealed a main effect for levels of interest, p = 0.54 .The purpose of this study was to compare the visual attention of adolescents with and without ADHD. We used a change-blindness task on an age group that has not been studied before, that is, adolescence. Contrary to our hypothesis and a previous study among children , the adoPerceptual load has been operationally defined as either the quantity of stimuli entailing perceptual processing or the complexity of perceptual judgments (The lack of difference between the ADHD and TD groups on performance metrics such as the detection rate and detection times can be interpreted in light of the perceptual cognitive load theory . Accordiudgments . When thudgments , 37.In the current study, the change-blindness task necessitated complex perceptual judgement. For example, the marginal condition required inhibition of distracting features that were semantically relevant to the scene displayed, although they were irrelevant to the required task of detecting change. The analysis of results did not yield evidence that change-detection times were longer in participants with ADHD compared to those with typical development. The ADHD group did not show different speed–accuracy tradeoffs that could be a sign of them being tired or having difficulties concentrating. Hence, the “perceptual cognitive load” required by the change-blindness task may have helped those with ADHD to focus. This explanation is in line with a study that tested the perceptual cognitive load theory in individuals with ADHD  and whosTime to first fixation and TFD on the changed items followed the same trend as percentage of errors and detection times—that is, there were no differences between participants with ADHD and the TD controls. These results contrast with the results of Türkan et al. , who fouNonetheless, one can deliberate that in the wake of the current knowledge of executive functioning difficulties, such as working memory, in people with ADHD , the tasA feasible argument for the ability of the participants in the current study to overcome working-memory difficulties is compensatory attentional processes, such as stimulus-driven attention, as opposed to goal-directed attention. Working-memory deficits might not affect attentional control adversely in individuals with ADHD when the task design or stimuli provide extrinsic reinforcement of the task set and rules. For instance, Burgess et al.  administBurgess et al.'s  results Differences were nevertheless found when analyzing gaze dispersion. Those differences did not appear in mean and total scan paths measures, probably because such metrics were too coarse. They did appear, however, when considering the convex hulls of fixation points. It appears that the participants with ADHD tended to survey a larger portion of the image. The increase in gaze fixation area may reflect a greater proclivity to attend to a new stimulus, even when asked to goal orient on detecting a change, and a relatively attenuated propensity to continue processing the current stimulus, creating fixation scatter.It is further possible that “fixation scatter” may reflect an imbalance between the bottom-up stimulus-driven and the top-down attentional-control mechanisms that govern visual attention . These rThis is the first study to our knowledge that used change blindness to assess visual attention in adolescents with ADHD. Two previous studies , 27 showAn additional issue for further investigation is that of ecological validity; that is, the extent to which the stimuli and protocol approximate the real-life situation of adolescents with ADHD. This study may shed light on the visual-attention patterns adolescents with ADHD exhibit when required to attend to images portraying various real-life contexts. However, we strongly recommend investigating whether the conclusions hold when associated with everyday tasks that require “functional attention.”This study attempted to gain insight on the attentional performances of adolescents with ADHD, using a change-blindness paradigm with naturalistic images. The use of eye tracking enabled analyzing gaze patterns, such as TFF and TFD on the changing item, as well as the scan paths and fixation dispersion. Adolescents with ADHD detected changes with similar accuracy and speed compared to controls but with gaze dispersed across larger areas. Our results with regards to accuracy should not be taken as conclusive because there possibly was a ceiling effect related to the difficulty of the tasks, and that more difficult tasks would result in some more subtle between-group differences. The greater gaze dispersion in the ADHD group sheds light on the distinctive attentional mode of people with ADHD, suggesting less structured gaze patterns and a lack of inhibition of intrusive saccades. Future directions should investigate whether this gazing behavior is beneficial over time, or if it causes fatigue or lower efficiency when completing longer tasks. Furthermore, this study substantiates the potential assets of eye tracking as a comprehensive tool for assessing attentional deficits in those who are suspected of having 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 Helsinki Committee Shaare Zedek Medical Center. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.MH conceptualized, designed and performed experiments, analyzed data, and co-wrote the paper. AA provided Helsinki approval management and medical guidance. OG analyzed data and co-wrote the paper. All authors contributed to the article and approved the submitted version.Open access publication fees received from Ariel University.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In this study, chromatic pupil campimetry (CPC) was used to map local functional degenerative changes of cones and rods in Stargardt disease (STGD1).ABCA4 mutations and a clinical diagnosis of STGD1 and 12 age-matched controls  underwent scotopic (rod-favoring) and photopic (cone-favoring) CPC. CPC evaluates the local retinal function in the central 30° visual field via analysis of the pupil constriction to local stimuli in a gaze-corrected manner.19 patients  with genetically confirmed Scotopic CPC revealed that the rod function of patients with STGD1 inside the 30° visual field was not impaired when compared with age-matched controls. However, a statistically significant faster pupil response onset time (∼ 40 ms) was observed in the measured area. Photopic CPC showed a significant reduction of the central cone function up to 6°, with a minor, non-significant reduction beyond this eccentricity. The time dynamic of the pupillary response in photopic CPC did not reveal differences between STGD1 and controls.The functional analysis of the macular region in STGD1 disease indicates reduced central cone function, corresponding to photoreceptor degeneration. In contrast, the rod function in the central area was not affected. Nevertheless, some alteration of the time dynamics in the rod system was observed indicating a complex effect of cone degeneration on the functional performance of the rod system. Our results should be considered when interpreting safety and efficacy in interventional trials of STGD1. ABCA4) gene.ABCA4-associated retinopathy typically begins with central or pericentral vision loss and develops to various extents of macular atrophy. However, areas beyond the macula can also be affected and can lead to difficulties under dark adaptation, giving rise to fundus flavimaculatus, cone–rod dystrophy, and retinitis pigmentosa phenotypes.–Stargardt disease (STGD1) is a rare autosomal recessively inherited macular dystrophy with central vision loss caused by biallelic mutations in the ATP-binding cassette transporter , specifically designed to evaluate photoreceptor function at the local retinal level, targeting either the cone or the rod population.ABCA4 mutations, and a clinical diagnosis of STDG1 at baseline visit for an interventional trial (EudraCT no.: 2018-001496-20). The genetic report before the inclusion to the trial had to include at least two causal variants of the ABCA4 gene and, in most patients, was based on panel sequencing or genome sequencing in a diagnostic–genetic setup. Visual acuity between 0.2 and 0.8  in both eyes was one of the inclusion criteria. All participants underwent a full ophthalmological examination to exclude any possible additional interfering pathology, including best-corrected visual acuity testing, slit-lamp examination, fundus ophthalmoscopy, optical coherence tomography, and fundus autofluorescence imaging. Additionally, fixation stability was evaluated using mesopic microperimetry . CPC was measured only in one eye with the other eye patched. Detailed characteristics of the subjects including genetic finding and preferred retinal locus (PRL) position distance to fovea calculated from mesopic microperimetry are presented in Examinations were obtained from 19 patients  with genetically confirmed In 14 subjects, the right eye was tested and in 5 subjects the left eye was the study eye. Thus, a direct averaging was not recommended, because the temporal and nasal retinal locations would be confounded. To ensure that no effect was driven by left to right eye retinotopic differences, in the case that the left eye was measured, all results were mirrored.Twelve age-matched adults with normal vision served as controls . The data of the control group have partially been published.All patients gave written informed consent before participation. The pupils were not dilated medically before the CPC measurement and none of the patients had reported taking any psychosomatic drug that could have influenced the pupillary response. The study was conducted in concordance with the Declaration of Helsinki and approved by the local Ethics Committee.2, stimulus wavelength 620 ± 30 nm full width at half maximum, 1.7 × 10−5 watt, with an interstimulus interval of 4.5 seconds). An automatic control controls the return of the pupil to the baseline value, and, if this is not achieved, then the stimulus is repeated. The repetition of stimuli is also triggered if the gaze correction could not be performed (loss of gaze tracking or to large deviation from the fixation point). Beside these two conditions, also the eye blink artifact during stimuli presentation will trigger the repetition of a stimulation. The recording time of the photopic recording is therefore not fixed, but dynamic and subject dependent and approximately 8 to 9 minutes.For an objective evaluation of local rod and cone function within the central 30° visual field, separate CPC protocols for scotopic (rod-favoring protocol with blue stimuli) and photopic (cone-favoring protocol with red stimuli) evaluation were used. The stimuli were presented on a wide screen organic light-emitting diode monitor within the central 30° (LG organic light-emitting diode 55C7V). A correction of the refractory error is not used in our setup. A gaze-tracking algorithm was used to ensure correct retinotopy. Pupillary response and gaze tracking were recorded with an infrared camera with a sampling frequency of 100 Hz. Recording is started with 5 minutes of specific light exposure (weak blue light of the same intensity as stimulus used for the scotopic protocol). The photopic measurement after light adaptation consists of 41 red stimulation points inside of the 30° visual field. For the photopic protocol, red stimuli were presented on a dim blue background . Duration of scotopic measurement is in average approximately 6 to 7 minutes. Stimulus characteristics and protocols have been described in more details previously, including validation and the test–retest reliability profile.–After the photopic measurement, the subject is dark adapted for 20 minutes. After that, the scotopic measurement is performed; dim blue stimuli were presented on a totally black background .Pupil responses were normalized to the baseline pupil diameter and these relative values of amplitude were used for further analyses in accordance with the standards in pupillography.The time dynamics of the neuronal network controlling pupillary reflexes were evaluated through the analysis of the time from stimulus onset to pupil constriction onset (latency). This latency was calculated from the intersection between the estimated linear fit of pupillary constriction (period of 200 ms with constant first derivation) and the linear fit of the baseline period (0–500 ms).t-tests were used. The analysis of specificity and sensitivity of CPC in detecting STGD1 induced macular change was performed for the steepness angle with the receiver operating characteristic (ROC) curve.To test for a group difference between patients with STGD1 and age-matched control subjects, two-tailed P of less than 0.05 was considered statistically significant. For eccentricity-specific analyses, the P value was adjusted according to Bonferroni correction 0.01 (5 nonindependent t-tests). All analyses were performed in MatLab .Results are presented as mean ± standard deviation. A The baseline pupil size did not show a statistical difference between groups in both conditions: Controls had an average baseline pupil  comparable with STGD1 . The retinal sensitivity maps for photopic and scotopic measurements averaged over the control group and STDG1 are presented in P < 0.001; control relMCA = 25 ± 5%; STGD1 relMCA = 13 ± 5%) and at 6° eccentricity , but did not differ between the two groups beyond the central 10° (statistics see The difference between group averages (STGD1 vs. controls) for photopic and scotopic measurements are presented in A ROC analysis was performed to test the specificity and sensitivity of the steepness angle in detection of macular defects under photopic conditions in the patients with STGD1 compared with the controls. The results indicate that this factor has a high classification (area under the curve of 0.92) in detecting macular defects for the STGD1 group .P < 0.005) in all eccentricities of the STDG1 group for the scotopic protocol compared with the control group.Bar plots of the latency to constriction onset of the pupillary response for different eccentricities are shown in P = .056). All other examination parameters including best-corrected visual acuity, relMCA, or the latency of the pupil responses at different eccentricities were far from statistical significance (The dependency of the steepness angle between relMCAs to central and peripheral stimulation in the photopic measurement and age for STGD1 subjects showed a trend not reaching statistical significance (ificance .–These results validate the macular defect of cone function in early and middle stages of STGD1 with a novel objective functional diagnostic, namely, the CPC. This macular defect measured by the photopic CPC is characterized by a remarkable loss of the typical central CPC response hill of the relMCAs otherwise seen in the control subjects. The ROC analysis with the steepness angle of CPC response between peripheral and central stimulation under photopic condition resulted in an area under the curve of 0.92, indicating a good classification of the macular defect in patients with STGD1 in comparison with the control group. Although this deficiency in cone response is obvious for all patients, that functional defect is not absolute. All patients with STGD1 still have elicitable pupillary responses in the central region, indicating a substantial population of functioning cones. Our previous results pointed to a connection between the pupillary response to monochromatic local stimuli and the density of responding photoreceptors cells in the respective stimulated region.The progression of the disease expressed as a decrease of the steepness angle showed a possible correlation with patients’ age. Although this correlation presents only a trend, interestingly, no other readout such as the averaged relMCA, time onset of pupillary responses, or best-corrected visual acuity showed a similar relationship with age. The lack of correlation of these readouts is likely related to the genetic heterogeneity within our cohort, which presents a limitation in establishing better predictors for functional degeneration. The evaluation of the time dynamics of the pupil response shows that the cones in the whole tested area, but also in the area of damage, are properly connected to the inner retina. This finding may indicate that the degeneration does not exceed photoreceptors. In contrary to this finding, our earlier study in patients with AMD showed a prolongation of the foveal pupillary response latencies of approximately 80 ms.–CNGA3-achromatopsia, in whom a hyperactivity in the rod system has been shown by full-field pupillography.In contrast with the clearly visible defect in the cone function in STGD1, we did not observe this effect in the rod system. The higher susceptibility of cones to STGD1 are known.A limiting factor of this study is the fact that patients with STGD1 do not always have the PRL in the fovea; thus, the retinotopic stimulation could have been altered by this shift. The analysis of PRL in our cohort from microperimetric examinations showed that only in two subjects , this woIn conclusion, the CPC measurement revealed several new characteristics of the STGD1-related degeneration of photoreceptors. First, the functional degeneration in early and middle phases of STGD1 is predominantly affecting cones. The loss of cones is highest in the foveal region, but is not absolute and does not seem to affect the interconnection with the inner retina. Second, changes in the rods’ time dynamics in affected regions indicate some level retinal network alteration up to the mid periphery, which should be considered in future therapeutic interventions. In the current setup, CPC presents a strong complement to classical retinal functional testing. With its previously shown high reliability and repeatability, this objective evaluation of the local rod and cone function respectively may be a valuable modality for testing the retinal function in therapeutic interventions for STGD1.


Objective: To assess the effectiveness of physical activity (PA) intervention on attention-deficit/hyperactivity disorder (ADHD)-related symptoms.Method: Studies that investigated PA intervention for ADHD-related symptoms were identified through searching PubMed, Web of Science, Cochrane Library, and Embase databases from inception through June 2021. Standardized mean difference (SMD) with 95% confidence interval (CI) was used to assess the effectiveness of PA intervention on improving ADHD-related symptoms. The meta-analyses were conducted using fixed-effect or random-effect models according to the heterogeneity of the studies.Results: Nine before–after studies (232 participants) and 14 two-group control studies (162 participants/141 controls) were included in this meta-analysis. Combined results for before–after studies indicated significant improvements on all studied ADHD-related symptoms . Meta-analyses for two-group control studies further confirmed that PA intervention significantly improved the inattentive symptom . Subgroup analyses suggested significant beneficial effect on inattention symptoms in children. Moreover, closed motor skills were beneficial for hyperactive/impulsive problems , while open motor skills were beneficial for attention problems . When excluding studies with combined medication, the studies in unmedicated participants in before–after studies still showed significant results in all studied ADHD-related symptoms as in the overall analysis. Given the limited sample size, the best frequency and intensity of PA intervention need further investigation.Conclusion: Our results suggested that PA intervention could possibly improve ADHD-related symptoms, especially inattention symptoms. Closed-skill and open-skill activities could be beneficial for hyperactivity/impulsivity and inattention symptoms, respectively. Further high-quality randomized clinical trials with large sample size are needed. ADHD is one of the most prevalent mental disorders in children and usually lasts into adulthood, with a worldwide prevalence of about 5.9% . In addiAt present, the major treatments for ADHD are medication  and behaGrowing evidence shows that moderate physical activity (PA) can improve psychological health through enhancement of neurotransmitter systems and upregulation of the brain-derived neurotrophic factor (BDNF) and neurogenesis . As a poMotor skills are defined as physical activities involving a single or a group of movements performed with a high degree of precision and accuracy . Based oGiven that the effect of PA on ADHD symptoms is a major concern clinically, we conducted this systematic review and meta-analysis to establish the clinical effectiveness of PA on ADHD related symptoms across ages and environmental settings.This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline  27). Th. Th27). * OR attention-deficit hyperactivity disorder* OR attention deficit disorder* OR attention deficit disorder* with hyperactivity OR attention deficit hyperactivity disorder* OR attention deficit-hyperactivity disorder* OR attention deficit disorder hyperactivity OR attention deficit hyperkinetic disorder OR ADHD OR adhd OR addh OR add OR attention deficit OR child attention deficit disorder OR inattenti* OR attention problem* OR hyperactiv* OR hyperkinetic syndrome* OR syndrome* hyperkinetic OR hyperkinetic syndrome childhood OR hyperkinetic disorder OR hyperkinet* OR overactive* OR overactive child syndrome OR syndrome hyperkinetic OR hyperkinetic syndrome OR hyperactivity disorder OR hyperactive child syndrome OR childhood hyperkinetic syndrome) and . PA is defined as any body movement produced by contraction of skeletal muscle that substantially increases energy expenditure  clinical trials investigated PA intervention; (2) studies examined the effect of PA intervention on ADHD symptoms as compared to the no-intervention condition ; (3) study participants had clinical diagnosis of ADHD, or ADHD-related symptoms; and (4) studies reported ADHD-related symptom scores. Studies were included regardless of medication status (medications for ADHD or any other treatment) or sex ratio. We excluded literatures for the reasons below: (1) studies had not reported the data as mean/SD or were short of data of pretest or posttest; (2) ADHD symptoms are not measured using scale symptom scores, ; (3) study compared with other treatment group . Comorbidities in all or part of the study participants were exclusionary.http://getdata-graph-digitizer.com/) , PA programs , and measurements of ADHD symptoms. If the ADHD symptom scores were only provided in figures, we extracted data from the bar charts using GetData Graph Digitizer v.2.25 software (er.com/) , 30.According to the Cochrane handbook for systematic reviews of interventions , all effIn consideration of the heterogeneity of included studies and to control the impact of the self-healing factor, we conducted two separated meta-analyses for before–after studies  and two-group control studies (PA intervention group vs. PA free group).I2 and combined with the p-value to determine which model to be used. I2-values were interpreted as low (25%), moderate (50%), and high (75%) . SMD with 95% confidence interval (CI) was calculated for each outcome. The heterogeneity of the included results was quantified by gh (75%) . Followigh (75%) , the ranIn order to find the source of heterogeneity, subgroup analyses were conducted stratified by ADHD diagnostic status (yes vs. no), study population (children vs. adults), type of motor skills (closed motor skills vs. open motor skills), PA intensity (moderate intensity vs. moderate-to-vigorous intensity), and PA frequency (<3 times per week vs. ≥3 times per week). We also analyzed the effect in the non-medicated group but were unable to compare un-medicated with medicated group due to limited study (only 1) for the latter. Publication bias was examined based on asymmetry inspection and quantified by Egger's linear regression method . Moreoven = 5) or moderate-to-vigorous intensity (n = 7) PA intervention. During 4–24 weeks' PA intervention, the frequency of PA ranged from one to five times per week, and the duration ranged from 10 to 180 min each session. Stratified by the type of motor skills, 13 studies focused on open skills , and 8 studies focused on closed skills . The following ADHD-related outcomes were reported across all included studies: inattention (n = 17), hyperactivity/impulsivity (n = 15), and emotional (n = 15) and behavioral problems (n = 12). Eight studies reported dropouts in the study samples. The average dropout rate was 20%.A total of 9,293 articles were identified through searching four electronic databases, and 7,504 papers were left after removed duplicated literatures. By screening the abstract and the full text, 7,440 papers were further excluded due to non-English literature, no full text, or irrelevance. Finally, nine self-control trials –50, fivep < 0.001; hyperactivity/impulsivity: SMD = 0.676, 95% CI: 0.401–0.950, p < 0.001; emotional problems: SMD = 0.416, 95% CI: 0.283–0.549, p < 0.001; behavioral problems: SMD = 0.347, 95% CI: 0.202–0.492, p < 0.001; I2 were 51.1 and 66.3%, respectively). The combined effect sizes of the two-group control studies suggested that PA intervention only significantly improved the attention problems , but open skills could not . While meta-analyses for two-group control studies confirm that PA intervention can significantly improve the attention problems in ADHD. PA may be especially beneficial for inattention and hyperactivity/impulsivity symptoms in children/adolescents compared to adults. Subgroup analysis stratified by ADHD diagnostic status indicated that compared with subthreshold ADHD participants, the improvement effect of PA intervention on ADHD patients was more significant. Closed motor skills are beneficial for hyperactive/impulsive problems, and open motor skills are beneficial for inattention problems. However, we did not find the evidence that different intensity and frequency of PA can lead to different effects. PA intervention on un-medicated patients also had significant effect on ADHD symptoms.Increasing evidence shows that PA plays a role in improving psychological health. A meta-analysis including 13 trials suggested a short-term effect of exercise on depression . FrederiThe exact mechanisms by which PA intervention is beneficial for inattentive symptom in ADHD patients are still unknown. Currently, the leading biological hypothesis of ADHD is based on the dysfunction of catecholamines  . As one Subtype analysis in the children/adolescent group found significant improvement of ADHD inattention symptoms. Although the results might be biased by the high heterogeneity, it provided further evidence in young patients. A meta-analysis indicated that the efficacy of non-pharmacological interventions can vary substantially between children/adolescents and adults with ADHD . Some anThere are various forms of PA intervention for ADHD, including walking, treadmill, and yoga –75. StraPotential dose response may influence the effectiveness of PA intervention on ADHD symptoms. Subgroup analyses suggested that moderate intensity of PA intervention might have better performance, which was inconsistent with the finding by Ng et al.  that modAlthough PA is beneficial for ADHD, whether PA can be used as an effective treatment is still controversial. A study argued that PA is only an adjunctive treatment for ADHD . DiffereI2-values suggested no significant heterogeneity in the pooled effect size for emotional and behavior problems, and I2-values were 28.5 and 0.0%, respectively. Fourth, most study participants in this analysis were children; hence, extrapolating these findings to adult populations should be taken with caution. Finally, the effect of PA intervention can be impacted by other factors that may be not fully considered in the present study, including biological factors , environmental factors , and intervention settings . Future studies are needed to provide more information about these factors.The present systematic review and meta-analysis included a relatively large number of clinical trials allowing the preliminary exploration on effectiveness of PA intervention on ADHD symptoms. Nevertheless, there were also several limitations in this study. First, the limited number of participants might have resulted in a low statistical power to detect underlying differences. Although 23 eligible studies were included, the insignificant findings should be interpreted with caution. To assess the effectiveness of PA intervention, more high-quality clinical trials with large sample are needed. Second, individual studies might account for the findings in subgroup analyses. Given the insufficient statistical power for small sample size, subgroup analyses are exploratory, and these findings need further confirmation. Third, the measurements of emotional and behavior problems varied across studies, which might introduce confounders to the pooled estimates. However, the Our results suggest that PA intervention could possibly improve ADHD-related symptoms, especially inattention symptoms. However, due to a lot of confounders, such as age, gender, ADHD subtypes, the lack of rigorous double-blinded randomized-control studies, and the inconsistency of the PA program, our results still need to be interpreted with cautions. Whether PA could be an effective alternative therapy to improve the clinical symptoms of ADHD and how to provide targeted exercise intervention for patients with different ages, subtypes, symptoms, and functional impairments need more accumulation of relevant evidence to be confirmed.The original contributions presented in the study are included in the article/YR: took responsibility for the integrity of the data and the accuracy of the data analysis. YR and LY: study concept and design, MS editing, and study supervision. YX, XG, YS, XZ, and MC: data extraction and analysis. YX and XG: drafting of the manuscript. All authors reviewed and revised the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.This work was supported by grants from National Key R&D Program of China (2016YFC1306103), the Major State Basic Research Development Program of China , National Natural Science Foundation of China (81761128035), and the Ministry of Education of Humanities and Social Science Foundation (21YJA890025).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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