Severe irritability is one of the commonest reasons prompting referral to mental health services. It is frequently seen in neurodevelopmental disorders that manifest early in development, especially attention-deficit/hyperactivity disorder (ADHD). However, irritability can also be conceptualized as a mood problem because of its links with anxiety/depressive disorders; notably DSM-5 currently classifies severe, childhood-onset irritability as a mood disorder. Investigations into the genetic nature of irritability are lacking although twin studies suggest it shares genetic risks with both ADHD and depression. We investigated the genetic underpinnings of irritability using a molecular genetic approach, testing the hypothesis that early irritability (in childhood/adolescence) is associated with genetic risk for ADHD, as indexed by polygenic risk scores (PRS). As a secondary aim we investigated associations between irritability and PRS for major depressive disorder (MDD). Three UK samples were utilized: two longitudinal population-based cohorts with irritability data from childhood (7 years) to adolescence (15–16 years), and one ADHD patient sample (6–18 years). Irritability was defined using parent reports. PRS were derived from large genome-wide association meta-analyses. We observed associations between ADHD PRS and early irritability in our clinical ADHD sample and one of the population samples. This suggests that early irritability traits share genetic risk with ADHD in the general population and are a marker of higher genetic loading in individuals with an ADHD diagnosis. Associations with MDD PRS were not observed. This suggests that early-onset irritability could be conceptualized as a neurodevelopmental difficulty, behaving more like disorders such as ADHD than mood disorders. Within DSM-5, irritability is included as a feature of a number of different diagnostic categories. Severe chronic childhood irritability has recently been categorized by the new DSM-5 diagnosis of disruptive mood dysregulation disorder (DMDD) and classed as a mood disorder because of links with later depression.6 However, childhood irritability behaves similarly to ADHD  in that onset is early in development and levels tend to decline from childhood to adolescence,8 raising the possibility that earlier-onset irritability behaves more like a neurodevelopmental difficulty such as ADHD, rather than a mood disorder.Severe irritability has long been recognized as a common accompanying difficulty to neurodevelopmental disorders that manifest early in development. Irritability is commonly defined as a heightened propensity to react with anger, grouchiness, or tantrums relative to peers and is particularly common in attention-deficit/hyperactivity disorder (ADHD).9 Yet, despite the clinical importance of irritability, there is a limited understanding of its genetic architecture. Twin studies suggest that irritability has a heritability estimate of 30–40%.10 To date, one twin study has reported significant genetic overlap between emotional dysregulation (a construct closely related to irritability) and ADHD symptoms,11 and family studies also suggest that emotional lability is elevated in family members of individuals with ADHD.13 However other twin study findings suggest that irritability shares genetic liability with depression.14 Molecular genetic investigations could help clarify the genetic underpinnings of irritability but currently investigations at a molecular level are lacking.Irritability is one of the most common reasons prompting referral to mental health services.15 Given that irritability is so strongly associated with ADHD, our primary aim was to test the hypothesis that early irritability would be associated with ADHD PRS. We set out to test this hypothesis in two longitudinal population-based cohorts with irritability measured in childhood and adolescence, and in a clinic-based sample of young people with ADHD. As a secondary aim, given the new classification of chronic childhood irritability as a mood disorder in DSM-5, we also investigated associations between irritability and PRS for major depressive disorder (MDD).Large genome-wide association studies of patients and controls can be used (as discovery samples) to derive individual composite genetic risk scores (PRS—polygenic risk scores) that serve as an index of genetic liability for the disorder in an independent (target) sample.17 and the National Child Development Study, NCDS)18 and one clinical sample ).19Three UK samples were included in the study: two population based cohorts . Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.The Avon Longitudinal Study of Parents and Children (ALSPAC) is a well-established prospective, longitudinal birth cohort study. The enrolled core sample consisted of 14 541 mothers living in Avon, England, who had expected delivery dates of between April 1, 1991 and December 31, 1992. Of these pregnancies 13 988 children were alive at 1 year. Where families included twins, we included the oldest sibling. When the oldest children were ~7 years of age, the initial sample was augmented with eligible cases who had failed to join the study originally, resulting in an additional 713 children being enrolled. There was a total of 14 701 children alive at 1 year of age. In total 9912 ALSPAC children were genotyped, of whom 8365 passed quality control. Full details of the study, measures and sample can be found elsewhere.18 Ethical approval for the biomedical survey from which genetic data were available was obtained from the South East Multicentre Research Ethics Committee.The National Child Development Study (NCDS) is another well-established prospective, UK birth cohort. The study recruited 18 558 children from England, Wales and Scotland born during one week in 1958. Genotype data collected at age 44 years were available for 5257 individuals following quality control. Full details of the study are described elsewhere.19 Ethical approval for the study was obtained from the Wales Multicentre Research Ethics Committee.The Study of ADHD, Genes and Environment (SAGE) is a clinical sample of children with ADHD recruited from UK child psychiatry and pediatric clinics between 2007 and 2011. The sample consisted of 696 participants  aged 6–18 years  with a clinical diagnosis of ADHD that was confirmed by research diagnostic interviews. Genotype data were available for 569 individuals following quality control. Full details of the study are described elsewhere.20 ADHD and MDD risk alleles were identified from Psychiatric Genomics Consortium (PGC) analysis of case-control GWAS. For testing ADHD PRS in ALSPAC, 9 ADHD studies were included in the ADHD discovery data set (5621 cases and 13 589 controls).23 As the ADHD discovery GWAS included data from NCDS (controls) and SAGE (cases), meta-analyses (using the standard error scheme in METAL) excluding these samples were performed to identify risk alleles for the purpose of generating PRS in NCDS and SAGE . For all three samples, eight studies were included in the MDD discovery data set (9240 cases and 9519 controls).24 Primary analyses defined risk alleles as those associated at p-threshold<0.5 ; associations across a range of p-thresholds are shown in 25 and are given in PRS were generated as the weighted mean number of disorder risk alleles in approximate linkage equilibrium using standard procedures.28 and counted as present if they occurred frequently in the young person  at ages 7 years 7 months, 10 years 8 months and 15 years 6 months. Individuals were categorized as irritable if they were rated as having at least one of three symptoms  ‘a lot more than others’.In ALSPAC, irritability was assessed at three time-points using the Development and Well-Being Assessment (DAWBA)30 at three time points—ages 7, 11 and 16 years. Individuals were categorized as irritable if they were rated as being ‘frequently irritable, quick to fly off the handle’.In NCDS, irritability data were available from a single item from the abbreviated Rutter A scale31 (a semi-structured research diagnostic interview). Individuals were categorized as irritable if they were rated as having at least one of three symptoms . These had to occur frequently over the past three months , uncontrollably, and interfere with at least two activities. For sensitivity analyses a continuous score (possible range 0–3) was also generated.In the clinical sample of participants with ADHD (SAGE), irritability was assessed at one time point (age range 6–18 years) using the Child and Adolescent Psychiatric Assessment (CAPA)ADHD symptoms were measured using the parent-reported DAWBA in ALSPAC , the Rutter A scale in NCDS  and the CAPA in SAGE .We first examined irritability in each of the samples: specifically, how common it was, the prevalence at different ages, and associations with sex and total ADHD symptom scores.R2). Developmental differences were assessed in the longitudinal population samples, by comparing genetic risk associations with irritability in childhood and adolescence. In the clinical ADHD sample, measures were available at only one time point; thus, sensitivity analyses were run splitting the sample into two age groups (<12 years (N=408) and ⩾12 years (N=288)). In all three samples, effects of age were investigated by testing for a PRS-by-age interaction (a random effects model was included for the population samples where irritability was assessed at multiple time points).The primary analyses tested for associations between ADHD PRS and irritability using logistic regressions in SPSS. Sex and 10 population stratification principal components were included as covariates in all PRS analyses. Proportion of variance explained was calculated as the difference between the Nagelkerke pseudo-R-square in the model including PRS compared with the null model that did not include PRS (ΔP<0.001) whereby irritability decreased from ages 7 to 15 in boys and increased in girls .In ALSPAC, around 4% of the sample met the criteria for irritability at each of the three time points . More boys than girls met the criteria in childhood (ages 7 and 10) but not in adolescence (age 15)—there was a sex-by-age interaction  whereby irritability decreased from age 7 to 16 in boys and increased in girls .In NCDS, between 9 and 13% of the sample met the criteria for irritability at each of the three time points . Again, more boys met the criteria in childhood (age 11), while more girls met the criteria in adolescence (age 16), with a sex-by-age interaction  of irritability in the two population samples, both showed similar developmental trends and sex differences.2(1)=8.36, P=0.004).In SAGE, the patient sample, 91% of the sample met criteria for irritability, with no sex difference in prevalence although irritability was more common in the ‘younger’ (⩽11 years) than ‘older’ (⩾12 years) subsamples . Within the ADHD clinical sample (SAGE), ADHD PRS were associated with irritability. Because of the high prevalence of irritability in the clinical sample, a continuous measure of irritability was also examined. The pattern of association was similar, but non-significant , P=0.053) and there was no evidence of any interaction between ADHD PRS score and either age or sex at P<0.05 in any of the samples.Sensitivity analyses in the clinical ADHD sample indicated no clear age effects (younger subsample OR=1.48 (0.92–2.39), P=0.448; older subsample OR=1.19 (0.77–1.81), P=0.435). The only evidence of an interaction between MDD PRS score and age across samples was a stronger association at age 7 than age 10 in ALSPAC ; there was no evidence for an interaction between MDD PRS and sex at P<0.05 in any of the samples.Associations between MDD PRS and irritability are shown in 23 The results from the patient ADHD sample further suggest that irritability is a clinical marker of genetic loading in this group.This study aimed to investigate the genetic underpinnings of early irritability, by testing the hypothesis that it would be associated with ADHD genetic liability, as indexed by polygenic risk scores for clinical ADHD. We observed associations between ADHD PRS and early irritability in a population-based cohort and in an ADHD clinical sample. These findings are in keeping with those from a previous twin study and suggest modest genetic overlap between ADHD and irritability at a molecular (common variant) level.32 It also appears to show similar epidemiological patterns to ADHD and many other DSM-5 neurodevelopmental disorders—symptom levels have been reported to be highest in childhood and to reduce with age,8 a pattern we observed in males. We also found a male preponderance for irritability in our population samples, at least in childhood,33 although sex differences in irritability have not been consistent in previous work (see below). There is also some evidence that effective ADHD treatment with stimulant medication improves irritability in children with ADHD.34 However, symptoms of irritability are not prominent in all children with ADHD1 , suggesting that irritability might provide additional information regarding severity of disorder and genetic loading within those with ADHD. Notably, associations between ADHD PRS and irritability were similar after taking into account ADHD (and Conduct Disorder) symptom levels in our clinical sample, suggesting these are not entirely the same constructs  is classified as a mood disorder in the DSM-5. The DSM-5 classification of childhood-onset irritability as a mood disorder would predict an association between early irritability and MDD PRS, which we did not find. However, interestingly, in both of our population-based cohorts we found developmental differences in the pattern of prevalence rates of irritability for males and females; the prevalence decreased from childhood to adolescence in males  but increased for females . Although previous studies have not consistently found sex differences in irritability,45 the age range and type of sample  in which irritability has been measured has varied across studies, which may in part explain the differing findings. We suggest that the manifestation of irritability might represent different underlying problems depending on age and sex; that is, it could be more like ADHD in childhood and more like mood disorder later in development. The findings from this study suggest that future studies need to adopt a developmental approach in defining and investigating irritability, for example by considering age of onset, even though this is not an explicit requirement in R-DoC.47Although our study suggests that early irritability is associated with ADHD genetic risk scores, it is also important to note that previous longitudinal studies have found associations between early irritability and later emotional/mood disorders in general population samples:N=18 759 for MDD; N=19 210 for ADHD), MDD PRS will be underpowered compared with ADHD PRS for several reasons, including that MDD is more common and less heritable than ADHD.48 Another difference worth noting is that while the ADHD PRS were generated based on a GWAS on children with ADHD, the MDD PRS were generated based on a GWAS of adult MDD. Indeed, there is emerging evidence that the genetic architecture of MDD may differ by age-at-onset48 and MDD PRS derived from a GWAS of younger patients with MDD may have resulted in stronger associations with childhood irritability. Nevertheless, if childhood irritability is an early manifestation of later, adult, mood problems, an association between childhood irritability and adult-MDD PRS would be predicted. Thus, while we can likely exclude large effect sizes of MDD PRS on early irritability, we cannot rule out an association with genetic liability for depression, especially given findings from twin studies.40 Large scale international molecular genetic studies show genetic overlap between ADHD and depression,51 and these disorders co-occur more often than would be expected by chance;52 as a result, it is possible that irritability is a common factor between the two.Secondary analyses found no association between irritability and PRS for MDD in our samples see . However53 We encourage future work investigating irritability across different developmental stages, across sex and within different disorders to help identify similarities, as well as differences in presentation, associated characteristics and treatment response. The findings from this study suggest that while irritability is a trans-diagnostic construct, future studies need to adopt a developmental approach in defining and investigating it.Another explanation is that early irritability is neurodevelopmental in nature , but its links with later depression are mediated via gene-environment correlation . Such mechanisms would be incorporated into estimates of shared genetic effects in twin studies. Research into whether irritability mediates the association between ADHD and later depression is ongoing.55 although in ALSPAC parents were asked about irritability compared with others, while in SAGE parents were asked about the presence/absence of irritability. In NCDS we were limited to one irritable item, which asked about the frequency of irritability, and was more frequently endorsed than in ALSPAC  and thus likely represents a less severe presentation of irritability. Measurement differences may have influenced observed associations. Despite different measures we did observe associations between ADHD PRS and irritability in both the ADHD clinical sample and the other population sample (ALSPAC). In fact, these consistent findings across samples and varying instruments and definitions of irritability increase confidence about their robustness. It is also worth noting that the level of irritability we are measuring in all three samples (at least one frequent irritable symptom), is not equivalent to the chronic severe irritability that characterizes the new diagnosis of DMDD, which has been researched by others.Although there are a number of strengths to this study—in particular the use of three independent samples—there are also a number of limitations that should be noted. First, measurement of irritability varied across the three samples. In ALSPAC and SAGE we used three items, which have previously been used to measure irritability ,57 This may have been particularly problematic in NCDS where DNA was collected at age 44 years .5 Such bias may have resulted in an underestimation of the association between ADHD PRS and irritability, particularly in adolescence when there was more attrition.Second, ALSPAC and NCDS are longitudinal birth cohort studies that show non-random attrition. Specifically, individuals with lower ADHD PRS and lower levels of irritability are more likely to have remained in the studies.58 (with SNP heritability estimated to be roughly 0.2–0.3 for ADHD and MDD20). Nevertheless, they are useful biological indicators of disease risk,20 that can aid the investigation of the genetic architecture of phenotypes in different samples. Our effect sizes are in line with other work using similar approaches.59Finally, the PRS were based on an available discovery GWAS and only explain a small proportion of phenotypic variance due to current discovery sample sizes,14In conclusion, this study suggests that irritability, when manifest during childhood and adolescence in the general population and in patients with ADHD, is associated with ADHD genetic liability as indexed by PRS. This finding, coupled with observations that irritability tends to decline from childhood to adolescence, suggests early irritability is similar to ADHD and, when early in onset, may be better conceptualized as a neurodevelopmental difficulty rather than a mood disorder-related problem. Further work is needed to better understand the developmental nature of irritability and its links with psychiatric disorders.


Attention deficit hyperactivity disorder (ADHD) is a chronic and progressive mental disorder related to the childhood period. This study aims to compare the oral health of two groups of ADHD children: those under pharmacotherapy and those under neuro-feedback therapy.p<0.05.72 ADHD children (aged 6–12) were divided into two 36 member groups: The pharmacotherapy group and the neuro-feedback therapy group. Unstimulated salivary flow (USF), DMFT, and plaque index were assessed in these children. Statistical analysis was carried out on the data with the independent t-test, which was performed using SPSS 16. The significance level of the study was p=0.002). Also, the plaque index  and DMFT scores  were significantly higher for the pharmacotherapy group.In this study, the USF of ADHD children who used Ritalin was found to be significantly less than that of the neuro-feedback group (1.25 ± 1.21 vs. 1.91 ± 1.16 ml/min; Neuro-feedback therapy is preferable to Ritalin treatment for ADHD children in terms of their oral health status. Key words:Attention deficit hyperactivity disorder, drug therapy, neurofeedback, oral health. Attention deficit hyperactivity disorder (AHDH) is a chronic and progressive mental disorder related to the childhood period. An evident characteristic is the manifestation of actions unrelated to the age of the individual such as unrest, doing things or acting without taking situations into account, weak organizational behaviors, and the inability to concentrate. Around 3–7% of school-aged children are affected by this disorder ,2. EnvirTreatment of ADHD generally includes combining pharmacotherapy and behavioral-cognitive methods. Although the frontline of the therapy consists of chemical medicines, nowadays non-medicinal methods are favored more due to the side effects caused by drugs, parents’ negative attitude toward medicines, and the probability of the illness recurring after medicine consumption is terminated -6. The fet al. found a significant difference in saliva flow, plaque index, and dental caries among ADHD children/adults under Ritalin treatment and those who were not under pharmacotherapy. Meanwhile, the saliva flow was generally lower in ADHD children as compared to normal subjects  and Dextroamphetamine. Other drugs used to treat this disorder include Bupropion, Risperidone, and tri-cyclic antidepressants (TCA)-11. Ritasubjects ,14.Considering that no consensus has been attained in the above mentioned studies about the oral side effects of Ritalin in ADHD children, the following question arises: “Are reduced saliva flow and oral side effects the result of the illness itself or due to the pharmacotherapy”? Therefore, this paper investigated oral health status  in ADHD children under pharmacotherapy  and ADHD children under non-medicinal therapeutic methods (neuro-feedback therapy).This cross-sectional/comparative study was performed during September 2015–April 2017 on ADHD children, aged 6–12 years, who were referred to the professional psychiatric clinics of Tabriz University of Medical Sciences. The study protocol was explained fully to the parents/legal guardians, and written informed consents were obtained. The study design was in accordance with the Helsinki Declaration on Ethical Principles for Medical Research Involving Human Subjects and was independently reviewed and approved by the Committee for Research Ethics at Tabriz University of Medical Sciences (Ref number: TBZMED.REC.1394.1076).Considering α=0.05, power = 80%  and 10% -Assessment of Unstimulated saliva flow et al.    and clasa glass) . Owing ta glass) ,21. Also-Assessment of DMFT/dmft and plaque indices in the two groupsDMFT/dmft index was determined by a common method—using a mouth mirror and dental explorer under ample light . Plaque -Statistical analysisP<0.05 was considered significant in this study.The variables were described using mean and standard deviation (SD) and were evaluated by the Kolmogorov-Smirnov test and Q-Q plot to check the normal distribution of data. Levene’s test was used to assess the equality of variances ,25. The A total of 18 girls and 52 boys with a mean age of 9.8 ± 3.1 years were included into the study.p=0.002).The mean and standard deviation of USF in ADHD children under Ritalin treatment was 1.25 ± 1.21 ml/min. This figure was 1.91 ± 1.16 ml/min in children receiving neuro-feedback therapy Fig. . The resp=0.008).The mean and standard deviation of DMFT/dmft scores in ADHD children under Ritalin treatment was 5.9 ± 3.1. This figure was 3.94 ± 1.9 in children receiving neuro-feedback therapy Fig. . The resp=0.018).This study aimed to compare the oral health of ADHD children under pharmacotherapy and neuro-feedback therapy. The initial symptoms of ADHD usually appear during the preschool/early elementary school years and rarely later than early adolescence . ADHD coAlthough there is some inconsistency in the literature, most studies have revealed unhealthy oral status and higher caries among ADHD children ,30,31. Fet al. showed that Ritalin-based oral dryness is dose-dependent, and 8.11% of their patients reported mouth dryness. On the other hand, only 1.2% of subjects in placebo group reported dryness of mouth  could not show a significant difference in terms of USF in children with ADHD using different medicines as compared to normal children. However, DMFS/dmfs was higher in this group than the control group  on 13-year-old children with ADHD, no significant difference was observed in terms of DMFT between normal and ADHD subjects  on 17-year-old children showed that ADHD children had a higher DMFT than the control group  analyzed the saliva and oral status of ADHD children. It was done by separating them into subjects under pharmacotherapy and subjects undergoing no treatment ,14. In tIn overall, our results showed better oral health for ADHD children under neuro-feedback therapy which indicates the importance of therapies for ADHD children that are non-medicinal and less invasive. These types of treatments result in fewer dental and oral side effects in addition to the improvement of behavioral problems in ADHD children. Although the results of this study indicate lower USF and higher PI in ADHD children under pharmacotherapy, because of the multitude of factors influencing dental caries and many intervening factors in this kind of study, further studies are required to make conclusions with certainty and resolve these contradictions, specifically by using a bigger sample size and eliminating other influencing factors.The results of this study showed that children with ADHD undergoing medical treatment by Methylphenidate  had lower unstimulated saliva flow (USF) index and higher DMFT and plaque index (PI) than ADHD children under neuro-feedback therapy. Therefore, Neuro-feedback therapy is preferable to Ritalin treatment for ADHD children in terms of their oral health status.


A recent study has claimed that the global rate of Attention Deficit Hyperactivity Disorder (ADHD) is 5.29%. Any variation in such rates in specific studies, argue the authors, was due to methodological problems, rather than differences in the actual distribution of ADHD. Such reports strengthen the flawed notion that ADHD is a universal and essential disorder, found in all human populations across time and place. While it is true that the concept of ADHD has spread from the USA, where it emerged during the late 1950s, to most corners of the globe, such superficial pronouncements mask profound differences in how ADHD has been interpreted in different countries and regions. In this paper, I compare ADHD's emergence in Canada, the UK, Scandinavia, China and India, arguing that, while ADHD can be considered a global phenomenon, behavioural and educational imperfections remain very much a product of local historical, cultural and political factors. Diagnostic and Statistical Manual of Mental Disorders (DSM) was published amidst a fog of controversy.DSM have served as lenses through which the state of American psychiatry can be viewed. DSM-II (1968), for example, presented a profession dominated by psychoanalysis, but also in the midst of turmoil, as social psychiatrists and biological psychiatrists threatened to undermine psychoanalytic hegemony.DSM-III was published, it was clear that American psychiatry had entered a new biological—and pharmaceutical—age, in which mental illness was perceived in neurological terms and psychiatric treatment often started and finished with some scribbling on a prescription pad.DSM-5  appears to indicate a profession in flux once again. While psychiatry remains ensconced in a biological, psycho-pharmaceutical paradigm, many individuals, including many within psychiatry, have raised questions about the mechanistic determinism of neurologically-oriented psychiatry, the efficacy and safety of many psychiatric drugs, and the influence of the pharmaceutical industry on both diagnosis and treatment. As depicted in Steven Soderburgh’s Side Effects , American psychiatry has never been more ubiquitous, or more intrusive, but its role in American society is growing increasingly ambiguous.In May 2013, the fifth edition of the American Psychiatric Association’s DSM, have been on the march, spreading American notions of and pharmaceutical treatments for mental illness around the world like so many Happy Meals. As journalist Ethan Watters has argued, disorders which first took hold in the USA, ranging from anorexia to depression, are now commonplace in Asia and Africa.But what about the role of American psychiatry in the global context? While American psychiatry may be in a muddle, American psychiatric disorders, with the invaluable help of Perhaps the best and most worrying example of such psychiatric colonisation is Attention Deficit Hyperactivity Disorder (ADHD), the subject of this essay, which has morphed from a disorder only recognised in the USA to one that is diagnosed and treated worldwide. ADHD has been the most commonly diagnosed childhood disorder in the USA since the 1960s. Children diagnosed with ADHD are perceived to be ‘imperfect’ by virtue of behaviours that are often recognised in childhood, including hyperactivity, inattention and impulsivity. The authors of the first description of what we would now call ADHD  in 1957 noted that it was ‘striking’ that such behaviour was not so different from that of normal children.Great efforts have been made by proponents of ADHD to downplay the possibility that cultural, social and environmental factors play any role in the prevalence or diagnosis of the disorder. In 2007 an article by a team of largely Brazilian researchers calculated ADHD’s global prevalence. Attempting to explain the marked variations in ADHD rates in different countries, the team pored through epidemiological studies between 1978 and 2005, determining that the disorder occurred in 5.29 per cent of the world’s childhood population. Why the variable rates? These, the researchers argued, were due to the methodological differences that existed between studies, rather than differences in the actual distribution of ADHD internationally. In other words, children with ADHD were evenly distributed throughout the planet; no one country had a monopoly over the disorder.DSM version of ADHD unhesitatingly, psychiatrists—as well as parents and patients—from other countries or parts of different countries have adapted, modified and, indeed, contested American notions of ADHD. Just as the story of ADHD in the USA can only be properly understood by uncovering the historical context in which it emerged, the uptake of ADHD in other countries needs to be viewed in light of a host of social and cultural factors. In this paper, I analyse, using primarily medical literature, how ADHD has been taken up in Canada, the UK, Scandinavia, India and China, tracing the debates that have characterised its acceptance, rejection or modification in these jurisdictions. I have selected these countries for two primary reasons. First, they represent countries where the reception of ADHD has varied considerably and in fascinating ways, despite some of the countries’ similarities.Leaving the methodological problems with such meta-analyses aside, along with evidence that, even within the USA, rates of ADHD vary considerably—ranging from 5.6 per cent in Nevada to 15.6 per cent in North Carolina—the magical 5.29 per cent figure amounts little more to than a grandiloquent distraction from the real story of ADHD’s propagation throughout the globe.During a 1969 speech, Canadian Prime Minister Pierre Trudeau (1919–2000) described how being a neighbour to the USA was ‘like sleeping with an elephant. No matter how friendly and even-tempered is the beast, if I can call it that, one is affected by every twitch and grunt’.Canadian Family Physician, for example, discussed aggressive, impulsive, spontaneous and delinquent behaviour in adolescents, but not in terms of a distinct disorder.The educational, ideological and geographical links between American and Canadian physicians, along with the cultural connections between the two countries more generally, contributed to ADHD’s relatively speedy migration across the 49th parallel. Whereas the first American medical articles discussing such a disorder, described as hyperkinetic impulse disorder, date from 1957, Canadian medical journals began to discuss it less than a decade later.What may surprise those who assume that ADHD is of purely American provenance is that many of the features that allowed it to become a globally-diagnosed condition that was treated with stimulants and could be identified in girls and adults (as well as just boys) were first recognised not by American researchers, but by a team working at McGill University in Montreal.In addition to their influential research on stimulant therapy, the Montreal group established of the first long-term follow-up study of ADHD.The majority of children who have difficulties with the world around them are not primarily hyperactive but are reacting to an environment that does not provide them with the necessary ingredients for their development. An understanding of these developmental needs can only be gained when we assess the total life-space of a child, which includes school, family and the child himself … . Children who receive little personal attention from their environment and get much of their entertainment from watching television are often bored and become restless, impulsive and aggressive. These children most often need people who they can trust, rather than drugs.Weiss’ intricate approach to understanding ADHD was also reflected in other members of her Montreal team, particularly psychiatrist Klaus Minde, whose longstanding interest in Africa and the cultural aspects of psychiatric disorders spurred him to investigate the disorder in Uganda.Overlooking these social and environmental aspects, Minde warned, resulted in the over-prescription and over-dosage of drugs such as Ritalin.Another member of the Montreal team would challenge ideas about what lay behind the disruptive behaviour of children. Virginia Douglas had been involved in researching the effects stimulant drugs had on hyperactive children during the 1960s, but by the early 1970s she had also begun to wonder about the core symptoms of the disorder. What actually drove such energetic, impulsive and rumbunctious behaviour? Douglas suspected that attention-deficits were actually the underlying explanation.DSM-III (1980), but there were other significant implications. The new focus on inattention meant that such children need not be troublemakers, delinquents or class clowns; they could also be day-dreamers who struggled academically but failed to cause enough disruption to be recognised as problematic, let alone pathological. Although hyperactivity would re-enter the terminology in DSM-III-R (1987), with the term Attention-Deficit/Hyperactivity Disorder (ADHD), the new emphasis on inattention still suggested that the disorder could go unnoticed for years.The most obvious result of this shift in focus was that what had variously been described as hyperkinesis, hyperkinetic impulse disorder, minimal brain dysfunction (MBD) or simply hyperactivity, was now termed Attention Deficit Disorder (ADD) in The focus on inattention had a major impact for ADHD’s epidemiology. Specifically, it gave an answer to a conundrum that had been plaguing researchers for years, namely, why was the disorder seen more often in boys than girls?Canadian Medical Association Journal in 1988, Canadian physician Ray Holland described prescribing Ritalin to one of his hyperactive patients, but suspected food allergies in another, and found that a more structured social environment was most important for four others. For Holland, the DSM definition of the disorder had become too vague, leading to over-diagnosis and shifting the blame away from society itself, which was not set up properly for children to reach their potential.Through the various contributions of the McGill team, it could be argued that Canadian understandings of ADHD shaped how Americans would see the disorder even more than the reverse. There were limits, however, to this influence. The relatively holistic and measured approach to hyperactivity espoused by psychiatrists such as Minde and Weiss remained more prominent in Canada than in the USA. Writing to the British Medical Journal in 1968, when Philip Graham and Michael Rutter published one of their influential Isle of Wight surveys of child psychiatric disorders.Lancet was in 1970, but this was merely a letter to the editor from some American psychiatrists, which was replied to by another American psychiatrist.When compared to their Canadian counterparts, British psychiatrists took somewhat longer to embrace ADHD, with hyperactivity first making an appearance in the Lancet asked: ‘Are the Americans ahead of the British, or behind them, or do their children’s brains dysfunction in such an ostentatiously exotic transatlantic fashion that they require drug therapy?’Although there were many reasons for the initial British reluctance, American ideas about the mental health of children had previously been influential in the UK. The American child guidance movement, for instance, found fertile soil in the UK following the First World War. As with ADHD in the USA during the 1950s and 1960s, child guidance in the UK was ‘an important constituent of a wider concern for political and social stability’, as John Stewart has described.The very terminology used to describe such troublesome children was also a factor. While British schoolchildren were often described by educators as ‘maladjusted’ or ‘medium educational subnormal’, British psychiatrists might diagnose them with ‘conduct disorder’, ‘school phobia’, ‘emotional disorder’ or even ‘autism’. Lest one believe that conduct disorder in the UK might equate to hyperactivity in the USA, British children with such problems were still seen in psychosocial rather than biological terms and drugs were rarely prescribed, highlighting fundamental conceptual differences.Furthermore, in many such cases, environmental causes for this behaviour, such as food additives, heavy metal exposure and malnutrition, were often emphasised. Three of the British associations that raised awareness about the disorder during the 1970s, for example, stressed the role of environmental factors, including food chemicals, as important causes of hyperactivity.Lancet editorial in 1986 concurred that ‘British paediatricians, family practitioners and child psychiatrists are far less ready than their colleagues in the USA to diagnose and treat … hyperactivity’, but also cautioned that ‘severe and pervasive hyperactivity is a risk factor and can handicap social development’ and that ‘British medicine and education will need to make its modification a higher priority’.Nevertheless, there was little indication of a hyperactivity epidemic in Britain during the 1980s. A 1984 article stated that, while the disorder dominated 30–40 per cent of the clinical population seen by North American child psychiatrists, there had been only 73 hyperactive children seen at the Maudsley and Bethlem Royal Hospitals in London between 1968 and 1980.DSM criteria used by North American physicians was less stringent than that of the WHO’s International Classification of Disease, which was preferred in the UK. According to the National Institute for Health and Clinical Excellence in England and Wales (NICE), when ICD was used, only 1–2 per cent of children would be diagnosed as hyperactive; when DSM-IV was used the rate was 3–9 per cent. Preferring the North American criteria, Eric Taylor and psychiatrist Peter Hill published a protocol in 2001 for dealing with ADHD which was based on DSM-IV criteria, and, using these, subsequently estimated similar British rates to those in the USA.As the 1990s dawned, North American approaches to hyperactivity were increasingly finding favour.But even as British rates of ADHD increased and stimulants became more common, significant differences remained. Although official bodies such as NICE have affirmed the validity of ADHD as a medical condition, they have also recognised that opposing positions are justifiable. NICE has also been less confident about ADHD’s causes and treatment, stating recently that: ‘The diagnosis of ADHD does not imply a medical or neurological cause … . The aetiology of ADHD involves the interplay of multiple genetic and environmental factors’.Guardian, ‘there is no single solution to mental disorder, nor single approach to helping patients’.All of this has amounted to the UK adopting a less rigid and more open-ended approach to ADHD. As president of the Royal College of Psychiatrists recently said in an article in the When the history of ADHD in non-Anglo countries is examined, the picture becomes even more complex.Sweden’s ADHD history certainly demonstrates how national circumstances have influenced how the debates surrounding the disorder have evolved. During the late 1960s, one might have thought the concept of the disorder, along with the drugs prescribed to treat it would have been unwelcome in Sweden, due largely to fears about amphetamine abuse. In fact the Swedish government decided to ban Ritalin in 1968, a move widely reported in the American media. Many Swedish physicians were supportive, believing that the benefits of the drug did not outweigh the risks of abuse, and felt resentful that American medical journals continued to advertise such dangerous products.By the 1980s, however, Swedish physicians and the Swedish National Board of Health began to warm to the concept of hyperactivity and biological psychiatry. Part of this was due to external influences, and the fact that Swedish health and educational authorities began screening young children for behavioural problems, but equally important was the role of child psychiatrist Christopher Gillberg. Much as Eric Taylor would carry the flag for ADHD in the UK, Gillberg was Sweden’s most prominent ADHD advocate, also writing prolifically about autism spectrum disorders . During the 1970s, Swedish interest in hyperactivity was limited, but once Gillberg began to lead the charge in the early 1980s, awareness of the disorder in Sweden mushroomed in parallel to his prodigious academic output.Swedish Medical Journal, his sociologist colleague Eva Kärvfe, a mother of five children herself, got involved, writing a book that questioned the validity of DAMP.But Gillberg’s influence on the history of ADHD in Sweden did not end there. In 2002, paediatrician Leif Elinder and sociologist Eva Kärvfe, both based at the University of Lund, began demanding access to the files from one of Gillberg’s studies, a a longitudinal study of children with DAMP , which began in 1977. According to journalist Jonathan Gornall, the Lund academics’ interest in Gillberg’s trial began in 1996, when Gillberg and Elinder, childhood acquaintances, met at a summer party.Gillberg was outraged and accused Elinder and Kärvfe of basing their arguments on documents supplied by Scientology . Elinder and Kärvfe, in turn, accused Gillberg of fraudulently manipulating the data for his DAMP study and demanded access his data. Gillberg refused, protesting that the material was confidential, and court action ensued, with the court ruling in 2003 that Elinder and Kärvfe were entitled to view the data. But before they could do so, Gillberg had the files shredded. Although Gillberg claimed that he was merely following the confidentiality agreement signed by the participants, the courts disagreed, resulting in fines and conditional sentences for him and his collaborators. By 2010, the case had reached the European Court of Human Rights, which ruled against Gillberg, claiming that the public had a right to know how the research had been conducted.The episode divided the Swedish scientific community, with some accusing Gillberg of being an agent for the pharmaceutical industry and others claiming Elinder and Kärvfe of having connections to Scientology. More broadly, however, the vitriolic way in which the dispute was conducted will likely contribute to widening the gulf of opinion about hyperactivity in Sweden. Although recent Swedish research, including a study on the effect of ADHD medications on criminals and reoffending rates, might suggest that proponents of the disorder in Sweden are beginning to overcome the damage done by the Gillberg affair, the ultimate effect of the episode remains to be seen.Sweden might have experienced the most scandalous ADHD history in Scandinavia, but more banal factors have also influenced its acceptance or rejection in the other Nordic countries. A recent study on the remarkable variation in the use of ADHD drugs in Nordic countries, for instance, suggested that the availability of ADHD drugs and non-pharmacological treatments, training of mental health practitioners, and clinical practices all contributed to these differences.Four Letters Apart—Children in the Age of ADHD (2013), directed by Norwegian Erlend Mo, not only hints that hyperactive behaviour can be exacerbated by a host of triggers, but also demonstrates the value of non-pharmaceutical therapy and meticulous educational interventions.More research is undoubtedly needed to explore further how ADHD has been variously perceived in the Nordic countries. While some might suggest that these differences are simply due to abnormalities in diagnostic procedures and misunderstandings about treatment, this is most likely only part of the story. One indication that the picture is somewhat more complex can be found in the ADHD research conducted in Nordic countries, which has long examined the role of numerous social factors in contributing to it and other psychiatric disorders.Similar pluralistic thinking has jostled with aggressive attempts to market ADHD globally as a universal and essential disorder. The history of psychiatry in the colonies of the British Empire provides a useful comparison for the spread of mental disorder of American origin today. Pioneered by Waltraud Ernst, Jonathan Sadowsky and others, the history of colonial psychiatry demonstrates how it proved untenable to extend British concepts of mental health and illness to colonial contexts.DSM-influenced conceptualisations of ADHD.A superficial overview of ADHD epidemiology in India might suggest that the second most populous country on the planet was rather sluggish in jumping on the ADHD bandwagon.It is no surprise that ADHD would come to India, pushed by pharmaceutical companies and pulled by Indian physicians eager to promote western medicine. But there has been another pull factor, one that has often been unappreciated in the debates about ADHD, specifically, the willingness of parents to accept an ADHD diagnosis in the hopes that it will help their children to live up to their potential. The reasons why parents have rejected, tolerated or even embraced an ADHD diagnosis are understandably complex. Such is the case in India, as in every country in the world, but here, again, local circumstances provide some explanations. According to medical anthropologist Stefan Ecks, while most Indian parents are quite reluctant to agree to ADHD drugs for their children, this is not always the case.Elsewhere, however, drug treatments have been viewed suspiciously. In one study, 20 out of the 24 Indian subjects refused to adhere to their prescriptions for one month. The reasons provided for this ‘unexpected’ recalcitrance included side effects, inefficacy, fears that the drugs would lead to addiction, cost, the opposition of other family members or physicians, the ‘careless attitude of caregivers’ and the refusal of children to take the drug.Many of the explanations cited for non-adherence centred on concerns about the drug itself or lack of understanding about the disorder (particularly complaints about children not grasping its apparent significance). But parents in other studies have presented more fundamental arguments to counter biomedical explanations for their children’s behaviour. For example, a survey of Indian parents from a lower socioeconomic grouping in Goa demonstrated greater willingness to consider psychological, educational, social or domestic explanations, including their own parenting techniques. Instead of opting for drugs, these parents tended to rely on educational or religious interventions. The researchers concluded that, regardless of the marketing strategies of pharmaceutical companies, ‘locally acceptable illness models’ needed to be employed in order to help parents of children with behavioural problems in developing countries.Other researchers have similarly focussed on even more basic factors believed to affect child behaviour. Environmental and nutritional explanations for hyperactivity have long been highly controversial, with the food additive-free Feingold diet being the most infamous, yet enduring, example.Psychiatry in Chinese History attests.As with the history of psychiatry in the British empire, the history of Chinese psychiatry has attracted increased interest recently, as Howard Chiang’s edited collection Unlike in India, Chinese psychiatrists have recognised hyperactivity as being prevalent in the childhood population for decades.One emerging exception to this tendency, according to Simmons, was hyperactivity, which was found to be present in children at roughly the same rates as in the USA(8–10 per cent). A large number of other studies emerged during the late 1980s and 1990s charting Chinese hyperactivity rates and comparing them to the USA, something fairly unusual for a specific disorder in China. Although amphetamines were used to treat such children, traditional herbal stimulants were also used, and most parents and teachers expected that some form of behavioural intervention also be made, rather than a complete reliance on pharmaceuticals.While the rates tended to be similar, a common explanation for any differences was variation in child-rearing practices, with Chinese families not only being found to be stricter, but also more stable, boasting multiple parenting figures and allowing children to remain dependent on their elders for a longer period of time.In sum, China provides an interesting case for the take up of ADHD, one that bears the hallmarks of a complex society that has been shaped by ancient traditions, 65 years of communism and selective flirtations with the west. Many of the factors involved in the emergence of the disorder in the USA during the 1950s have also been present in China, helping to account for why it was accepted there long before it was in other countries.DSM diagnosis and present in 5.29 per cent of the world’s children, these histories, only sketched out here, demonstrate that it has been a much more flexible, mutable phenomenon, a notion that has been rejected as often as it has been accepted. And, as in every history, there has always been a good story to explain why this has been the case.Worldwide, interest in ADHD continues apace. A recent study of global medical literature between 1980 and 2005 confirmed that not only had articles about ADHD grown exponentially during the period, but also that no saturation point was in sight.DSM-determined criteria of behaviour, learning and development, we should do the opposite, and encourage creativity, courage and flexibility in our children, and in ourselves.Given such a collage of different stories, then, is it possible to glean any more general lessons from ADHD’s local and national histories? One issue that emerges, which should also spur future historical research, involves the role of the child in debates about ADHD. Too often historical research on childhood disorders, such as ADHD, fails to keep the child central to the story.


The main purpose of this two-part study was to examine the effects of acute, moderate intensity exercise on task switching in children with attention-deficit/hyperactivity disorder (ADHD). In Study 1, we compared the task switching performance of children with and without ADHD. Twenty children with ADHD and 20 matched controls performed the task switching paradigm, in which the behavioral indices and P3 component of event-related potentials elicited by task-switching were assessed simultaneously. The amplitude and latency of P3 reflected the amount of attention resource allocated to task-relevant stimulus in the environment and the efficiency of stimulus detection and evaluation, respectively. The task switching included two conditions; the pure condition required participants to perform the task on the same rule  whereas the mixed condition required participants to perform the task on two alternating rules . The results indicated that children with ADHD had significantly longer RTs, less accuracy, and larger global switch cost for accuracy than controls. Additionally, ADHD participants showed smaller amplitudes and longer P3 latencies in global switch effects. In Study 2, we further examined the effects of an acute aerobic exercise session on task switching in children with ADHD. Thirty-four children with ADHD performed a task switching paradigm after 30 min of moderate-intensity aerobic exercise on a treadmill and after control sessions (watching videos while seated). The results revealed that following exercise, children with ADHD exhibited smaller global switch costs in RT compared with after control sessions. The P3 amplitude only increased following exercise in the mixed condition relative to the pure condition, whereas no effects were found in the control session. These findings suggest that single bouts of moderate intensity aerobic exercise may have positive effects on the working memory of children with ADHD. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common disorders in children, present in approximately 8.7% of children in the U.S. , and appThe executive function model  has beenSome studies have shown a positive effect of exercise or physical fitness on several aspects of EF in children with ADHD. For example, motor ability  and physIn addition to behavioral indicators, event-related potentials (ERPs) have been used to assess the neurophysiological processes involved in the performance of executive function tasks. P3, one of the most studied ERP components, is a positive-going deflection in the ERP waveform that occurs in response to a stimulus, with the amplitude of the component reflecting the allocation of neural resources toward the stimulus . TherefoMost of the studies examining the effects of acute exercise on EF in children with ADHD have focused on sustained attention , inhibitChildren with ADHD have shown impaired performance in task switching. Studies comparing task switching performance between children with and without ADHD have shown that children with ADHD demonstrate substantially larger switch costs than children without ADHD. However, when on medication, ADHD children’s switch performances were equivalent to those of control children. In addition, medication was observed to reduce ADHD children’s switch cost . Adults Based on the evidence mentioned above, acute exercise may be particularly beneficial for executive function. However, there are many different aspects of executive function. To our knowledge, no ERP studies to date have directly compared the differences between individuals with ADHD and healthy controls, and the effects of acute moderate exercise on the working memory, inhibition, and mental flexibility aspects of executive function in ADHD as measured by task switching have not yet been explored. Accordingly, we conducted two studies. In Study 1, we compared the task switching performance of children with and without ADHD to examine components of executive function deficiencies in task switching performance of children with ADHD. In Study 2, we further examined the effects of a single bout of acute aerobic exercise on components of executive function using the task switching performance of children with ADHD, particular regarding the aspects of working memory, inhibition, and mental flexibility. Based on previous findings, it was hypothesized that children with ADHD would show deficient task performance in task switching, along with reduced activation of the P3 component. Furthermore, acute exercise would improve performance during the task switching as well as demonstrate increased P3 amplitude and decreased P3 latency elicited by the task switching paradigm.In total, 20 children with a clinical diagnosis of ADHD and 20 healthy match control children  were recruited through advertisements placed at a local elementary school and ADHD association. To be included in this study, participants had to meet the following criteria: (1) aged between 8 and 12 years (2) lack of hearing or vision problems and free of brain injury and disease  and (3) lack of comorbid developmental disorders including learning difficulties, dyslexia, Tourette’s syndrome, epilepsy and pervasive developmental disorder. All participants had not received medication for at least 24 h before the experiment. This study was conducted in accordance with the Declaration of Helsinki and approved by the National Taiwan University Institutional Review Board. Written assent was obtained from the children, and written informed consent was provided by their legal guardians. In addition to the formal diagnosis provide by a pediatrician or psychiatrist, their legal guardians confirmed the presence of the ADHD symptoms a priori by using the Chinese version of the ADHD test  originalAfter receiving ethics approval, the participants visited the lab on two separate days. During the first visit, the experimental procedure was explained to participants and their legal guardians. Then a health history, demographics questionnaire, ADHD-T, CBCL, and an informed consent form were completed by their legal guardians. The participants were then requested to complete IQ and MABC-2. All of the participants’ heights and weights were also measured to calculate their body mass indexes (BMI).At the second visit, the task switching experiment was explained and carried out in a sound and magnetic shielded room with dimmed lights. Before the formal experiment, the participants were outfitted with an electrode cap and instructed on the task. Both the pure and mixed condition trials were practiced until a criterion of 80% correction rate was reached by participants.Cognitive performance was assessed using the task switching paradigm modified from Event-related potential was measured with an electrode cap with electrodes placed at 30 sites using the 10–20 system; each electrode was referenced to an average of the mastoid electrodes, and the impedances were kept below 10 kΩ. Continuous data were digitized at a sampling rate of 500 Hz and amplified 500 times with a DC to a 70 Hz filter, and a 60-Hz notch filter was applied using a Neuroscan SynAmps2 amplifier. Only the ERP data recorded from the midline frontal (Fz), central (Cz), and parietal (Pz) locations were analyzed in this study . The offt-test was applied to compare the demographic data between the two groups. A 2  × 2 (Condition: Pure and mixed) and a 2  × 2 (Condition: non-switching and switching) mixed ANOVA were employed to analyze the RT and accuracy of the global switch and local switch, respectively. In addition, separate independent sample t-tests were used for global (the difference in RT and accuracy between the mixed and pure conditions) and local  switch cost between the exercise and resting sessions. The P3 ERP component was assessed separately for amplitude and latency in 2  × 2  × 3  mixed ANOVAs for global and local switch.To ensure equivalence between the ADHD and control groups, a t(38) = 0.09, p > 0.05], BMI , IQ , MABC-2 score , suggesting equivalence between the two groups. However, as expected, the results indicated that children with ADHD scored significantly higher than the healthy controls on the ADHD-Q  and CBCL . The demographic characteristics of participants in both groups are summarized in Table 1.There were no significant differences between the groups in age .F = 13.99, p < 0.001, F = 54.76, p < 0.001, F = 12.80, p < 0.001, F = 39.20, p < 0.001, F = 15.78, p < 0.001, F = 54.76, p < 0.001, F = 54.76, p < 0.001, Figure 1).For response accuracy, a two-way ANOVA revealed main effects of Group .Regarding reaction time, a two-way ANOVA revealed main effects for Group  or the interaction of Group × Condition , a significant main effect of Group  or local switch costs  for the reaction time. However, a global switch cost for accuracy was observed . Examination of the means indicated that the global switch cost in ADHD participants  was significantly higher than that in controls . There was no group difference in local switch cost for accuracy .There were no significant differences between groups in the global switch costs , with a greater amplitude in controls  than in participants with ADHD . Furthermore, a significant Site effect in the ADHD group was revealed , with a shorter latency in controls  than in ADHD participants . However, there were no significant effects for mixed trials. Furthermore, a significant Condition effect in controls  was observed, with a shorter latency in pure trials  than in mixed trials . No effects were found in the ADHD group.A three-way ANOVA revealed an interaction of Group and Condition  and post-HR , but not pre-HR . Examination of the means showed that the avg-HR and post-HR were significantly higher for the exercise than for the resting session.The descriptive data for HR and RPE are summarized in Table 5 presents the detailed behavioral data for the task switching indices for each group. For reaction time, the results of the 2 × 2 repeated ANOVA revealed no significant main effects of Session , but significant main effects of Condition  and post-resting . However, no significant differences in pure  or mixed  conditions were observed between the two types of sessions.F = 0.41, p > 0.05] or for the interaction of Session × Condition , a significant main effect of Condition  and the interaction of Session × Condition  were not significant.For reaction time, a 2 × 2 mixed ANOVA revealed that there was a significant main effect of Condition  or Condition  or the interaction of Session × Condition .For response accuracy, no effects were observed for the main effect of Session  between post-resting  and post-exercise sessions . However, no significant differences in local switch costs  were observed.As for RT, there were significant differences in global switch costs  and local switch costs  were observed.With regards to response accuracy, no significant differences in global , with a greater amplitude in mixed trials  than in pure trials . However, no effects were found in the post-resting session . Regarding P3 latency, no three- or two-way ANOVA interactions or main effects were observed.A three-way ANOVA revealed an interaction of Session and Condition [No three- or two-way ANOVA interactions or main effects were observed in P3 amplitudes and latency.The purposes of this two-part study were to examine the differences in task switching performance in children with and without ADHD and to examine the effects of acute exercise on the switching aspect of executive function, particularly regarding the aspects of working memory, inhibition, and mental flexibility in children with ADHD. In Study 1, the results indicated that children with ADHD demonstrated significantly longer RTs and less accuracy during global switch and local switch conditions than controls. Moreover, children with ADHD had higher global switch cost for accuracy. The ERPs of ADHD participants showed smaller amplitudes and longer latencies in P3 in global switch effects. As for Study 2, the results revealed that following a single 30-min bout of exercise, children with ADHD exhibited smaller global switch costs on RT compared with the costs after a control session. The P3 amplitude only increased following exercise in mixed conditions relative to the pure condition, whereas no effects were found in the control session.The slower RT in both task switch condition and higher global switch cost for accuracy in children with ADHD are consistent with those of The smaller P3 amplitudes in global switch effects in children with ADHD suggest deficiencies in neural resource allocation when challenged with demands on inhibition, mental flexibility, and working memory. Despite the limited research on task switching using ERPs in ADHD participants, the available studies on different executive function tasks also demonstrated smaller P3 amplitudes in ADHD participants. Specifically, during a continuous performance test, a task that demands sustained attention, children with ADHD-com showed smaller frontal N1 and N2 amplitudes and parietal P2 and P3 amplitudes to target stimuli, indicating diminished evaluative and processing capabilities . SimilarAdditionally, compared to healthy controls, children with ADHD demonstrated a longer P3 latency in the pure condition. Furthermore, only healthy controls showed differences in P3 latency between pure and mixed conditions. This longer P3 latency during task switching in ADHD participants was also observed in other tasks involving executive function. For example, Although children with ADHD have shown deficiency in working memory as reflected in higher global switch cost, acute exercise can improve working memory. Specifically, compared with the control session, the acute exercise resulted in smaller global switch costs in RT in children with ADHD. The selective effect of acute exercise on global switch cost is consistent with findings regarding chronic exercise in elderly participants. Enhanced P3 amplitudes in the mixed condition relative to the pure condition after acute exercise suggests enhancement of working memory processes and is consistent with the behavioral results. A previous study using a flanker task found that following acute exercise, both children with ADHD and healthy controls exhibited larger P3 amplitudes . SimilarAlthough the mechanisms behind the beneficial effects of acute exercise on task switching in children with ADHD have yet to be fully understood, the facilitation effects of acute exercise may potentially be explained by changes in arousal. As the hypoarousal model of ADHD  suggestsIt is important to note that although this study provides evidence supporting the beneficial effects of acute exercise on task switching in children with ADHD using behavioral and neuroelectric measures, several issues should be considered for future research efforts. First, the severity of ADHD symptoms was not evaluated in this study. However, given that 41% of the children in the present study were not receiving medication, it is likely that the participants had mild to moderately severe ADHD symptoms. Therefore, the extent to which we can generalize our results to individuals with more severe ADHD symptoms is unknown. Thus, future research should characterize ADHD symptoms to better understand the utility of acute exercise in enhancing switching ability in these populations. Second, issues related to exercise intensity, types of exercise modality, dose–response relationships, potential moderators , and time delay effects , need toThe present study extends current knowledge on the relationship between acute exercise and executive function in children with ADHD. This study showed that children with ADHD experience certain deficiencies in performing task switching compared to healthy controls. Additionally, the findings indicated that acute bouts of exercise can ameliorate these deficiencies, especially those regarding switching conditions that require greater working memory involvement.CLH is responsible for the research idea, implementing the study and manuscript writing up. CJH is responsible for the statistical support and discussion commentary. YJT is responsible for assisting on the data collection and analysis. YKC is responsible for consulting the methodology and interpretation of the findings. TMH is responsible for the discussion of the research idea, supervision of the data collection, and comment on the manuscript writing up.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.


Previous near-infrared spectroscopy (NIRS) studies using a verbal fluency task (VFT) have consistently reported that adults with attention-deficit hyperactivity disorder (ADHD) showed significantly smaller oxygenated-hemoglobin [oxy-Hb] activations in the prefrontal cortex (PFC) compared to those in healthy controls (HC). Despite this consistent evidence of brain dysfunction in ADHD, ADHD is currently diagnosed based only on subjective clinical and scoring measures, which are often unreliable. Hence, it is necessary to establish objective neuroimaging biomarkers for ADHD. While most NIRS studies have utilized averaged [oxy-Hb] values during the whole task period for group comparisons, we used a cluster-based non-parametric randomization test to compare the [oxy-Hb] time-course changes with a 0.1-s time resolution between drug-naïve adults with ADHD and HC, which may provide us with more details regarding abnormal prefrontal activation patterns in ADHD. A total of 101 participants, consisting of 63 drug-naïve adult individuals with ADHD and 38 HC, were included in this study. We identified that adults with ADHD showed significantly smaller [oxy-Hb] activations than those in HC at spatially and temporally connected clusters located in the bilateral PFC (more prominent on the left) and temporal brain region (more prominent on the left). We further found that aberrant [oxy-Hb] activation differs according to the time period during the task or according to brain location. Our findings indicate more detailed aberrant prefrontal and temporal activation patterns of ADHD compared with those in previous studies, possibly representing a biological marker for ADHD. Although attention-deficit hyperactivity disorder (ADHD) has been classically recognized as a childhood disorder, previous longitudinal studies have found that in over half of all children with ADHD, symptoms persist into adulthood, especially with respect to inattention and impulsivity , 2. ThusA growing neuroimaging literature has addressed the neurobiological substrates of adults with ADHD using functional magnetic resonance imaging (fMRI). Deficits in neural circuits connecting brain regions of the prefrontal cortex and the striatum have been associated with this condition –7. DespiNear-infrared spectroscopy (NIRS) is an optical neuroimaging technique that allows the non-invasive measurement of changes in the concentrations of oxygenated and deoxygenated hemoglobin , which is a reflection of changes in regional cerebral blood volume , 9. NIRSIn the statistical analysis of NIRS data, the multiple comparisons problem (MCP) is a concern. NIRS data have a spatiotemporal structure that includes 52 channels covering the bilateral frontotemporal brain region and 1,251 time-points throughout the whole experimental period . This number is usually on the order of several tens of thousands of data points. In most neuroimaging studies, including functional and structural MRI, the use of the family-wise error rate (FWER) is one way to solve the MCP by lowering the critical alpha level; however, this approach is overly conservative for NIRS because of the large number of dependencies in space and time. Thus, in most NIRS studies including two-adult ADHD studies , 14, twoContrary to the familiar parametric statistical framework like the FWER, a cluster-based non-parametric randomization test is an alternative method that combines cluster-based inference with assumption-free techniques like permutation, which have been shown to outperform analytic techniques in solving the MCP . In partIn this study, we used the cluster-based non-parametric randomization test to compare [oxy-Hb] time-course alterations with a 0.1-s time resolution between drug-naïve adults with ADHD and HC, which may provide more detailed prefrontal activation patterns in ADHD. We hypothesized that during the VFT, adults with ADHD would show significantly smaller [oxy-Hb] activations, compared with HC, in prefrontal and temporal brain regions.A total of 101 participants, consisting of 63 drug-naïve adult individuals with ADHD and 38 HC, were included in this study Table . ParticiThe task procedure in the present study was similar to that used by Takizawa et al. . ParticiDuring the task period, participants were instructed to produce as many nouns as possible beginning with a designated syllable without the use of repetitions or proper nouns. Three sets of initial syllables  were presented in counterbalanced order to the subjects while changing each syllable every 20-s during the 60-s task. The subtraction method (task minus pre- and post-task baselines) minimized the vocalization effects during the VFT. The total number of correct words generated during the VFT was taken as a measure of task performance.We utilized a 52-channel NIRS machine  using two different wavelengths (695 and 830 nm) with a 0.1-s time resolution to measure the relative changes in absorbed near-infrared light. These changes were transformed into concentration changes of [oxy-Hb], [deoxy-Hb], and total-hemoglobin  as indicators for brain activity using a modified Beer–Lambert law . The univia the international 10–20 system (We utilized 33 optrodes consisting of 17 light emitters and 16 detectors with an inter-optrode distance of 30 mm. A channel (measuring point of activation) was defined as the region between one emitter and one detector. Thus, the optrode set consisted of 52 channels and measures [Hb] in the bilateral prefrontal , superior temporal, and middle temporal cortical regions. The panel was fastened to the head by elastic straps. The correspondence between the optrode positions and the measurement areas on the cerebral cortex was confirmed based on a previous multi-subject study of anatomical craniocerebral correction 0 system , 27.The obtained data were analyzed using the “integral mode”; the pre-task baseline was determined as the mean over a 10-s period just prior to the task initiation, and the post-task baseline was determined as the mean over the last 5 s of the post-task period; a linear fitting was applied to the data between these two baselines. A moving average using a window width of 5 s was applied to remove any short-term motion artifacts. Furthermore, we calculated the median and the SD of each group at each channel and rejected data above or below three SDs of the median value. As a result, we rejected 28/3,276  channel time series from the ADHD group and 20/1,976 data points from the HC group. We focused on the [oxy-Hb] concentrations during the whole experimental period including the pre- and post-task baselines and the task period, since the [oxy-Hb] change was assumed to reflect cognitive activation more directly than the [deoxy-Hb] change as shown by a stronger correlation with the blood-oxygenation level-dependent (BOLD) signal measured using fMRI  in the [oxy-Hb] data, we first compared the time-course [oxy-Hb] changes during the whole baseline and the VFT periods using a cluster-based non-parametric randomization test (P < 0.05 corrected) based on Monte-Carlo estimates, as described by Maris and Oostenveld  were identified from a one-way analysis of variance (ANOVA). Subsequently, spatially and temporally contiguous points in terms of channels and time-points over this threshold were defined as a cluster. Then, the sum of F values for a given cluster was used for cluster-level statistics. By repeatedly resampling the data across all the subjects, cluster-level F values were created from 10,000 randomization routines, and a histogram of the largest summed F value distribution (H0 distribution) was constructed. For the second-level statistics, we first performed an ANOVA in the original data set and obtained the sum of the F values in each spatially and temporally contiguous cluster. The P value was estimated from that summed F value of the original dataset according to the proportion of the randomization distribution (H0 distribution)  and temporal brain regions (more prominent on the left). The brain regions in our findings were consistent with two previous NIRS studies in adults with ADHD. Schecklmann et al.  reportedPrevious meta-analysis studies using fMRI in HC have indicated that processing of the VFT is associated with the activation of brain regions primarily in the left prefrontal gyrus, particularly in the left VLPFC and DLPFC, and in the medial frontal gyrus  and the anterior cingulate gyrus BA 24, 32) , 32. Mor , 32. MoTo our knowledge, this is the first study to compare group differences in the time-courses of [oxy-Hb] changes with a 0.1-s time resolution, since most previous psychiatric NIRS studies average the total values of the [oxy-Hb] changes during the activation task period for each channel and compare the resulting mean values between groups. Thus, when a group difference in [oxy-Hb] changes is confined to a very short time, this conventional averaging method of analysis may miss small differences. However, the cluster-based non-parametric randomization test has the advantage of being able to detect fine differences in [oxy-Hb] activations more clearly. Therefore, this study enabled detailed measurements of time-course changes and provides important insights into differences in executive function related to the VFT between adults with ADHD and HC. For instance, a time-course difference was observed immediately after the activation task in clusters located in the bilateral frontal pole . However, this difference only persisted for a short period (about 3–5 s), suggesting that the initial increase in the [oxy-Hb] response to the VFT in the frontal pole is both decreased and slower in adults with ADHD than in HC. On the other hand, hypofrontality in patients with ADHD was seen throughout the task period in the left DLPFC and VLPFC, meaning that despite the fact that the load of the task continued, the initial increase in the left lateral prefrontal hemodynamic response to the task stimulus was smaller and the response failure continued until the end of the task. Briefly, a deficit in the initial activation in the frontal pole and the discontinuance of the left lateral frontal hemodynamic response may reflect the symptoms of ADHD, such as discrepancies in effective initiation, cognitive flexibility, and mental shifting skills. Taken together, our study may provide new neurobiological evidence that prefrontal and temporal [oxy-Hb] activations differ by a certain period of time during the activation task or brain location, possibly representing the pathophysiology of adults with ADHD.An advantage of this study is that it used participants who had never taken any stimulants or other psychiatric medication at the time of measurement. Therefore, this study excluded the confounding effects of continuous stimulant use on PFC function at the time of the measurement and allowed us to observe unmedicated prefrontal responses in adults with ADHD. Moreover, we confirmed that hypofrontality in ADHD, which may represent a potential biological marker for ADHD, was a consistent finding using a relatively large sample of 101 participants. An advantage of the non-parametric method is the freedom to use any test statistic one considers appropriate. This freedom allows us to solve the MCP in a simple way, and it also allows us to incorporate prior knowledge about the type of effect that can be expected.F value threshold required for a cluster-based non-parametric randomization test. Therefore, it is not clear how to choose this threshold to obtain maximum sensitivity for an unknown effect present in the data: for a weak and widespread effect, the threshold should be low, while it should be high for a strong and localized effect. In this study, we plotted the F value time series of each channel  activation differs according to the time period during the task or according to brain location. These findings suggest that aberrant prefrontal and temporal activation patterns may represent a potential biological marker for ADHD. Considering the safety, low cost, portability, and high temporal resolution of NIRS, the present study provides further evidence to support its potential clinical application in practical psychiatric settings.The study protocol was approved by the Ethics Committee of Showa University and Tottori University and prepared in accordance to the ethical standards of the Declaration of Helsinki.BY and AI designed the study; BY, SP, and AI performed research; BY, YT, and TI analyzed the data; BY, YT, TI, SP, JH, MM, and AI interpreted the data and wrote the article.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.