Various nutrients and diet quality have been suggested to be involved in the pathophysiology of ADHD. The purpose of this review was to examine data from recent cohort studies and dietary interventions to determine whether nutrition may play a role in the management of ADHD.Preliminary evidence suggests that minerals might have beneficial effects on ADHD symptomatology. Probiotics might offer novel strategies to prevent or treat ADHD. Inverse associations between adherence to “healthy” diets and ADHD symptoms have been observed. Children with ADHD responding to the few-foods diet (or oligoantigenic diet) with an elimination of individually identified food items show substantially improved behavior and cognitive functioning.Evidence from recent research does not allow any recommendations regarding the use of micronutrients or probiotics in the management of ADHD. The few-foods diet may become an additional therapeutic option for children with ADHD. Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric diagnoses in children and adolescents and is also increasingly diagnosed in adults . ADHD isWhile short-term improvements of inattention, hyperactivity, and impulsivity can be achieved in children and adolescents with a diagnosis of ADHD by medication with psychostimulants, behavior therapy, and parent management training, the degree of efficacy of these therapies remains a matter of debate . NumerouThe administration of drugs such as methylphenidate almost certainly yields some short-term symptom reduction in children and adolescents with ADHD. However, the extent of therapeutic efficacy is unclear due to the low quality of outcome measures and possible bias of trials. While randomized controlled trials supporting long-term effectiveness of psychostimulants for more than a few months are lacking , 5, the Various lifestyle factors, including diet and nutrition, have been proposed to be involved in the pathophysiology and management of ADHD –9. EmergElectronic search of PubMed was conducted to find original research articles, cohort studies, interventional trials, systematic reviews, and meta-analyses published from 2018 to 2022. Boolean search was conducted using  AND (“attention-deficit hyperactivity disorder” OR “ADHD” OR “attention deficit”) AND (2018/01/01:2022/12/08[dp]). A total of 873 papers were retrieved. Following title and abstract screening, duplicate studies, animal studies, articles without a special focus on ADHD and nutrition, papers published in journals without peer review, editorials, letters, notes, and conference abstracts were removed. According to these criteria, 54 studies examining the association of ADHD with nutrition were included in the present review.A sufficient supply of micronutrients, such as minerals and vitamins, is required for normal brain development. Micronutrient deficiencies may contribute to dysfunctioning of the prefrontal cortex and other brain regions believed to play a role in the pathophysiology of ADHD . AssociaHair trace element and mineral levels were examined in 52 boys with ADHD and 52 typically developing boys . StatistFurther studies on magnesium, zinc, and iron in ADHD have been published recently.People with ADHD have been assumed to be deficient in magnesium due to a low intake or elevated requirement. For example, in a group of 44 boys aged 4 to 9 years with ADHD, hair magnesium content was decreased by 11% compared to a control group of 32 typically developing boys . EvidencThe findings of preclinical studies have suggested that the administration of L-threonic acid magnesium salt in rodents is associated with neurofunctional effects that may offer clinical benefits in the therapy of ADHD. In an open-label pilot study, 15 adults with ADHD of moderate severity received L-threonic acid magnesium salt for up to 12 weeks . Almost A randomized, double-blind, placebo-controlled clinical trial of 66 children with ADHD examined the effect of both magnesium (6 mg/kg/day) and vitamin D  supplementation for 8 weeks . The useZinc deficiency has been suggested to increase the risk of ADHD, while sufficient zinc supply is thought to improve ADHD symptoms. Since various studies regarding the zinc status in ADHD yielded inconsistent results, a recent systematic review and meta-analysis attempted to estimate the association between ADHD and serum/plasma and hair zinc concentrations . This meA systematic review and dose–response meta-analysis, including six double-blind randomized controlled trials with a total of 489 children aged 7 to 10 years with a diagnosis of ADHD (245 children in the zinc group and 244 in the control group), attempted to quantify the efficacy of zinc supplementation on clinical ADHD symptoms in children . Daily dSystemic iron status in individuals with ADHD has been explored in numerous studies. A systematic review of available literature has examined whether children with ADHD have reduced serum or brain iron concentrations in comparison with healthy children . This reAn association between iron deficiency in infancy (ages 12 and 18 months) and sluggish cognitive tempo or ADHD symptoms, as rated by the children’s mothers, in childhood and adolescence  was examined in 959 children in Chile . After aA qualitative systematic review of nine randomized clinical trials examined the efficacy of iron-zinc supplementation in the treatment of children and adolescents with ADHD . The resThe findings of several observational studies have suggested a role of vitamin D in the pathophysiology of ADHD. The pooled data of a meta-analysis including eight observational studies  showed statistically significant reduced 25(OH)D levels in children with ADHD compared to controls . Large cN = 642). While a higher omega-6/omega-3 ratio in cord plasma was associated with a higher ADHD index at age 7 years, no association was found at 4 years. No associations were observed for ADHD symptom diagnostic criteria [Deficiencies in and supplementation of polyunsaturated fatty acids have been suggested to play a role in the etiology and therapy of mental disorders . The asscriteria . These rIn recent years, various clinical trials have examined the efficacy of omega-3 supplements in children with ADHD. A randomized placebo-controlled trial, including 162 children and adolescents aged 6 to 15 years with moderate ADHD symptoms, evaluated the effects of supplements containing docosahexaenoic acid and eicosapentaenoic acid or of a placebo, which were administered for 3 months . This trThe effects of omega-3/omega-6 fatty acid supplementation in 40 preschool children aged 3 to 6 years with elevated levels of ADHD symptoms were investigated in a 4-month randomized, double-blind, placebo-controlled trial . IntentiA systematic review of seven randomized controlled trials with a total of 926 participants examining the effects of omega-3 supplementation in children and adolescents with ADHD found no significant reduction in ADHD scores, as measured by Conners’ rating scales . Thus, tIn summary, the evidence of therapeutic efficacy of polyunsaturated fatty acids regarding ADHD core symptoms appears to be marginal or non-existent. Pre-treatment status of omega-3 fatty acids may influence the effects of supplementation, and therapeutically relevant effects may be confined to people with omega-3 deficiency. Potential adverse effects of long-term omega-3 fatty acid supplementation should be considered .Intestinal microbiota and probiotics may affect brain activity, behavior, and mental health , 48. TheLactobacillus rhamnosus GG ATCC53103 on ADHD symptoms and health-related quality of life in 32 drug-naïve children and adolescents aged 4–17 years with a diagnosis of ADHD [Lactobacillus rhamnosus reported significantly better health-related quality of life as well as physical, social, school, and emotional functioning after 3 months of treatment in comparison with placebo controls. This suggests that administration of Lactobacillus rhamnosus could be beneficial. However, the psychometric results of parent and teacher reports showed no clear benefits of probiotic supplementation [Preliminary interventional evidence has suggested preventive and therapeutic efficacy of probiotics in ADHD . More re of ADHD . Childreentation . Future In conclusion, while probiotics may offer novel strategies in the prevention or treatment of ADHD, the role of intestinal microbiota in the pathogenesis of ADHD and of probiotics in the management of ADHD requires further robust evidence from high-quality, large-scale intervention trials targeting microbiota.Certain dietary patterns, whole diets and other lifestyle-related factors, rather than single nutrients have been suggested to be helpful in the management of ADHD •. SeveraThe findings of several studies exploring potential associations between ADHD and dietary exposures have suggested adverse effects of increased intake of sucrose. A recent birth cohort study from Brazil has investigated the association between the consumption of sugar in children aged 6 to 11 years, as estimated using a food frequency questionnaire, and the presence of ADHD, as assessed by mothers with the development and well-being assessment . No assoA cohort study from Norway explored associations between the quality of the diets of mothers during pregnancy and of their children at age 3 years, as assessed using diet quality indices, and ADHD symptoms and ADHD diagnosis in the children, as assessed at age 8 years using a parent rating scale for disruptive behavior disorders and a patient registry, respectively . On the Nutrient intake and dietary patterns were assessed in a case–control study from Iran, comprising 200 children aged 5 to 13 years  . In compA study from Spain with 259 preschool children aged 3 to 6 years (57 with ADHD and 202 control children) examined dietary patterns of children with and without ADHD diagnosed according to DSM-5 . PrincipAnother study investigated the longitudinal association between dietary patterns in 4-year-old children and ADHD symptoms in the same children at age 6 years . DietaryData from a prospective nationwide cohort study conducted in Korea were used to investigate the relationship between changes in dietary intake and prevalence of ADHD in 1733 elementary school children with ADHD scores and information on dietary intake, as assessed both at baseline (phase 1) and 2 years later (phase 2) . A notabA case–control study from Iran, conducted with a total of 360 children and adolescents (120 cases and 240 controls) aged 7 to 13 years, found that a higher dietary phytochemical score, indicating the percentage of daily energy intake from phytochemical-rich foods , was associated with a lower risk of ADHD, as diagnosed using the DSM-IV-TR . This reIn a case–control study comprising a total of 400 preschool and school children aged 4 to 12 years , a significant inverse association was observed between polyphenol intake, as assessed using a food-frequency questionnaire, and the presence of ADHD, as diagnosed according to the DSM-5 criteria .The association between adherence to a Mediterranean diet containing vegetables, legumes, nuts, fruits, grains, and fish, as assessed using a food frequency questionnaire, and the odds of ADHD, as diagnosed using the DSM-IV, in primary school children aged 7 to 13 years was investigated in an age- and sex-matched case–control study from Iran . After aSeveral components of the dietary approaches to stop hypertension diet, such as high amounts of fruits, vegetables, low-fat dairy products, and vitamin C and low amounts of simple sugars, have been suggested to improve ADHD symptoms. A randomized controlled trial investigated the effect of this diet administered for 12 weeks to 80 children with ADHD aged 6 to 12 years . FollowiN = 8816) suggest that a “healthy” dietary pattern, which is high in vegetables, fruits, seafood, polyunsaturated fatty acids, magnesium, zinc, and phytochemicals, is associated with a significantly reduced risk of ADHD, while the “western” dietary pattern, which includes large amounts of confectionery, red meat, processed meats, refined grains, fried potatoes, crisps, soft drinks as well as animal and hydrogenated fats, and the “junk food” pattern, consisting of biscuits, chocolate bars, buns, cakes, pizza, sweets, crisps, and fizzy drinks, are associated with an elevated risk [The results of a systematic review and meta-analysis of six dietary pattern studies , and dietary intake was assessed at age 8 years using a validated food-frequency questionnaire . MultivaN = 184) and typically developing children (N = 104) completed a lifestyle questionnaire assessing water intake, consumption of sweetened beverages, use of multivitamins or supplements, reading, screen time, physical activity, and sleep. A lifestyle index score was formed from these domains. After adjustment for age, sex, intelligence quotient, use of ADHD medication, household income, and other comorbid mental conditions, children with ADHD were almost twice as likely to have fewer healthy behaviors [Other lifestyle factors than nutrition may also play an important role in the management of ADHD. The question of whether individuals with and without ADHD differ from one another in regard to healthy lifestyle behaviors has been explored •. The paehaviors •. These ehaviors .Recent evidence suggests that the investigation of the role of food hypersensitivities in ADHD is a promising avenue worthy of further exploration. In particular, a large randomized controlled study has sparked interest in the idea that food additives may trigger hyperactivity in children . While sSome children with ADHD have been hypothesized to show hypersensitivities or allergic reactions to a variety of food items , which hSeveral double-blind placebo-controlled studies examining the effects of the few-foods diet in children with ADHD have shown that foods can trigger ADHD, suggesting the existence of a food-related subtype of ADHD . MoreoveIn an uncontrolled, open-label dietary intervention study of a small sample of eight children aged 8 to 14 years with a diagnosis of ADHD according to ICD-10, food items which are commonly related to intolerances were eliminated for 4 weeks . Five ofA further study attempted to reveal how foods that may impact ADHD symptoms can be identified •. In thiIn order to examine the effect of a few-foods diet on physical complaints, such as headache, asthma, rhinitis as well as gastrointestinal and sleep problems, unpublished data from previously published studies have recently been analyzed . ChildreIn the Netherlands, the approach using the few-foods diet in children with ADHD is applied in practice. A retrospective study, including data from all children who started the few-foods approach in three specialized healthcare facilities during three consecutive months, has assessed the effectiveness of the few-foods approach in ADHD and oppositional defiant disorder in real life •. The fiA recent study investigated the long-term effects of a few-foods diet on ADHD symptoms ••. TwentThe mechanisms underlying the reduction in ADHD symptoms following a few-foods diet are unknown. An open-label intervention study examined whether behavioral changes after a few-foods diet are associated with altered brain function during inhibitory control in 79 boys aged 8 to 10 years with ADHD . AccordiIn summary, the available findings regarding the few-foods diet confirm the hypothesis that food intolerances are a possible cause of ADHD.Whether or not individuals with low concentrations of minerals, vitamins, or omega-3 fatty acids are more responsive to dietary administration is unclear. Subgroups of people with ADHD who are likely to benefit from micronutrient or omega-3 fatty acid supplementation need to be identified. Supplementation above a certain threshold of micronutrient status might be ineffective. Moreover, since various comorbid psychiatric conditions are very common in individuals with ADHD, the efficacy of nutritional supplements may vary depending on the comorbidities of trial participants. The question of whether the administration of certain nutrients is effective at any time during the life span or confined to critical time windows also remains to be investigated. Nutrition-based prevention of ADHD may need to focus on pregnancy and infancy. This should be examined in future investigations. Dosage of dietary supplements is a critical issue, since the high-dosage administration of seemingly healthy minerals, vitamins, and other nutrients may carry the risk of adverse effects. In addition, the ill-defined nature of ADHD and the lack of biomarkers underpinning the concept of ADHD may hinder the identification of the role of nutrients and diet. Given the complexity and heterogeneity of the multiple biological, environmental, and social factors underlying ADHD, a simple one-fits-all solution regarding micronutrients and diets in the management of ADHD is unlikely to exist.While the findings of observational studies suggest a role of dietary patterns in the management of ADHD, the designs of these studies are unable to establish a causal relationship between ADHD and diet. Associations between a low prevalence of ADHD and adherence to healthy dietary patterns do not necessarily imply protective effects of the foods consumed in childhood. For example, the mothers of children consuming healthy diets may also have eaten healthy foods during pregnancy and have therefore provided their offspring with essential nutritional compounds during critical phases of brain development. The associations observed between ADHD risk and dietary habits may also be explained by reverse causation, with ADHD behaviors leading to a preference for certain foods. Furthermore, associations between diet and ADHD may be caused by other  factors, which were not assessed. For example, lifestyle factors such as physical activity may correlate with dietary habits and may be more important factors in ADHD symptomatology. Children with ADHD may benefit from generally improved lifestyle choices. Therefore, the interaction between nutrition and lifestyle should play a greater role in investigations of the management of ADHD.Evidence from recent research does not suffice to recommend the administration of micronutrients, omega-3 fatty acids, or probiotics in the management of ADHD. However, emerging evidence suggests that subgroups of children and adolescents with ADHD may benefit from the elimination of certain foods. A major benefit of the few-foods diet is that it may be tailored to the individual. The high response rate to this diet, of up to 60% reported in several studies, indicates an important role of food intolerances in the pathophysiology of ADHD. This promising personalized nutrition-based approach to the management of ADHD deserves further systematic investigation and should be considered in all children with ADHD. Individual nutritional recommendations on the basis of the elimination of certain food items may become an additional therapeutic option for individuals with ADHD.


We found that associations between ADHD maternal and paternal polygenic scores and child ADHD traits decreased significantly when adjusting for the child polygenic score , suggesting genetic transmission of ADHD risk. Similar patterns suggesting genetic transmission of risk were observed for smoking, educational attainment, and cognition. The maternal polygenic score for neuroticism remained associated with children’s ADHD ratings even after adjusting for the child polygenic score, indicating genetic nurture. There was no robust evidence of genetic nurture for other parental factors. Our findings indicate that the intergenerational transmission of risk for ADHD traits is largely explained by the transmission of genetic variants from parents to offspring rather than by genetic nurture. Observational associations between parental factors and childhood ADHD outcomes should not be interpreted as evidence for predominantly environmentally mediated effects.Identifying mechanisms underlying the intergenerational transmission of risk for attention-deficit/hyperactivity disorder (ADHD) traits can inform interventions and provide insights into the role of parents in shaping their children’s outcomes. We investigated whether genetic transmission and genetic nurture  underlie associations between polygenic scores indexing parental risk and protective factors and their offspring’s ADHD traits. This birth cohort study included 19,506 genotyped mother-father-offspring trios from the Norwegian Mother, Father and Child Cohort Study. Polygenic scores were calculated for parental factors previously associated with ADHD, including psychopathology, substance use, neuroticism, educational attainment, and cognitive performance. Mothers reported on their 8-year-old children’s ADHD traits ( Intergenerational psychiatry aims to understand how parents contribute to the emergence of psychiatric risk in their offspring . A fundaObservational studies have identified many parental factors associated with offspring ADHD: parental psychiatric conditions including ADHD itself, depression, anxiety disorders, schizophrenia, bipolar disorder and autism spectrum disorder (autism) –10; persSeveral genetically informed designs for causal inference , 25 suchc), and (ii) the indirect genetic effects of parental alleles not due to influences of alleles inherited by the offspring (paths m and f). In this trio design, the associations between parental polygenic scores and offspring traits are adjusted for the offspring polygenic score to account for the confounding induced by the transmission of genetic variants from parents to offspring. Such adjusted associations are called indirect genetic effects, which originate in parental genomes but affect their offspring via environmental pathways . In the case of ADHD, parental ADHD variants influence parental ADHD traits, which in turn may shape the child rearing environment , ultimately affecting their offspring’s ADHD traits. This indirect parental genetic effect is henceforth referred to as “genetic nurture” [Intergenerational transmission can be investigated in population-based samples with genotype data on parents and offspring and phenotypic measures on offspring outcomes , 32. Insnurture” .Fig. 1WiN = 2518 families).To date, only one study, in the Netherlands Twin Register cohort, has used polygenic scores to investigate the association between parental factors and their offspring’s ADHD traits . They foIn the present study, we use a large population-based cohort of genotyped mother-father-offspring trios to systematically investigate a range of putative parental risk factors for offspring ADHD, including psychiatric conditions, substance use, neuroticism, educational attainment (EA) and cognitive performance. We jointly model maternal, paternal and offspring polygenic scores to quantify genetic versus environmental routes of risk transmission.The Norwegian Mother, Father and Child Cohort Study (MoBa) , 36 is aThe eligible sample was MoBa families with genotypic data  availablN = 19,506 genotyped family trios) imputed from polygenic scores  and 23 auxiliary variables previously found to predict ADHD in MoBa [Children’s ADHD traits were reported by mothers using the Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD)  that con in MoBa , includiPolygenic scores were used as indicators of genetic liabilities for the corresponding parental factors . Polygenic scores are individual-level scores that summarize common variant genetic risk for a given phenotype. The scores are calculated as the weighted sum of effect alleles for all measured single nucleotide polymorphisms (SNPs) in an individual. SNP weights are obtained from summary statistics from Genome-Wide Associations Studies .p-value thresholds, which increases the predictive accuracy of polygenic scores while avoiding overfitting  of 5% was applied to account for multiple testing , the numFor each of the 12 parental factors, offspring ADHD traits were regressed onto three polygenic scores, i.e., for father, mother, and child , as well as on the two ADHD subscales (inattention and hyperactivity-impulsivity).pΔβ < 0.05) [All analyses controlled for child sex and year of birth. We tested whether estimates from the unadjusted, trio and across factor models differed significantly across models ( < 0.05) .Sample demographic characteristics are summarized in Table c in Fig. pΔβ = 1.48 × 10−14 for paternal and pΔβ = 9.95 × 10−17 for maternal estimates), findings which indicate that genetic transmission accounted for associations between parental polygenic scores and offspring ADHD traits, with little evidence for genetic nurture  – findings in line with the genetic transmission of risk. Offspring’s polygenic scores for cognitive performance and EA similarly indicated direct genetic effects. The paternal polygenic score for EA showed evidence of attenuation between unadjusted and trio models (pΔβ = 1.42 × 10−8), consistent with the genetic transmission.For smoking polygenic scores, Fig. The maternal polygenic score for neuroticism was associated with offspring ADHD traits in unadjusted models and remained significant in trio models, which supports genetic nurture as a mechanism linking maternal neuroticism to offspring ADHD traits.The findings suggested some genetic nurture effects in unexpected directions, which should be interpreted with caution (see Discussion). The paternal polygenic score for alcohol use was negatively associated with offspring ADHD traits in both unadjusted and trio models, which would suggest genetic nurture as a mechanism linking paternal liability to drink more drinks per week with decreased ADHD traits in offspring. In trio models only, higher maternal polygenic scores for cognitive performance and EA associated with increased offspring ADHD traits.β = 0.01, 95% CI: −0.02 to 0.04), nor genetic nurture effects from either parent  and for maternal autism (pΔβ = 0.183), depression (pΔβ = 0.051), and cannabis use (pΔβ = 0.796). As such, genetic nurture effects may not have been supported due to limited power of current polygenic scores.Some parental polygenic scores were associated with offspring traits in unadjusted models, and while confidence intervals for genetic nurture estimates overlapped with zero, trio model estimates showed little evidence of attenuation (suggesting genetic transmission) for paternal autism  factors and offspring ADHD traits. We used a multivariate within-family trio design that simultaneously models polygenic scores for parents and offspring. The trio design provides estimates of genetic nurture, unconfounded by direct genetic effects due to parent-to-offspring genetic transmission. Conversely, it provides estimates of direct genetic effects on offspring ADHD traits accounting for confounding by genetic nurture effects. Several parental polygenic scores correlated with offspring ADHD traits prior to accounting for genetic transmission, including ADHD itself, autism and smoking, maternal scores for depression, neuroticism and cannabis use, and paternal scores for EA and alcohol use. Trio models provided strong evidence that the offspring polygenic scores for ADHD and smoking predicted ADHD traits while parental effects were no longer evident and attenuated compared to the unadjusted parental effects. These findings support the role of parent-to-child genetic transmission of ADHD, smoking and EA-associated alleles as important mechanisms underlying associations between these parental factors and their children’s ADHD traits, with little evidence of genetic nurture. Evidence of genetic nurture was found in the case of maternal neuroticism since higher maternal polygenic liability associated with children’s ADHD traits in trio models.We found that both parental ADHD polygenic scores associated with offspring ADHD traits prior to accounting for genetic transmission. However, that was no longer the case in within-trio analyses and associations between parental polygenic scores and offspring ADHD attenuated significantly, consistent with the genetic transmission. This finding is in line with a previous polygenic score study in a Dutch sample . An adopSimilar patterns were observed for smoking, suggesting that genetic transmission partly explains the association between parental smoking and offspring ADHD traits. These findings are consistent with evidence from multiple genetically informed and causal inference methods, showing that the association between maternal smoking and offspring ADHD traits is likely due to genetic transmission, rather than to the impact of smoking per se , 57–59. We found evidence that maternal genetic liability to neuroticism not transmitted to their offspring associated with offspring ADHD traits – findings in line with environmental mechanisms of transmission . Neuroticism reported by parents have been phenotypically associated with parenting difficulties , which mhigher EA and cognition, a finding which was not robust across complementary analyses. Instead, our findings suggest that direct genetic transmission likely explains the direction of these genetic nurture effects since offspring predisposition to lower EA and cognition remained stronger predictors of their ADHD traits in trio models.Contrary to previous evidence that children’s ADHD is associated with lower parental cognitive performance and EA , 12, we fewer drinks per week associated with offspring ADHD traits in both unadjusted and trio models, albeit not robustly so in complementary analyses of the hyperactivity-impulsivity subscale. A possible reason for this direction of association may be that lower polygenic scores for the number of drinks consumed per week index lower socioeconomic status [We also found that paternal genetic predisposition to drinking c status . Nonethec status , 19, 20.Our findings suggest that genetic transmission plays an important role in explaining associations between parental factors and their children’s ADHD traits. Genetic transmission means that phenotypes arise separately in parents and children due to genetic influences they share, but independently of the environment created by parents. Conversely, genetic nurture effects imply that some parental factors matter as they foster environments that affect their offspring (either within the home like parenting or outside like school selection). Implications for interventions are diametrically opposed. In the case of genetic nurture, the effects of interventions targeting parental factors would be expected to affect child attention and hyperactive-impulsive behaviours and cascade across generations. In the case of sole genetic transmission, interventions directly targeting parental factors may successfully improve parental health, but benefits are unlikely to transfer to the child’s attention and hyperactive-impulsive behaviours. Instead, interventions directly aiming to support regulation of attention, activity and impulsivity in children may be more beneficial, whether such interventions are medical, school-based or parent-mediated . Such fiDespite relying on the largest genotyped cohort of trios so far, power may be an issue to detect small intergenerational effects, especially given the limited accuracy of current polygenic scores. However, power unlikely accounts for our finding that genetic transmission is prominent in explaining the intergenerational transmission of risk for ADHD. For example, maternal genetic nurture effects for ADHD were close to zero with an upper CI of 0.023, whereas the lower CI for child-direct genetic effects was 0.075. Replications of findings in multiple cohorts will help with addressing limitations such as generalizability and power. In the meanwhile, while our findings clearly demonstrate the importance of genetic risk transmission, the limited evidence of genetic nurture effects should be considered as suggestive rather than definitive.Although polygenic scores can, under strict assumptions, provide estimates of the causal effect of risk factors equal to those obtained from Mendelian randomisation , expliciWhile mothers rated their children’s ADHD traits (model outcome), polygenic scores for the child, the father and even the mother (model predictors) did not depend on maternal ratings, limiting possible biases due to shared raters. However, maternal liability to ADHD as indexed by polygenic scores may still influence how they rate their children’s traits. Replication of our findings with non-parental ADHD ratings would be informative. We also did not account for variation in parental involvement in children’s upbringing . Future studies should test whether genetic nurture effects are moderated by parental involvement .r = 0.11), which suggests assortative mating . However, simulation research indicates that assortative mating and population stratification may lead to inflated estimates of genetic nurture while estimates of direct parent-to-offspring genetic transmission effects are expected to be unaffected [We cannot rule out possible bias due to assortative mating or population stratification. For educational attainment, maternal and paternal polygenic scores were correlated r = 0.1, which affected . As suchIn conclusion, our study provides the most reliable evidence from genomic data to date, and the first evidence on many parental factors considered here, that genetic transmission may partly account for associations between some parental factors and children’s ADHD traits. Our findings also corroborate results from other genetically informed designs on the importance of genetics in the intergenerational transmission of ADHD. The implication for psychiatry is that the benefits of interventions targeting parental risk factors  are likely to be restricted to the parental generation rather than extend across generations to the child’s ADHD. Directly targeting children’s traits should be more effective to improve children’s outcomes.Supplementary material


Attention-deficit/hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder, that typically manifests itself during childhood and persists in a majority of the affected individuals into adulthood, negatively affecting physical and mental health. Previous studies have shown detrimental effects of the COVID-19 pandemic on mental health in individuals with ADHD. Thus, telemedicine could be a useful tool for optimizing treatment-outcomes in adult ADHD by improving treatment adherence and persistence. However, data on telemedical treatment outcomes in adult patients with ADHD is scarce.We report here the sub-cohort analysis of a naturalistic cohort of adult patients (N = 254) recruited between April 2020–April 2021, comparing the effects of telemedical treatment on participants either clinically diagnosed with depression (N = 54) or ADHD (N = 67). Participants were asked to fill out the WHO-5 repetitively during >12 weeks of telemedical treatment. Furthermore scores of WHO-5, SCL-90R and BDI-II, psychopathology, psychosocial functioning, sociodemographic data, medical records and a feedback survey were analyzed for both groups and compared. Participants with ADHD were further stratified according to the development of well-being during the study period in order to identify factors associated with a satisfactory treatment outcome.p = 0.03, Mann–Whitney-U-Test), suggesting successful treatment was hampered by the combination of ADHD and depressive symptoms. Furthermore, female sex among ADHD patients was correlated with an unfavorable treatment outcome during the course of the study  as well as living with children .Participants with depression reported a significant improvement of well-being during the course of the study, while no such effect could be seen in participants with ADHD on a group level. Despite the good outcome, participants with depression were more severely affected at baseline, with significantly worse psychopathology and a more precarious labor and financial situation. A detailed analysis of ADHD participants without clinical improvement revealed significantly higher BDI-II scores than for ADHD participants with a satisfactory outcome (Besides screening for depressive symptoms before telemedical treatment, future research should address the specific needs of female ADHD patients as these patients may be at a particularly high risk of being overburdened with family work. AtteThe COVID-19 pandemic was associated with high rates of symptoms of insomnia, anxiety, depression and psychological distress in the general population , with yoAt the initial stages of the COVID-19 pandemic, telemedicine was - despite limited evidence - considered as an additional means of expanding the delivery of mental health services to patients with ADHD  and faciThe current analysis - building on the sample of the exploratory study mentioned above  – invest2.2.1.Here, we report the analysis of a sub-cohort of our recently published study . This moRecently, we determined a robust and favorable response to telemedical treatment among patients with depressive disorders in this patient cohort, whereas patients with chronic neurodevelopmental disorders like ADHD did not experience significant improvement at a group level . Therefo2.2.All participants analyzed in this study (N = 67 with ADHD and N = 54 with depression) gave informed consent to analyze their medical records, including sex, age and sociodemographic data as well as their psychiatric history and standardized professional ratings of psychopathology for the purpose of the study. As described previously , all men2.3.2.3.1.We used the WHO-5 for the assessment of overall well-being during telepsychiatric counseling. The WHO-5 is a short self-administered measure of well-being, covering the last 2 weeks before completion of the questionnaire . The WHO2.3.2.The SCL-90-R by Derogatis  measures2.3.3.During the second or third online survey via REDCap participants could also complete the BDI-II. 19 (35.2%) of the participants diagnosed with depression and 33 (49.3%) of the participants diagnosed with ADHD completed the BDI-II. The BDI-II is a widely used 21-item instrument, validated for the self-report of depressive symptoms experienced during the past 2 weeks , 36. Ind2.3.4.While the WHO-5, SCL-90-R and the BDI-II are self-report questionnaires focusing on the subjective perception of overall well-being and different symptom domains, the GAF and CGI were used as clinician-rated scales to document the global impairment due to patients’  health conditions. CGI  scores i2.3.5.Thirty-two (59.3%) of the participants with depression and 45 (67.2%) of the participants with ADHD completed an evaluation questionnaire asking for feedback concerning technical details . Moreover, patients were asked for their overall satisfaction with telepsychiatric consultations. Participants were asked how helpful they found the telemedical interventions during the study period and if they were comparable to conventional face to face consultations. Patients were also requested to state their preference about using telepsychiatry in the future again. Participants were also asked if and how the COVID-19 Pandemic had influenced their mental well-being.2.4.All data acquired during surveys and from medical records were entered into an Excel master file and then translated to SPSS Version 27 and R Version 4.2.0.1. for further analysis. The descriptive statistics of the sample were computed for the sociodemographic characteristics, consisting of frequencies and percentages for categorical values and mean and standard deviations (SD) and for scale variables. Differences between two groups of patients (patients with depression vs. ADHD patients or ADHD patients with or without improvement on the WHO-5 well-being index) were assessed using the Mann-Witney-U test for the different non-parametric clinical scale variables or the Chi-Square tests for frequencies of the categories in the sociodemographic parameters.r. For all tests, a value of p of less than 0.05 was considered statistically significant.A paired Wilcoxon signed-rank test was used to assess differences in the levels of mental health variables, e.g., the results of the WHO-5 during subsequent inquiries. To this end, only data from subjects was included, who had participated in all inquiries .3.We previously reported that telemedical treatment in a naturalistic patient cohort N = 254) during the COVID-19 pandemic supported mental well-being as measured by the WHO-5 well-being index and the SCL-90-R  and 8–12 weeks . In contrast, ADHD patients without children benefited more from telemedical treatment during the COVID-19 pandemic than ADHD patients who were living together with children during the study period . Further analyses, examining correlations between the outcome on the WHO-5 and different sociodemographic factors  were not conclusive (Thirty-three patients with ADHD (49.3% of the participants diagnosed with ADHD) also completed the BDI-II. Participants with ADHD and no improvement or even a further decline on the WHO-5 during the course of the study , had sighe WHO-5 . Female nclusive .4.The data presented here builds on an earlier exploratory study that aimed at describing the changes of symptoms of psychiatric outpatients during telemedical treatment during the COVID-19 pandemic, identifying patient groups with beneficial or less favorable treatment outcomes, determining sociodemographic factors with an impact on the effectiveness of telepsychiatric treatment, and specifying patients’ experiences with telepsychiatric consultations compared to conventional face to face treatment by mental health experts. The objective of the current analysis was to identify factors that distinguish patients with a depressive disorder, who experienced the best treatment outcome, from patients with poorer treatment results on a group level, namely patients with ADHD. Secondly, the data was screened for factors that allowed for a better differentiation between ADHD patients with a satisfactory treatment outcome and ADHD patients with a stagnating or even worsening mental health status.Comparing the two groups of patients that experienced the highest and the least improvement in well-being during telemedical psychiatric treatment in our study, namely patients with either clinically confirmed depression or ADHD, patients with depression more frequently reported financial debt and unemployment. At the same time patients with ADHD were more likely to have children. Nevertheless, sociodemographic characteristics could not explain the significant difference in treatment outcomes between both groups. Clinical diagnoses of depression and ADHD were mirrored by clinicians’ standardized ratings of psychopathology, substantiating the validity of diagnostic procedures during telemedical treatment. Patients with depression reported a significantly greater impairment in well-being on the WHO-5 index and a higher burden of psychopathology on the SCL-90-R in combination with a lower clinician-rated global functioning on the GAF and CGI scales at baseline. However, during the course of the study, patients with depression experienced a substantial improvement of well-being, while ADHD patients’ well-being scores stagnated or even deteriorated on a group level. There was a statistically non-significant tendency of patients with ADHD to engage in less telemedical appointments than their depressed counterparts. However, patients with depression and participants with ADHD were equally satisfied with the treatment they received. Stratification of patients with ADHD according to the development of well-being during the study period revealed no differences in well-being, psychopathology and global functioning at baseline between patients with an improvement in well-being and those without. Hence, patients with ADHD who experienced improvement during telemedical treatment were not already less impaired at the beginning of treatment. The frequency of telemedical consultations was also evenly distributed between both groups of patients. Yet, ADHD patients with a lack of improvement or even a further decline of well-being during the study reported a higher load of depressive symptoms on the BDI-II than ADHD patients with a favorable treatment outcome. Furthermore, female patients with adult ADHD and patients living with children were more likely to experience an unfavorable treatment outcome.Generally, quality of life is significantly reduced in patients with ADHD compared to their healthy peers . DepressAttention-deficit/hyperactivity disorder research on psychiatric treatment and support during the COVID19 pandemic has largely neglected adults, older adults and females as well as minority groups . On the On a general level, our findings basically corroborate results from an earlier study that found female children and adolescents with a mental illness during the COVID-19 pandemic to be at a higher risk for psychological burden than their mentally healthy peers . Yet, inIn this context, it has to be emphasized that the presence of depressive symptoms on the BDI-II does not necessarily imply the clinical diagnosis of depression . FurtherFinally, the results of our study overall corroborate earlier findings that remote communication for psychiatric assessment and treatment during the COVID-19 pandemic was found useful, effective, reliable and satisfactory by adult patients with ADHD , albeit There are several limitations that have to be taken into account concerning the interpretation of the above mentioned data. Due to the pandemic situation, a randomization of participants to different treatment modalities (face to face vs. telemedicine) was not feasible. Furthermore, treatment choices were purely guided by patients’ preferences and experienced clinicians’ advice and experience. Thus, heterogeneity in treatment modalities during the course of telemedical treatment, e.g., the administration of behavior-therapy oriented and mindfulness-based interventions vs. generic counseling in combination with psychopharmacological treatment, cannot be excluded. Furthermore, women with mental disorders may have higher odds of COVID-19 infection than males with the strongest gender disparity for ADHD . Partici5.When assigning adult patients with ADHD to telemedical treatment options in clinical practice, special attention needs to be paid to monitoring the development of symptomatology and treatment outcomes. A change to face to face treatment should be a low-threshold offer despite patients’ subjective satisfaction with telemedical treatment modalities. Women with ADHD, patients living with children and ADHD patients with a high load of depressive symptoms and/or diagnosed with a depressive disorder might not respond adequately to telemedical treatment. Therefore, such treatment options should be considered with caution during the treatment of patients with the aforementioned characteristics.Future cross-sectional and longitudinal research should focus on sex differences in ADHD symptoms and treatment outcomes and the development of responsive interventions , aiming The original contributions presented in the study are included in the article/The studies involving humans were approved by Ethics committee II of the medical faculty Mannheim, University of Heidelberg approved under license no. 2020-562 N. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.A-SW and PP designed the study. TR, PP, and A-SW acquired the data. AB developed the online survey tool. A-SW and TP analyzed the data. OH, HT, and AM-L advised and discussed the data. PP, TP, and A-SW wrote the manuscript with the help of all authors. All authors contributed to the article and approved the submitted version.


Introduction: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that interferes with multiple aspects of daily functioning and is associated with impairments in several domains. It may affect academic, educational, vocational, social, emotional, interpersonal, and health domains, and worsen risks to health outcomes. Objective: To identify and discuss medical conditions that commonly present with symptoms resembling ADHD. Method: This review is selective and not systematic. It is conducted through a focused literature search through PubMed, Google Scholar, and EMBASE. Search term included “ADHD misdiagnosis”, “medical conditions with ADHD like symptoms”, “ADHD AND medical problems”. Exclusion: giftedness, high IQ, and any article that does not list medical conditions. The limits applied were the following: the work must have been published in the past 20 years, be on humans, and be in the English language. Results: There are several medical conditions that can be misdiagnosed as ADHD and may show a similar presentation to ADHD, particularly with inattentive symptoms. Examples include, but are not limited to, absence seizure disorder, diabetes, thyroid dysfunction, sleep deprivation, post-concussion states, inflammatory bowel disease, iron deficiency states and anemia, and disordered breathing. Conclusions: Our review suggests that a thorough medical evaluation should be conducted prior to the diagnosis of ADHD. Allied health professionals and psychologists who diagnose ADHD should seek medical clearance from a physician prior to making the ADHD diagnosis in order to reduce misdiagnosis rates and improve patient outcomes. ADHD diagnosis should follow guidelines and be carried out under a systematic standardized approach. A full medical evaluation should be conducted to assess for medical conditions that may look like ADHD or be associated with ADHD. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that interferes with multiple aspects of daily functioning. The diagnosis requires the presence of developmentally inappropriate levels of inattentive and/or hyperactive–impulsive symptoms, at least six symptoms in children and adolescents and five in adults, lasting for at least 6 months, occurring in different settings, and first manifesting in childhood prior to the age of 12 . SymptomADHD is associated with impairments in several domains. It may affect academic, educational, vocational, social, emotional, interpersonal, and health domains, and worsen risks to health outcomes ,9.Diagnosis of many psychiatric disorders cannot be made if the disorder is attributable to physiological effects of substance or another medical condition. DSM-5 is the diagnostic and statistical manual that is used by clinicians for the diagnosis of mental disorders; however, the DSM-5 diagnostic criteria for ADHD do not contain the exclusion phrase that applies to several other disorders such as depression ,2. ADHD The objective of this review is to identify and discuss medical conditions that commonly present with symptoms resembling ADHD.This review is selective rather than systematic and comprehensive. It attempts to provide guidance on several questions that are relevant to clinicians, such as what general medical conditions could produce symptoms like these of ADHD. A focused literature search was conducted in PubMed, Google Scholar, and EMBASE, using the search terms: “Attention deficit hyperactivity disorder”, “ADHD”, “attention”, “hyperactivity”, “impulsivity”, and “general medical condition”, “ADHD”, and any of the following: “endocrine”, “intellectual disability”, “sleep”, “seizure”, and “anemia”), “ADHD misdiagnosis”, “medical conditions with ADHD like symptoms”, “ADHD and medical problems”. Exclusion: ADHD and giftedness, high IQ. Any article that does not list medical conditions was excluded. The relevant articles were selected and reviewed by the primary investigator. Few articles linked ADHD to medical conditions, but several articles described inattentive symptoms as part of the presenting symptoms of the medical condition.The limits applied were the following: works must published in the past 20 years, be about humans, and be in the English language. The relevant articles were reviewed, and the important findings are summarized below.Absence seizures can be typical or atypical. Typical absence seizures (TASs) are brief  and frequent, with an abrupt and severe loss of consciousness, characterized by gaze rigidity, freezing, and sometimes automatisms and chewing. The eyes may turn upwards and eyelids flutter. It usually lasts less than 10 s. They are brief, so they can be easily missed. The ictal electroencephalogram shows generalized discharges of high-amplitude spikes and waves around 3 Hz. Seizures appear during wakefulness in children with normal neurological examination and development. Atypical seizures last longer and may extend beyond 20 s. They have a slower onset and offset with a change in muscle tone and movement .The clinical presentation of children with TASs could be misdiagnosed as the inattentive subtype of ADHD . The inattentive ADHD-like presentation may depend on epilepsy-related characteristics such as the seizure frequency, duration of the illness, and antiepileptic medications . MissingPatients with TASs can also have comorbid anxiety, linguistic, and sleep disorders ,14.ADHD can also be misdiagnosed as absence seizures. Children with ADHD often present sleep problems Sleep disorders could lead to a behavioral and/or emotional dysregulation characterized by hyperactivity and impulsivity. Also, vigilance level disturbances can mimic absence seizures ,16,17.Diabetes comprises a group of metabolic syndromes characterized by hyperglycemia. Type 1 diabetes (T1DM) is called insulin-dependent, and type 2 is called noninsulin-dependent DM. Disturbances to the blood glucose can lead to a series of pathogenetic mechanisms involving neurological dysfunction, including neuronal apoptosis, abnormal energy metabolism, synaptic dysfunction, neurodegenerative changes, and oxidative stress in brain tissue ,19,20,21In T1DM, cognitive problems have been studied in several age groups. Some studies have suggested an impaired executive function and poor memory between the ages of 9 and 19. A lower verbal intelligence was noticed in the young T1DM group than in the non-diabetic control group ,23,24.Lower academic achievements were reported in students with T1DM than their classmates who are non-diabetic .Adult patients (>22 years old) with T1DM also showed cognitive changes in several studies. They showed a reduced sustained attention  and infoHyperglycemia or hypoglycemia can also be found in T1DM due to difficulty regulating glucose metabolism. Chronic hyperglycemia is associated with cognitive impairment, visuospatial abilities, and information processing, particularly with an early age of onset and long duration of illness ,30.Diabetic ketoacidosis is a complication of T1DM, and pediatric patients newly diagnosed with both show a clear pattern of poorer cognitive functioning, and they perform poorly in executive functioning .Cognitive impairment in type 2 diabetes (T2DM) may be related to reduced activation in the hemisphere temporoparietal regions . Damage There are additional metabolic problems on top of glucose control, such as disorders of lipid metabolism and increased levels of ghrelin, cortisol, and C-reactive protein, that may also lead to a decrease in neurological function ,35. ReseIn patients with T2DM, the single-nucleotide polymorphisms rs17518584 and Hp1-1 in patients with T2DM are associated with executive functions and attention/working memory, respectively ,37.4 and T3 concentrations. Subclinical hyperthyroidism has been associated with cognitive decline in some but not all studies [SCH cannot be diagnosed via clinical findings, but via an elevated serum TSH concentration and normal circulating free T studies .Younger people with SCH were observed to have mild cognitive impairment with subtle deficits in memory, executive function, difficulties in new learning, and attention problems . SeveralHypothyroidism can affect several cognitive domains ,42,43,44Hashimoto thyroiditis (HT) is the most common autoimmune disease of the thyroid gland that is characterized by the infiltration of hematopoietic mononuclear cells, mainly lymphocytes, in the thyroid follicles. The term HT includes the classic form, and other forms that are less prevalent, such as the fibrous variant, IgG4-related variant, juvenile form (from the age of 10 to 18), Hashitoxicosis, and painless thyroiditis (sporadic or post-partum). All forms are characterized pathologically by thyroid cells undergoing atrophy or transforming into a bolder type of follicular cell, rich in mitochondria, called a Hürthle cell (HT). Most HT forms ultimately evolve into hypothyroidism, although, at presentation, patients can be euthyroid or even hyperthyroid ,51.The diagnosis of HT relies on the presence of circulating antibodies to thyroid antigens (mainly thyroperoxidase and thyroglobulin) and reduced echogenicity on a thyroid ultrasound .There are several cognitive clinical manifestations of HT and hypothyroidism. An inability to concentrate, difficulty focusing, executive dysfunction, and poor memory are common and are reported by the majority of patients. It can be confused with ADHD, particularly early in the disease, when the patient is euthyroid. Local manifestations due to compression of the cervical structures that are anatomically close to the thyroid gland may include dysphonia, dyspnea, and dysphagia. Systemic manifestations originate from a loss of function of the thyroid gland and subsequent primary hypothyroidism. Examples of systemic manifestations include constipation, decreased peristalsis, and dry, cold, yellowish, and thickened skin, in addition to several cardiovascular implications. Muscles appear falsely hypertrophic. The respiratory system, hematopoietic system, and reproductive system may also be affected. Depression is also common. Diagnosis can be made through ultrasound, which has replaced fine-needle biopsy ,55,56,57Sustained or vigilant attention means the ability to maintain stable, focused attention across a time interval . It is aConsecutive days of sleep restriction may lead to a cumulative deficit in sustained attention .Patients with sleep deprivation can be misdiagnosed as having ADHD due to difficulty in sustaining attention. It is important to inquire about sleep quantity and quality in patients assessed for ADHD. A recent study suggested that sleep deprivation in early childhood is associated with a higher risk of ADHD in middle childhood .Poor sleep could lower inhibitory control and increase impulsivity . There mSleep alterations may produce ADHD-like symptoms and, on the other hand, an altered sleep architecture could exacerbate ADHD symptoms .The association of sleep with ADHD is quite complex. Problems with sleep may be an intrinsic feature of ADHD. Regular sleep disturbance can lead to the development of ADHD or ADHD-like symptoms, potentially resulting in misdiagnosis ,64.The effects of restricted, disordered, or disrupted sleep can manifest as symptoms, behaviors, or functional impairments that are remarkably like those of ADHD ,66. The Children with inadequate sleep may present with poor attention and behavioral symptoms that overlap with the core features of ADHD . Some stSleep-disordered breathing (SDB) includes several conditions such as obstructive sleep apnea (OSA) and primary snoring . SDB hasPost-concussion states, inflammatory bowel disease, iron-deficiency states, and anemia can present with symptoms of inattention that can be confused with the inattentive type of ADHD.The present review supports the notion that ADHD symptoms could be present secondary to a general medical condition, without the diagnosis of ADHD. Since the DSM-5 diagnostic criteria for ADHD do not contain an exclusion phrase that applies to several other disorders such as depression, we suggest a change in the DSM-6 to exclude the diagnosis of ADHD if the ADHD symptoms are attributable to physiological effects of substance or another medical condition.The review also suggests that a thorough medical evaluation should be conducted prior to the diagnosis of ADHD to reduce misdiagnosis rates and improve patient outcomes. Allied health professionals and psychologists who diagnose ADHD should seek medical clearance from a physician prior to making the ADHD diagnosis. ADHD diagnosis should follow guidelines and be carried out in a systematic, standardized way. A full medical evaluation should be conducted to assess medical conditions that may look like ADHD or be associated with ADHD.A misdiagnosis of ADHD and missing an important medical diagnosis such as seizure disorder, diabetes in children, or thyroid dysfunction may have life-threatening consequences and long-term implications on the quality of life of patients.Since hypothyroidism may present with cognitive difficulties, serum TSH should be ordered in patients with impaired cognitive function. Cognitive deficits related to thyroid dysfunction are largely reversible with levothyroxine therapy.The majority of the conditions listed in this review can be easily ruled out by a qualified medical practitioner and, at times, a simple blood test. It is understood that the general medical conditions that produce ADHD-like symptoms are rare and, in the majority of cases, there are clear signs to suggest the presence of a medical condition. Therefore, considering the secondary causes of ADHD can optimize patient care and should be the standard of care.Prior to an ADHD diagnosis, routine blood work should be ordered, and additional tests should include thyroid stimulating hormone (TSH), Hemoglobin A1c, complete blood count (CBC), an obstructive sleep apnea (OSA) questionnaire, and taking the patient history regarding seizures and sleep. These may help to rule out general medical conditions that produce ADHD-like symptoms. Any family history of sudden death and cardiovascular problems should also be obtained.Medical evaluation is also important as ADHD diagnosis can be missed in some medical conditions, such as chromosome 15 microdeletion syndromes or Fragile X.Clinicians who are faced with pressure to diagnose ADHD should seek support from colleagues and professional organizations to ensure that societal pressure does not lead to a misdiagnosis of ADHD. Patients might find the delay in ADHD diagnosis to order medical investigations frustrating, but when the rational of the delay is explained, most patients may accept that the process aims to protect them and ensure that they receive the appropriate diagnosis.ADHD diagnosis remains challenging and complex. Lauria’s neuropsychological theory adds another dimension of complexity to brain functioning, particularly due to the complex representation of the cultural psychological process in the central nervous system. It was emphasized that neuropsychological assessment helps in understanding the complex functional changes in the human brain, rather than localizing a lesion. Further research is needed in the diagnostic process of ADHD in adults.


This clinical trial aimed to determine the influence of attention-deficit/hyperactivity disorder (ADHD) on neuro-ophthalmologic function and brain-derived blood biomarkers following acute subconcussive head impacts.n = 30). Soccer players without ADHD were assigned into a non-ADHD group (n = 30). Participants performed 10 soccer headers with a soccer ball projected at a velocity of 25mph. King-Devick test (KDT), near point of convergence (NPC), and serum levels of NF-L, tau, GFAP, and UCH-L1 were assessed at baseline (pre-heading) and at 2 h and 24 h post-heading.The present trial consisted of age- and sex-matched samples with a ratio of 1:1 between two groups with a total sample size of 60 adults . Soccer players diagnosed with and medicated daily for ADHD were assigned into an ADHD group , and persisted at 2 h-post  and 24 h-post heading (NPC: p = 0.001). NPC significantly worsened over time in both groups compared to baseline . Conversely, improvements in KDT time compared to baseline occurred at 2 h-post in the non-ADHD group  and at 24 h-post in both groups . There were no group-by-time interactions for GFAP as both groups exhibited increased levels at 2 h-post  that returned to baseline at 24 h-post. NF-L levels increased at 2 h-post heading in the ADHD group , but no significant NF-L changes were observed in the non-ADHD group over time.There were no statistically significant group-by-time interactions in outcome measures. However, at baseline, the ADHD group exhibited lower neuro-ophthalmologic functions compared to the non-ADHD group . Research focusing on subconcussive head impacts has increased exponentially in the past two decades . The curADHD is the most common neurodevelopmental disorder , and as Unlike subjective measures such as self-reported symptoms, neuro-ophthalmologic function has shown to be one of the most sensitive functional metrics to reflect the severity of neural stress from subconcussive head impacts . Neuro-oTherefore, to address these limitations, we designed a clinical trial using our soccer heading model  and a mun = 30; non-ADHD group, n = 30; From March 2021 through March 2022, potential participants were simultaneously recruited from local universities and soccer clubs, and 87 potential participants were screened to be assigned into one of two groups: (1) individuals clinically diagnosed with and medicated for ADHD (ADHD group) and (2) age- and sex-matched individuals without ADHD diagnosis (non-ADHD group). For any non-ADHD participants whose age and sex demographics were not matched in the ADHD group, they continued to participate in the study but were not included in the analysis. As a result, a total of 69 participants completed the study and 60 were included in the final analysis . All participants provided written informed consent.Following recruitment, a self-reported health questionnaire was administrated to each participant to obtain demographic information, head impact history, and mental health conditions. Serum samples were collected, and participants performed NPC and KDT at three collection time points: . Following baseline measurements, participants performed 10 controlled soccer headers (see Subconcussion Model section). Participants remained in the laboratory until the 2 h-post heading time point. Participants returned to the laboratory approximately 24 h after the soccer heading for the final time point. The post soccer heading timepoints have been used previously in similar study designs and have been shown to be a sufficient timeframe to identify the neuro-ophthalmologic and cellular responses to subconcussive head impacts . From 3 p < 0.001). The coordinator and testers were blinded to status of the participants’ ADHD diagnosis. In compliance with the AISRS, participants in the ADHD group were required to report at least five symptoms from the symptom-checklist of the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) in either the inattentive or the hyperactive/impulsive domain and were free of symptoms unrelated to ADHD . Participants in the non-ADHD group were required to score below the AISRS threshold. Further validation for the ADHD group included documentation of their complete clinical ADHD diagnosis. Additional psychiatric assessments included the Beck Anxiety Inventory (BAI)  . Two addry (BAI) , Patientry (BAI) , Generalry (BAI) , Cannabiry (BAI) , and Dairy (BAI) .A soccer heading model was used to induce subconcussive head impacts , 8, 21. Assessment consisted of previously established protocols of NPC and KDT . NPC wasn = 5). In place of venipuncture, a non-invasive Tasso sampling kit (Tasso inc.) was placed on participants’ arms and used to collect a total of 400–600 uL of capillary blood per device. Clotted serum was centrifugated , aliquoted, and stored at-80 °C prior to running the assay. Serum levels of NF-L, Tau, UCH-L1, and GFAP were simultaneously ran over three assays using the Human Neurology 4-Plex A assay (N4PA) on a SR-X with single molecule array   at pre (baseline), 2 h-, and 24 h-post soccer heading for blood biomarker analysis. A selective sample were not valid for venipuncture methodology due to participant anxiety or phlebotomy difficulty (anterix) . SamplesTo address if ADHD is a modulating factor for subconcussive head impacts and account for differences between groups at baseline, the primary interest was to test the changes in KDT time and error, NPC distance, and in serum levels of NF-L, Tau, UCH-L1, and GFAP over time between the ADHD and non-ADHD groups (group-by-time interaction). Our secondary interest was to test the changes in neuro-ophthalmologic function and serum levels over time compared to baseline values within the ADHD group.n = 0, NF-L: n = 4, Tau: n = 1, UCH-L1: n = 1). Nine data points for UCH-L1 were below the LOD, and 5 samples were not valid for analysis due to phlebotomy or SR-X complications. The model was refit without these data being included. For each estimated outcome value (β coefficient), a 95% confident interval (CI) was calculated, and missing data was accounted for. The analysis was summarized by providing a contrast estimate with its 95% CI and a value of p in the following format: . The significance levels for all tests were set a priori to 0.05. Lastly, a post-hoc analysis of three independent t-tests  each with a Bonferroni adjusted alpha level of 0.016 was conducted to examine group differences in neuro-ophthalmologic function at each post-heading time point. All analyses were conducted using statistical software R version 3.5.2  with packages “lmer” and “lmerTest.”The assessment of demographic differences between the ADHD and non-ADHD groups at baseline consisted of student’s two-tailed independent t-tests for continuous variables  and Fisher’s exact tests for categorical variables . Independent samples t-tests were also used to compare baseline values of the outcome variables between groups. A series of mixed-effects regression models was used to test our hypotheses. The primary (fixed-effect) factors were groups (ADHD and non-ADHD), time of measurement , and the group-by-time interaction. Participants were treated as a random effect to account for individual differences at baseline. A sensitivity analysis was conducted to evaluate whether any demographic variables, regardless of group difference, were significantly associated with the outcome measures. Methods of outlier detection were calculated to examine unusual influence of individual data points on the fit of the model. Additional validation of Tasso measurements was used and data points that were identified as outliers were excluded from the group analysis. Following the removal of appropriate Tasso samples, six data points were identified as outliers , and the group difference persisted at 2 h (p = 0.007) and 24 h-post heading (p = 0.001). However, there were no group-by-time interactions at 2 h- or 24 h-post heading.Ten soccer headers significantly increased (worsened) NPC in both groups compared to their pre-heading baselines , whereas the ADHD group showed no changes at 2 h-post compared to baseline . However, the group-by-time interaction was not statistically significant at either time point (p = 0.018), as well as at 2 h-post heading (p = 0.014); however, the group difference disappeared at 24 h-post heading. No significant changes were observed in KDT error  but no change at 24 h-post heading . Conversely, the non-ADHD group displayed no significant change across all time points , and GFAP levels in both groups were normalized to baseline levels at 24 h-post heading   . Non-tox 0.9412) . This is 0.9412) . Fourth, 0.9412) , and tha 0.9412) . Ultimat 0.9412) , 46 by sOn the contrary, our data have demonstrated that ADHD may influence the axonal response to subconcussive head impacts. Blood NF-L levels in the ADHD group were shown to be sensitive to 10 controlled soccer headers, with serum levels increasing at 2 h-post heading. Elevations in blood NF-L concentration have been established as a reliable marker to assess axonal damage following subconcussive head impacts  and incrDespite also originating from the axon, serum tau levels opposed those of NF-L, as reflected by elevated tau levels in the non-ADHD group, and a significant group-by-time interaction, at 24 h-post heading. Tau is one of the most studied biomarkers in TBI research; however, majority of existing literature identifies acute exposure to subconcussive head impacts to be below the threshold for increased tau phosphorylation . The tauOur data supports the present literature that neural-injury blood biomarkers, KDT and NPC have the potential to aid in athlete monitoring. However, additional measurements, such as neuroimaging, should be evaluated to determine clinical decisions. Despite the possible vulnerabilities associated with ADHD that our studies suggest, exercise and sport participation has shown to improve mental and physical health in individuals with ADHD . CollectThe present study has several limitations that should be considered. We are unable to account for additional factors that may influence our outcome variables. For example, participants were unmonitored in between time points of 2 h- and 24 h-post heading. Individual variabilities may also have an impact on the outcome variables, as NF-L has been suggested to be associated with concussion history in prior studies . HoweverThe present study provides evidence that ADHD may have increased vulnerability to cellular and neuro-ophthalmologic deficits at baseline and after repetitive subconcussive head impacts. Regardless of ADHD diagnosis, subconcussive head impacts increased serum GFAP levels and impaired NPC. Conversely, further observation of ADHD-specific reduced resiliency to subconcussive-induced neural injury was reflected in increased serum NF-L levels and in blunted improvements in KDT time compared to their non-ADHD counterparts. We encourage future studies to use additional neurological measures to confirm these findings.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by Indiana University Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.MN: conceptualization, collection and curation of the data, interpretation, formal analysis, writing – original draft, writing – review and editing. WK: conceptualization, interpretation, formal analysis, writing – review and editing. DR: collection and curation of the data, writing – review and editing. OO and LK: collection of the data, writing – review and editing. PQ: conceptualization, interpretation, formal analysis, writing – review and editing. TM: conceptualization, interpretation, formal analysis, writing – original draft, writing – review and editing, administration, supervision. SN: conceptualization, interpretation, writing – review and editing, funding acquisition, supervision. KK: conceptualization, interpretation, formal analysis, writing – original draft, writing – review and editing, funding acquisition, administration, supervision. All authors contributed to the article and approved the submitted version.