Pathophysiology Of Attention-deficit/hyperactivity Disorder Research Articles

Neuroimaging in attention-deficit/hyperactivity disorder.

Purpose of reviewNeuroimaging research on attention-deficit/hyperactivity disorder (ADHD) continues growing in extent and complexity, although it has yet to become clinically meaningful. We review recent MRI research on ADHD, to identify robust findings, current trends and challenges.Recent findingsWe identified 40 publications between January 2019 and September 2020 reporting or reviewing MRI research on ADHD. Four meta-analyses have presented conflicting results regarding across-study convergence of functional and resting-state functional (fMRI and R-fMRI) studies on ADHD. On the other hand, the Enhancing NeuroImaging Genetics Through Meta-Analysis international consortium has identified statistically robust albeit small differences in structural brain cortical and subcortical indices in children with ADHD versus typically developing controls. Other international consortia are harnessing open-science efforts and multimodal data (imaging, genetics, phenotypic) to shed light on the complex interplay of genetics, environment, and development in the pathophysiology of ADHD. We note growing research in ‘prediction’ science, which applies machine-learning analysis to identify biomarkers of disease based on big data.SummaryNeuroimaging in ADHD is still far from informing clinical practice. Current large-scale, multimodal, and open-science initiatives represent promising paths toward untangling the neurobiology of ADHD.

Serum Heat Shock Protein 70 Level in Children with Attention Deficiency Hyperactivity Disorder.

Attention deficit hyperactivity disorder (ADHD) have quite complicated etiology. The relationship between ADHD and immune and oxidative imbalances is discussed in current researches investigating the pathophysiology of ADHD. The aim of the study is to determine whether heat shock protein 70 (HSP70) has a potential role in pathophysiologic mechanisms of attention deficit hyperactivity disorder. This study included 41 children that were diagnosed with ADHD and 32 typically developing children. Conners' Teacher Rating Scale (CTRS) was used to evaluate ADHD presentation and severity. Additionally, an enzyme-linked immunosorbent assay (ELISA) kit was used to evaluate serum HSP70 level. We have detected that the serum HSP70 levels of children with ADHD were lower than the typically developing group (p<0.01). No relationship was determined between HSP70 levels and either the severity of ADHD or predominantly ADHD presentations (p>0.05). With these findings, it can be proposed that HSP70 might have a crucial role in the etiological mechanisms of ADHD. Moreover, these changes in peripheral blood may have therapeutic and/or diagnostic value. However, more detailed prospective studies are needed to explain the link between ADHD and heat shock proteins.

Evaluation of hematological inflammatory markers in children and adolescents with attention deficit/hyperactivity disorder.

This study aims to investigate whether there is a relationship between attention-deficit/hyperactivity disorder (ADHD) and inflammation, using hematologic inflammatory parameters in a large sample of children and adolescents. This retrospective study comprises 347 children and adolescents with ADHD between 6 and 17 years of age who met the inclusion criteria as well as 205 healthy children and adolescents in the control group. Serum parameters such as white blood cell (WBC), neutrophil, lymphocyte, platelet, monocyte, eosinophil and basophil counts, mean platelet volume (MPV), and platelet distribution width (PDW) were recorded from complete blood count tests at the time of admission, while neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and other ratios were calculated based on these counts. NLR, PLR, MPV, PDW, WBC and neutrophil counts were significantly higher in children and adolescents with ADHD than in the control group. In the ADHD group, NLR, WBC and neutrophil counts were significantly higher in girls than in boys. The results of this study support the hypothesis that inflammation plays an important role in the complex pathophysiology of ADHD. In addition, our data confirm that easily obtainable and reliable hematological parameters can be used when investigating the role of inflammation in ADHD etiology (Tab. 4, Ref. 44).

The Co-occurrence of Pediatric Obesity and ADHD: an Understanding of Shared Pathophysiology and Implications for Collaborative Management.

To describe what is known about the association between obesity and attention-deficit hyperactivity disorder (ADHD) in children along with the co-occurring conditions of sleep dysfunction, loss of control/binge eating disorder (LOC-ED/BED), and anxiety. Obesity and ADHD share common brain pathways (hypothalamic, executive, and reward centers) with pathophysiology in these areas manifesting in partial or complete expression of these diseases. Sleep dysfunction, LOC-ED/BED, and anxiety share similar pathways and are associated with this disease dyad. The association of obesity and ADHD with sleep dysfunction, LOC-ED/BED, and anxiety is discussed. An algorithm outlining decision pathways for patients with obesity and with and without ADHD is presented. Future research exploring the complex pathophysiology of both obesity and ADHD as well as co-occurring conditions is needed to develop clinical guidelines and ultimately assist in providing the best evidence-based care.

Role of Oxidative Stress and Neuroinflammation in Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood. Although abnormalities in several brain regions and disturbances of the catecholaminergic pathway have been demonstrated, the pathophysiology of ADHD is not completely understood, but as a multifactorial disorder, has been associated with an increase in oxidative stress and neuroinflammation. This review presents an overview of factors that increase oxidative stress and neuroinflammation. The imbalance between oxidants and antioxidants and also the treatment with medications are two factors that can increase oxidative damage, whereas the comorbidity between ADHD and inflammatory disorders, altered immune response, genetic and environmental associations, and polymorphisms in inflammatory-related genes can increase neuroinflammation. Evidence of an association with these factors has become valuable for research on ADHD. Such evidence opens up new intervention routes for the use of natural products as antioxidants that could have potential as a treatment against oxidative stress and neuroinflammation in ADHD.

Effects of agmatine, glutamate, arginine, and nitric oxide on executive functions in children with attention deficit hyperactivity disorder.

In this study, we aimed to investigate the effects of agmatine, nitric oxide (NO), arginine, and glutamate, which arethe metabolites in the polyamine pathway, on the performance of executive functions (EF) in attention deficit hyperactivity disorder (ADHD). The ADHD group included 35 treatment-naive children (6-14years old)who were ewly diagnosed with ADHD. The control group consisted of 35 healthy children with the same age and sex, having no previous psychiatric disorders. In the study groups, Stroop test (ST) and trail making test (TMT) were used to monitor EF, and blood samples were collected to measure agmatine with ultra-high-performance liquid chromatography and NO, glutamate, and arginine with enzyme-linked immunosorbent assay (ELISA). The EFs were significantly impaired in the ADHD group. The agmatine and arginine levels of the ADHD group were significantly higher than their peers. The NO and glutamate levels were also higher in the ADHD group compared to the control group, but these differences did not reach statistical significance. Children with ADHD had more difficulties during EF tasks compared to healthy children. The elevated NO and glutamate levels may be related with the impairment during EF tasks. Therefore, agmatine and arginine may increase to improve EF tasks through its inhibitory effect on the synthesis of NO and glutamate. Further studies are needed about polyamine pathway molecules to shed light on the pathophysiology of ADHD.

Brain iron concentrations in the pathophysiology of children with attention deficit/hyperactivity disorder: a systematic review.

Attention deficit/hyperactivity disorder (ADHD) is a neurological disorder associated with iron dysregulation in children. Although previous focus was on examining systemic iron status, brain iron content may be a more reliable biomarker of the disorder. This systematic review examines whether children with ADHD have lower serum as well as brain iron concentrations, compared with healthy control subjects (HCS). A systematic literature search was conducted in Medline via PubMed, the Cochrane Library, Web of Science, Embase. and Ovid for papers published between 2000 and June 7, 2019. Studies were included if the mean difference of iron concentration, measured as serum iron, serum ferritin, or brain iron, between children with ADHD and HCS was an outcome measure. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Risks of bias within and between studies were assessed using the quality assessment tools of the National Institutes of Health. Of 599 records screened, 20 case-control studies met the inclusion criteria. In 10 of 18 studies in which serum ferritin concentration was assessed, and 2 of 10 studies that assessed serum iron, a significant difference between children with ADHD and HCS was observed. Results of systemic iron levels were inconsistent. In 3studies in which brain iron concentration was assessed, a statistically significant, lower thalamic iron concentration was found in children with ADHD than in HCS. The evidence, though limited, reveals that brain iron rather than systemic iron levels may be more associated with the pathophysiology of ADHD in children. Larger, longitudinal, magnetic resonance imaging studies are needed to examine any correlations of iron deficiency in specific brain regions and symptoms of ADHD.

Chiari Malformation and Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by inattention, hyperactivity, and impulsivity. Chiari malformations (CM), first described approximately a hundred years ago, refer to a spectrum of hindbrain malformations characterized by cerebellar herniation through the foramen magnum. We present the case of a 28-year-old woman with ADHD and concurrent Chiari malformation type I (CM-I) that was diagnosed by CT scan. There is growing evidence supporting the role of the cerebellum and its associated structures in the pathophysiology of ADHD. Thus, a cerebellar malformation such as CM may impact neurological circuitry in a manner favoring the development of a neuropsychiatric disorder such as ADHD. Our case highlights the need for further studies pertaining to the role of the cerebellum in the pathophysiology of ADHD and the importance of considering the presence of CM when evaluating a patient with ADHD.

Role of Neuropeptide S on Behavioural and Neurochemical Changes of an Animal Model of Attention-Deficit/Hyperactivity Disorder

Neuropeptide S (NPS) is a recently discovered peptide signalling through its receptor NPSR, which is expressed throughout the brain. Since NPSR activation increases dopaminergic transmission, we now tested if NPSR modulates behavioural and neurochemical alterations displayed by an animal model of attention-deficit/hyperactivity disorder (ADHD), Spontaneous Hypertensive Rats (SHR), compared to its control strain, Wistar Kyoto rats (WKY). NPS (0.1 and 1 nmol, intracerebroventricularly (icv)) did not modify the performance in the open field test in both strains; however, NPSR antagonism with [tBu-d-Gly5]NPS (3 nmol, icv) increased, per se, the total distance travelled by WKY. In the elevated plus-maze, NPS (1 nmol, icv) increased the percentage of entries in the open arms (%EO) only in WKY, an effect prevented by pretreatment with [tBu-d-Gly5]NPS (3 nmol, icv), which decreased per se the %EO in WKY and increased their number of entries in the closed arms. Immunoblotting of frontal cortical extracts showed no differences of NPSR density, although SHR had a lower NPS content than WKY. SHR showed higher activity of dopamine uptake than WKY, and NPS (1 nmol, icv) did not change this profile. Overall, the present work shows that the pattern of functioning of the NPS system is distinct in WKY and SHR, suggesting that this system may contribute to the pathophysiology of ADHD.

Disruption of CTNND2, encoding delta-catenin, causes a penetrant attention deficit disorder and myopia.

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with poorly understood pathophysiology and genetic mechanisms. A balanced chromosomal translocation interrupts CTNND2 in several members of a family with profound attentional deficit and myopia, and disruption of the gene was found in a separate unrelated individual with ADHD and myopia. CTNND2 encodes a brain-specific member of the adherens junction complex essential for postsynaptic and dendritic development, a site of potential pathophysiology in attentional disorders. Therefore, we propose that the severe and highly penetrant nature of the ADHD phenotype in affected individuals identifies CTNND2 as a potential gateway to ADHD pathophysiology similar to the DISC1 translocation in psychosis or AUTS2 in autism.

Caffeine Consumption plus Physical Exercise Improves Behavioral Impairments and Stimulates Neuroplasticity in Spontaneously Hypertensive Rats (SHR): an Animal Model of Attention Deficit Hyperactivity Disorder.

Attention deficit hyperactivity disorder (ADHD) is a prevalent and disabling disorder, mainly characterized by hyperactivity, inattention, and impulsivity, but also by olfactory and memory impairments that frequently persist throughout lifetime. The pathophysiology of ADHD is complex, involving several brain regions and neural pathways including alterations in adenosine neuromodulation. The administration of caffeine (a non-selective adenosine receptor antagonist) and physical exercise have been independently pointed as effective approaches for the management of ADHD symptoms. Here, we evaluated the effects of caffeine consumption (0.3mg/mL in drinking water) plus physical exercise in running wheels during 6weeks-starting during either adolescence (30days old) or adulthood (4-5months old)-on behavioral performance (including olfactory discrimination, open field, object recognition, and water maze tests) on the brain levels of monoamines (by high-performance liquid chromatography), on proteins related to synaptic plasticity and on brain-derived neurotrophic factor signaling (by Western blot analysis) in spontaneously hypertensive rats (SHRs), a validated animal model of ADHD. SHRs displayed persistent impairments of olfactory and short-term recognition memory from adolescence to adulthood, which were accompanied by lower levels of synaptosomal-associated protein 25 (SNAP-25) in the prefrontal cortex and hippocampus. The association of caffeine plus physical exercise during adolescence or adulthood restored the olfactory discrimination ability and, in an independent manner, improved short-term recognition memory of SHRs. These benefits were not associated to alterations in locomotor activity or in the hypertensive phenotype. The association of caffeine consumption plus physical exercise during adolescence increased the levels of SNAP-25, syntaxin, and serotonin in the hippocampus and prefrontal cortex, and striatal dopamine levels in SHRs. These results provide new evidence of the potential of caffeine and physical exercise, starting at adolescence or adult life, to improve behavioral impairments and stimulate neuroplasticity in ADHD.

The Relationship between Second-to-Fourth Digit Ratios, Attention-Deficit/Hyperactivity Disorder Symptoms, Aggression, and Intelligence Levels in Boys with Attention-Deficit/Hyperactivity Disorder.

ObjectiveObservations of sex differences have led some scientists to doubt whether the neuroendocrine system is involved in attentiondeficit/hyperactivity disorder (ADHD) etiology. One of the interesting study subjects in this context is prenatal steroid hormone exposure. The aim of the present study was to replicate and extend previous work by addressing two research questions: 1) Are second-to-fourth digit (2D:4D) ratios lower in ADHD than in controls? 2) Is there a correlation between 2D:4D ratios and symptoms of ADHD, aggression and intelligence scores in boys with ADHD? MethodsThe study included 100 treatment-naive male children diagnosed with ADHD and 55 healthy male children. We measured the ratios of 2D:4D and administered a Wechsler Intelligence Scale for Children-Revised to assess IQ scores, as well as behavioral rating scales, in children with ADHD and comparison individuals. ResultsWe observed lower 2D:4D ratios in the right hand in ADHD in comparison to the control group. The left-hand ratios of 2D:4D, however, did not differ between ADHD and control groups. There were negative correlations between the left-hand 2D:4D ratios and the hyperactivity scores. However, no significant correlation was detected between right-hand 2D:4D ratios and the psychological questionnaire scores. ConclusionThese results provide further evidence that fetal androgen exposure may contribute to the pathophysiology of ADHD, at least in boys.

Attention-Deficit/Hyperactivity Disorder Patients May Have Undiagnosed Narcolepsy.

BackgroundAttention-deficit/hyperactivity disorder (ADHD) patients have many comorbidities. Narcoleptic patients have a big prevalence of ADHD (15%-30%). Both groups suffer from similar symptoms and benefit from the same class of medications. As such, narcolepsy could be masked in ADHD patients. Low serum ferritin has been found both in ADHD patients as well as in patients with narcolepsy.Materials & methodsWe enrolled 26 participants (14 ADHD patients and 12 controls). They answered several questionnaires, and blood samples were obtained from 20 participants. We had clear exclusion criteria.ResultsUsing the Ullanlinna Narcolepsy Scale (UNS), we identified three possible narcolepsy patients within the ADHD group and no suspects in the control group. There was a statistically significant negative correlation between serum iron levels and ADHD symptom severity. No correlation was found measuring serum ferritin levels.ConclusionsNarcolepsy may be more common within ADHD patients than in the general population. Some of these patients could benefit from a change in medication. Low serum iron and ferritin levels could be relevant in ADHD pathophysiology. This requires further exploratory research.

Transcranial Direct Current Stimulation in ADHD: A Systematic Review of Efficacy, Safety, and Protocol-induced Electrical Field Modeling Results.

Transcranial direct current stimulation (tDCS) is a promising method for altering cortical excitability with clinical implications. It has been increasingly used in neurodevelopmental disorders, especially attention-deficit hyperactivity disorder (ADHD), but its efficacy (based on effect size calculations), safety, and stimulation parameters have not been systematically examined. In this systematic review, we aimed to (1) explore the effectiveness of tDCS on the clinical symptoms and neuropsychological deficits of ADHD patients, (2) evaluate the safety of tDCS application, especially in children with ADHD, (3) model the electrical field intensity in the target regions based on the commonly-applied and effective versus less-effective protocols, and (4) discuss and propose advanced tDCS parameters. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach, a literature search identified 14 empirical experiments investigating tDCS effects in ADHD. Partial improving effects of tDCS on cognitive deficits (response inhibition, working memory, attention, and cognitive flexibility) or clinical symptoms (e.g., impulsivity and inattention) are reported in 10 studies. No serious adverse effects are reported in 747 sessions of tDCS. The left and right dorsolateral prefrontal cortex are the regions most often targeted, and anodal tDCS the protocol most often applied. An intensity of 2mA induced stronger electrical fields than 1mA in adults with ADHD and was associated with significant behavioral changes. In ADHD children, however, the electrical field induced by 1mA, which is likely larger than the electrical field induced by 1mA in adults due to the smaller head size of children, was sufficient to result in significant behavioral change. Overall, tDCS seems to be a promising method for improving ADHD deficits. However, the clinical utility of tDCS in ADHD cannot yet be concluded and requires further systematic investigation in larger sample sizes. Cortical regions involved in ADHD pathophysiology, stimulation parameters (e.g. intensity, duration, polarity, and electrode size), and types of symptom/deficit are potential determinants of tDCS efficacy in ADHD. Developmental aspects of tDCS in childhood ADHD should be considered as well.

Protective Potential of Ginkgo biloba Against an ADHD-like Condition.

Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder commonly found in children, which is recognized by hyperactivity and aggressive behavior. It is known that the pathophysiology of ADHD is associated with neurobiological dysfunction. Although psychostimulants are recognized as the therapeutic drugs of choice for ADHD patients, the side effects might be of great concern. Ginkgo biloba is a promising herbal, complementary supplement that may modulate the neuronal system in an ADHD-like condition. The beneficial effect of Ginkgo biloba on ADHD-like symptoms may be related to the modulation of the system by novel molecular mechanisms. Ginkgo biloba is known to modulate dopamine, serotonin, and norepinephrine signaling. Flavonoid glycosides and terpene trilactones are the two major phytochemical components present in the Ginkgo biloba preparations, which can exhibit antioxidant and neuroprotective activities. The pharmacological mechanisms of the phytochemical components may also contribute to the neuroprotective activity of Ginkgo biloba. In this review, we have summarized recent findings on the potential of various Ginkgo biloba preparations to treat ADHD-like symptoms. In addition, we have discussed the pharmacological mechanisms mediated by Ginkgo biloba against an ADHD-like condition.

Investigating the Gut Microbiota Composition of Individuals with Attention-Deficit/Hyperactivity Disorder and Association with Symptoms.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Given the growing evidence of gut microbiota being involved in psychiatric (including neurodevelopmental) disorders, we aimed to identify differences in gut microbiota composition between participants with ADHD and controls and to investigate the role of the microbiota in inattention and hyperactivity/impulsivity. Fecal samples were collected from 107 participants (NADHD = 42; Ncontrols = 50; NsubthreholdADHD = 15; range age: 13–29 years). The relative quantification of bacterial taxa was done using 16S ribosomal RNA gene amplicon sequencing. Beta-diversity revealed significant differences in bacterial composition between participants with ADHD and healthy controls, which was also significant for inattention, but showing a trend in case of hyperactivity/impulsivity only. Ten genera showed nominal differences (p < 0.05) between both groups, of which seven genera were tested for their association with ADHD symptom scores (adjusting for age, sex, body mass index, time delay between feces collection and symptoms assessment, medication use, and family relatedness). Our results show that variation of a genus from the Ruminococcaceae family (Ruminococcaceae_UCG_004) is associated (after multiple testing correction) with inattention symptoms and support the potential role of gut microbiota in ADHD pathophysiology.

Tactile Discrimination, Praxis and Cognitive Impulsivity in ADHD Children: A Cross-Sectional Study.

Background: The study of attention deficit hyperactivity disorder (ADHD) has traditionally focused on deficit of inhibitory control and cognitive impulsivity. However, the pathophysiology of ADHD has also been associated with the somatosensory cortex. The aim of this study was to explore if there were differences in tactile discrimination and praxis between neurotypical and ADHD children and whether these differences could be explained by cognitive impulsivity. Methods: A cross-sectional study was conducted. The sample comprised 74 children aged 7 to 11 years divided in two groups: 43 with neurotypical development, 31 with ADHD. To assess tactile discrimination, the finger localization and the graphestesia tests were used. Praxis was assessed with the Kaufman Assesment Battery for Children (K-ABC) hand movement subtest, the action program and the Zoo Map subtests of the Behavioral Assessment of Dysexecutive Syndrome, and the complex figure of Rey–Osterrieth test (ROCF). Cognitive impulsivity was assessed using the Magallanes Computerized Impulsivity Scale test (EMIC). Results: Children with ADHD showed greater cognitive impulsivity (p = 0.038) and scored lower in Zoo Map (p = 0.023) and hand-movement subtests (p = 0.002), and in ROCF test (p = 0.004). Differences in praxis skills still remained after controlling by gender and cognitive impulsivity. Conclusion: Praxis deficit might have repercussions not only on the characterization of ADHD but also on its treatment.

Mind-wandering and sleepiness in adults with attention-deficit/hyperactivity disorder

Sleepiness and mind-wandering are frequently experienced by patients with attention-deficit/hyperactivity disorder (ADHD), without ever having been jointly explored. We aimed to investigate the co-occurrence of these two phenomena in ADHD adults.Drug-free ADHD adults (n = 25) and healthy controls (n = 28) underwent an online experience sampling of mind-wandering episodes and subjective sleepiness. Participants completed self-reported measures of mind-wandering and sleepiness in daily life.Higher trait of mind-wandering was observed in ADHD patients compared to controls. On the whole sample, self-reported mind-wandering propensity was strongly associated with the severity of inattentive, impulsive and hyperactive symptoms. During the probes, patients reported more frequent episodes of mind-wandering and mind-blanking, and higher sleepiness. Their mind-wandering episodes were less intentional and belonged less frequently to a structured succession of thoughts. In both groups, mind-wandering and mind-blanking were associated with higher sleepiness. On the SART, patients were less accurate than controls.We provide first initial evidence for higher propensity of mind-wandering and mind-blanking using experience sampling in patients with formal ADHD diagnosis. This propensity was associated with sleepiness without negatively impacting attention performances. Mind-wandering and sleepiness have common determinants potentially involved in ADHD pathophysiology. Correlates of mind-blanking in ADHD adults remain to be characterized.

Antioxidants as a Potential Target against Inflammation and Oxidative Stress in Attention-Deficit/Hyperactivity Disorder.

Psychostimulants and non-psychostimulants are the medications prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). However, several adverse results have been linked with an increased risk of substance use and side effects. The pathophysiology of ADHD is not completely known, although it has been associated with an increase in inflammation and oxidative stress. This review presents an overview of findings following antioxidant treatment for ADHD and describes the potential amelioration of inflammation and oxidative stress using antioxidants that might have a future as multi-target adjuvant therapy in ADHD. The use of antioxidants against inflammation and oxidative conditions is an emerging field in the management of several neurodegenerative and neuropsychiatric disorders. Thus, antioxidants could be promising as an adjuvant ADHD therapy.

Putative shared mechanisms in autism spectrum disorders and attention deficit hyperactivity disorder, a systematic review of the role of oxidative stress

Oxidative stress is now believed to play a crucial role for neurodevelopment disorders such as autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). To review the most recent literature regarding the role of oxidative stress for the pathophysiology of ASD and ADHD, we conducted a systematic search of the relevant literature and further discuss the clinical and research implications of this knowledge. A systematic search in PubMed database retrieved 132 articles, of which 33 were included in the review. This review found relevant evidence concerning the role of oxidative status in ASD and ADHD, albeit with some contradictory findings. In order to overcome the incongruities found, more studies are needed in the study of neurodevelopmental disorders, with more thorough study designs and particular attention to the accuracy of the diagnostic tools used for the cases included.