The aperiodic exponent of the electroencephalogram (EEG) power spectrum has received growing attention as a physiological marker of neurodevelopmental psychopathology, including ...attention‐deficit/hyperactivity disorder (ADHD). However, its use as a marker of ADHD risk across development, and particularly in very young children, is limited by unknown reliability, difficulty in aligning canonical band‐based measures across development periods, and unclear effects of treatment in later development. Here, we investigate the internal consistency of the aperiodic EEG power spectrum slope and its association with ADHD risk in both infants (n = 69, 1‐month‐old) and adolescents (n = 262, ages 11–17 years). Results confirm good to excellent internal consistency in infancy and adolescence. In infancy, a larger aperiodic exponent was associated with greater family history of ADHD. In contrast, in adolescence, ADHD diagnosis was associated with a smaller aperiodic exponent, but only in children with ADHD who had not received stimulant medication treatment. Results suggest that disruptions in cortical development associated with ADHD risk may be detectable shortly after birth via this approach. Together, findings imply a dynamic developmental shift in which the developmentally normative flattening of the EEG power spectrum is exaggerated in ADHD, potentially reflecting imbalances in cortical excitation and inhibition that could contribute to long‐lasting differences in brain connectivity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Background
Asthma and attention‐deficit/hyperactivity disorder (ADHD) are prevalent in childhood and may cause functional impairment and stress in families. Previous research supports an ...association between asthma and ADHD in children, but several aspects of this relationship are unclear.
Objective
Our aim was to study whether the association between asthma and ADHD is restricted to either the inattentive or the hyperactive/impulsive symptoms of ADHD, to explore the impact of asthma severity and asthma medication and the contribution of shared genetic and environmental risk factors on the asthma–ADHD relationship.
Methods
Data on asthma, ADHD, zygosity and possible confounders were collected from parental questionnaires at 9 or 12 years on 20 072 twins through the Swedish Twin Register, linked to the Swedish Medical Birth Register, the National Patient Register and the Prescribed Drug Register. The association between asthma and ADHD, the impact of asthma severity and medication, was assessed by generalized estimating equations. Cross‐twin–cross‐trait correlations (CTCT) were estimated to explore the relative importance of genes and environment for the association.
Results
Asthmatic children had a higher risk of also having ADHD odds ratio (OR) 1.53, 95% confidence interval (CI): 1.16–2.02. The association was not restricted to either of the two dimensions of ADHD. The magnitude of the association increased with asthma severity (OR 2.84, 95% CI: 1.86–4.35) for ≥ 4 asthma attacks in the last 12 months and was not affected by asthma treatment. The CTCTs possibly indicate that the genetic component in overlap of the disorders is weak.
Conclusions and Clinical Relevance
Childhood asthma, especially severe asthma, is associated with ADHD. Asthma medication seems not to increase the risk of ADHD. Clinicians should be aware of the potential of ADHD in asthma. Optimal asthma care needs to be integrated with effective evaluation and treatment of ADHD in children with co‐existing disorders.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
•Maternal psychological distress, life event stress, and objective exposure affect offspring outcome.•Functional and structural brain changes underlie the problems observed in the ...offspring.•Alterations in stress system, immune system, and gut microbiome play a significant role.•Epigenetic and telomere biology mechanisms are beginning to be explored.•Interventions focused on offspring also need to be guided by knowledge of changes in biological systems.
Accumulating research shows that prenatal exposure to maternal stress increases the risk for behavioral and mental health problems later in life. This review systematically analyzes the available human studies to identify harmful stressors, vulnerable periods during pregnancy, specificities in the outcome and biological correlates of the relation between maternal stress and offspring outcome. Effects of maternal stress on offspring neurodevelopment, cognitive development, negative affectivity, difficult temperament and psychiatric disorders are shown in numerous epidemiological and case-control studies. Offspring of both sexes are susceptible to prenatal stress but effects differ. There is not any specific vulnerable period of gestation; prenatal stress effects vary for different gestational ages possibly depending on the developmental stage of specific brain areas and circuits, stress system and immune system. Biological correlates in the prenatally stressed offspring are: aberrations in neurodevelopment, neurocognitive function, cerebral processing, functional and structural brain connectivity involving amygdalae and (pre)frontal cortex, changes in hypothalamo-pituitary-adrenal (HPA)-axis and autonomous nervous system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Numerous ubiquitous environmental chemicals are established or suspected neurotoxicants, and infants are exposed to a mixture of these during the critical period of brain maturation. However, ...evidence for associations with the risk of attention-deficit/hyperactivity disorder (ADHD) is sparse. We investigated early-life chemical exposures in relation to ADHD.
We used a birth cohort of 2606 Norwegian mother–child pairs enrolled 2002–2009 (HUMIS), and studied a subset of 1199 pairs oversampled for child neurodevelopmental outcomes. Concentrations of 27 persistent organic pollutants (14 polychlorinated biphenyls, 5 organochlorine pesticides, 6 brominated flame retardants, and 2 perfluoroalkyl substances) were measured in breast milk, reflecting the child's early-life exposures. We estimated postnatal exposures in the first 2 years of life using a pharmacokinetic model. Fifty-five children had a clinical diagnosis of ADHD (hyperkinetic disorder) by 2016, at a median age of 13 years. We used elastic net penalized logistic regression models to identify associations while adjusting for co-exposure confounding, and subsequently used multivariable logistic regression models to obtain effect estimates for the selected exposures.
Breast milk concentrations of perfluorooctane sulfonate (PFOS) and β‑hexachlorocyclohexane (β-HCH) were associated with increased odds of ADHD: odds ratio (OR) = 1.77, 95% confidence interval (CI): 1.16, 2.72 and OR = 1.75, 95% CI: 1.22, 2.53, per interquartile range increase in ln-transformed concentrations, respectively. Stronger associations were observed among girls than boys for PFOS (pinteraction = 0.025). p,p′‑Dichlorodiphenyltrichloroethane (p,p′-DDT) levels were associated with lower odds of ADHD (OR = 0.64, 95% CI: 0.42, 0.97). Hexachlorobenzene (HCB) had a non-linear association with ADHD, with increasing risk in the low-level exposure range that switched to a decreasing risk at concentrations above 8 ng/g lipid. Postnatal exposures showed similar results, whereas effect estimates for other chemicals were weaker and imprecise.
In a multi-pollutant analysis of four classes of chemicals, early-life exposure to β-HCH and PFOS was associated with increased risk of ADHD, with suggestion of sex-specific effects for PFOS. The unexpected inverse associations between p,p′-DDT and higher HCB levels and ADHD could be due to live birth bias; alternatively, results may be due to chance findings.
•We assessed associations between early-life exposure to 27 contaminants and doctor-diagnosed ADHD in school-age children•Odds of ADHD increased 75% per interquartile range increase in β-HCH levels•Odds of ADHD increased 77% per interquartile range increase in PFOS levels, with higher odds in girls than boys•p,p′-DDT was associated with lower odds of ADHD while HCB had a non-linear exposure–response
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Attention and executive function (EF) dysregulation are common in a number of disorders including autism and attention-deficit/hyperactivity disorder (ADHD). Better understanding of the relationship ...between indirect and direct measures of attention and EF and common neurodevelopmental diagnoses may contribute to more efficient and effective diagnostic assessment in childhood. We obtained cognitive (NIH Toolbox, Little Man Task, Matrix Reasoning Task, and Rey Delayed Recall) and symptom (CBCL, and BPMT) assessment data from the Adolescent Brain and Cognitive Development (ABCD) database for three groups, autistic (N = 110), ADHD (N = 878), and control without autism or ADHD diagnoses (N = 9130) and used ridge regression to determine which attention and EF assessments were most strongly associated with autism or ADHD. More variance was accounted for in the model for the ADHD group (31%) compared to the autism group (2.7%). Finally, we ran odds ratios (using clinical cutoffs where available and 2 standard deviations below the mean when not) for each assessment measure, which generally demonstrated a greater significance within the indirect measures when compared to the direct measures. These results add to the growing literature of symptom variably across diagnostic groups allowing for better understanding of presentations in autism and ADHD and how best to assess diagnosis. It also highlights the increased difficulty in differentiating autism and controls when compared to ADHD and controls and the importance of indirect measures of attention and EF in this differentiation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•MPH is a very effective treatment for ADHD but there are concerns about potential adverse effects of extended treatment on several systems, including growth.•Long term MPH appears to be associated ...with a statistically significant impact on height and weight in ADHD children and adolescents, but effect sizes are small, with possible minimal clinical effect.•Sensitivity analysis did not reveal a significant effect of dose, age and drug naïvity condition as possible clinical moderators.•Data on effect on pubertal maturation, although limited, seem to favour the exclusion of a possible drug effect on sexual maturation in ADHD subjects.•Current clinical practice guidelines indicate the need of a careful assessment of growth parameters before starting stimulant treatment and the periodic monitoring using standardised growth charts. Particular caution should be taken in pre-school children.
Methylphenidate (MPH) is an efficacious treatment for ADHD but concerns have been raised about potential adverse effects of extended treatment on growth.
To systematically review the literature, up to December 2018, conducting a meta-analysis of association of long-term (> six months) MPH exposure with height, weight and timing of puberty.
Eighteen studies (ADHD n = 4868) were included in the meta-analysis. MPH was associated with consistent statistically significant pre-post difference for both height (SMD = 0.27, 95% CI 0.16-0.38, p < 0.0001) and weight (SMD = 0.33, 95% CI 0.22-0.44, p < 0.0001) Z scores, with prominent impact on weight during the first 12 months and on height within the first 24-30 months. No significant effects of dose, formulation, age and drug-naïve condition as clinical moderators were found. Data on timing of puberty are currently limited.
Long-term treatment with MPH can result in reduction in height and weight. However, effect sizes are small with possible minimal clinical impact. Long-term prospective studies may help to clarify the underlying biological drivers and specific mediators and moderators.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To provide evidence- or consensus-based recommendations concerning the assessment and management of sleep problems in youths with attention-deficit/hyperactivity disorder (ADHD).
PubMed, Ovid, ...EMBASE, and Web of Knowledge were searched through October 31, 2012. When no evidence was available, consensus of the authors was achieved. The evidence-level of the recommendations on the management of sleep disturbances was based on the Scottish Intercollegiate Guidelines Network (SIGN) system.
A total of 139 original articles on sleep and childhood ADHD were retrieved, including 22 on treatment of sleep disturbances. This review focuses on behaviorally based insomnia, circadian rhythm disorder, sleep-disordered breathing, restless legs syndrome/periodic limb movement disorder, and sleep disturbances due to comorbid psychiatric disorders or ADHD medications. Healthy sleep practices are recommended as the foundation of management strategies. Behavioral interventions should be considered as first-line treatment of insomnia, although further evidence from randomized controlled trials (RCTs) is needed to prove their efficacy in ADHD. Among pharmacological treatments, RCTs support the use of melatonin to reduce sleep-onset delay, whereas there is more limited evidence for other medications.
Growing empirical evidence is informing assessment/management strategies of sleep problems in youths with ADHD. However, further RCTs are warranted to support current recommendations.
Background
Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it ...difficult to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015.
Objectives
To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD.
Search methods
We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate.
Selection criteria
We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non‐serious, general behaviour, and quality of life.
Data collection and analysis
Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel‐group trials and first‐period data from cross‐over trials formed the basis of our primary analyses. We undertook separate analyses using end‐of‐last period data from cross‐over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach.
Main results
We included 212 trials (16,302 participants randomised); 55 parallel‐group trials (8104 participants randomised), and 156 cross‐over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross‐over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male‐female ratio was 3:1. Most trials were carried out in high‐income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants.
Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias.
Primary outcomes: methylphenidate versus placebo or no intervention may improve teacher‐rated ADHD symptoms (standardised mean difference (SMD) −0.74, 95% confidence interval (CI) −0.88 to −0.61; I² = 38%; 21 trials; 1728 participants; very low‐certainty evidence). This corresponds to a mean difference (MD) of −10.58 (95% CI −12.58 to −8.72) on the ADHD Rating Scale (ADHD‐RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD‐RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low‐certainty evidence). The TSA‐adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68).
Secondary outcomes: methylphenidate may cause more adverse events considered non‐serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low‐certainty evidence). The TSA‐adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher‐rated general behaviour versus placebo (SMD −0.62, 95% CI −0.91 to −0.33; I² = 68%; 7 trials 792 participants; very low‐certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI −0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low‐certainty evidence).
Authors' conclusions
The majority of our conclusions from the 2015 version of this review still apply. Our updated meta‐analyses suggest that methylphenidate versus placebo or no‐intervention may improve teacher‐rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non‐serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear.
Due to the frequency of non‐serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials.
Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.
Background
Heavy prenatal alcohol exposure (AE) results in a broad array of neurobehavioral deficits. Recent research has focused on identification of a neurobehavioral profile or profiles that will ...improve the identification of children affected by AE. This study aimed to build on our preliminary neurobehavioral profile to improve classification accuracy and test the specificity of the resulting profile in an alternate clinical group.
Methods
A standardized neuropsychological test battery was administered to 3 groups of children: subjects with AE (n = 209), typically developing controls (CON, n = 185), and subjects with attention‐deficit/hyperactivity disorder (ADHD, n = 74). We assessed a large sample from 6 sites in the United States and South Africa, using standardized methodology. Data were analyzed using 3 latent profile analyses including (i) subjects with fetal alcohol syndrome (FAS) and controls, (ii) subjects with AE without FAS and controls, and (iii) subjects with AE (with or without FAS) and subjects with ADHD.
Results
Classification accuracy was moderate but significant across the 3 analyses. In analysis 1, overall classification accuracy was 76.1% (77.2% FAS, 75.7% CON). In the second analysis, overall classification accuracy was 71.5% (70.1% AE/non‐FAS, 72.4% CON). In the third analysis, overall classification accuracy was 73.9% (59.8% AE, 75.7% ADHD). Subjects that were misclassified were examined for systematic differences from those that were correctly classified.
Conclusions
The results of this study indicate that the neuropsychological effects of AE are clinically meaningful and can be used to accurately distinguish alcohol‐affected children from both typically developing children and children with ADHD. Further, in combination with other recent studies, these data suggest that approximately 70% of children with heavy prenatal alcohol exposure are neurobehaviorally affected, while the remaining 30% are spared these often‐devastating consequences, at least those in the domains under study. Refining the neurobehavioral profile will allow improved identification and treatment development for children affected by prenatal alcohol exposure.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Adolescents with attention‐deficit/hyperactivity disorder (ADHD) often experience greater sleep difficulties compared to those without. However, findings are mixed, and other mental health ...conditions are often overlooked. This study aimed to examine the relationship between sleep problems, ADHD, and other mental health conditions in a sample of adolescents. Data from 373 adolescents aged 10–19 years was used as part of the wider ‘Healthy Brain Network’ study, which targets children and adolescents experiencing mental health and neurodevelopmental difficulties. Mental health conditions were assessed via a comprehensive assessment. Sleep was measured by self‐ and parent‐report, as well as via up to a month of actigraphy data. Actigraphy data were analysed using mixed‐methods modelling, while subjective sleep data were analysed using multiple regression. Subjectively‐reported sleep was generally worse in adolescents who had ADHD and other mental health conditions compared to those with ADHD but no other conditions. There were no associations between ADHD status and objective sleep measures or self‐reported measures, but a significant association was found between ADHD status and parent‐reported sleep difficulties, even when accounting for other conditions. Parent‐reported sleep problems were associated not only with ADHD, but also with anxiety, depression, and externalising disorders. The strength of association between ADHD and sleep problems is potentially not as strong as previously thought when considering the role of other mental health conditions. Clinicians should consider the role of other mental health conditions when sleep problems are present, and vice versa. The study also highlights the importance of comprehensive, multi‐informant assessment of mental health conditions, including sleep.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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