Outcome measures in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children's functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. AIM: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. METHODS: The study sample consisted of 28 children with AS aged 2-18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. RESULTS: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). CONCLUSIONS: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. TRIAL REGISTRATION: Registered d.d. 23-04-2020 under number 'NL8550' in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075.

Bone health in children with Angelman syndrome at the ENCORE Expertise Center.

Angelman syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD), or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are observed frequently in our clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. In this prospective cohort study, we describe bone health in 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the bone health index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication use, mobility, body mass index (BMI), and onset of puberty. Children with AS had a mean BHI of -1.77 SDS (SD 1.4). A significantly lower BHI was found in children with a deletion (-2.24 SDS) versus non-deletion (-1.02 SDS). Other factors associated with reduced BHI-SDS were inability to walk and late onset of puberty. Children with a history of one or more fractures (22%) had a significantly lower BHI than children without fractures (-2.60 vs -1.56 SDS). Longitudinal analysis showed a significant decrease in BHI-SDS with age in all genetic subtypes.  Conclusions: Children with AS have a reduced bone health. Risk factors are deletion genotype, no independent walking, and late onset of puberty. Bone health decreased significantly with age. What is Known: • Children with neurological disorders often have a low bone health and higher risk of fractures. • Little is known about bone health in children with Angelman syndrome (AS). What is New: • Children with AS showed a reduced bone health and this was significantly associated with having a deletion, not being able to walk independently, and late onset of puberty. • Longitudinal analysis showed a significant decrease in bone health as children got older.

Hyperphagia, Growth, and Puberty in Children with Angelman Syndrome.

Angelman Syndrome (AS) is a rare genetic disorder caused by lack of maternal UBE3A protein due to a deletion of the chromosome 15q11.2-q13 region, uniparental paternal disomy, imprinting center defect, or pathogenic variant in the UBE3A gene. Characteristics are developmental delay, epilepsy, behavioral, and sleep problems. There is some evidence for hyperphagia, shorter stature, and higher BMI compared to neurotypical children, but longitudinal studies on growth are lacking. In this study, we analyzed prospectively collected data of 145 children with AS, who visited the ENCORE Expertise Center between 2010 and 2021, with a total of 853 visits. Children showed an elevated mean score of 25 on the Dykens Hyperphagia questionnaire (range 11-55) without genotype association. Higher scores were significantly associated with higher body mass index (BMI) standard deviation scores (SDS) (p = 0.004). Mean height was -1.2 SDS (SD 1.3), mean BMI-SDS was 0.6 (SD 1.7); 43% had a BMI-SDS > 1 and 20% had a BMI-SDS > 2. Higher BMI-SDS was significantly associated with non-deletion genotype (p = 0.037) and walking independently (p = 0.023). Height SDS decreased significantly with age (p < 0.001) and BMI-SDS increased significantly with age (p < 0.001. Onset of puberty was normal. In conclusion, children with AS showed moderate hyperphagia, lower height SDS, and higher BMI-SDS compared to norm data, with increasing deviation from the norm with age. It is uncertain how loss of maternal UBE3A function may influence growth. Attention to diet, exercise, and hyperphagia from an early age is recommended to prevent obesity and associated health problems.

Sleep problems in children with Angelman Syndrome: The effect of a behavioral intervention program.

BACKGROUND & AIMS: The aim of this study was to investigate the effect of a behavioral intervention on sleep problems, which are significant and an unmet clinical need in children with Angelman Syndrome (AS). METHODS & PROCEDURES: Children (2-18 years) with AS and sleep problems were randomized to a behavioral intervention program or a control group. Intervention consisted of a standardized program including home visits, psycho-education, feedback based on direct observation of bedtime routine and video footage of the night and behavioral treatment techniques by a behavioral therapist. Change in sleep duration (primary) and parental sleep, nighttime visits, sleep hygiene, daytime behavior, parental stress and quality of life (secondary) were assessed post-intervention and at follow-up using questionnaires, diary, actigraphy and videosomnography. OUTCOMES & RESULTS: The groups, 9 children in each, did not differ at baseline. We found a significant effect of intervention on wake after sleep onset with classical statistical analysis (videosomnography). With single case analysis we found a positive effect on total sleep time (diary and actigraphy) and wake after sleep onset (diary) with a persistent effect on total sleep time (actigraphy) and wake after sleep onset (diary). On secondary outcome there was a significant and persistent effect on sleep hygiene and several quality of life domains. CONCLUSIONS & IMPLICATIONS: Behavioral intervention has a positive and persistent effect on sleep problems in children with AS. We advise psycho-education for all parents and use of videosomnography for both evaluation of and feedback on sleep behavior patterns, individual behavioral advice and specific behavioral techniques for children with sleep problems.

Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1: A Cross-Syndrome Comparison.

Objective: The etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation. Methods: We assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non-syndromic ASD group (nsASD, n = 335), on both ASD severity scores and ASD symptom profiles. Severity scores were compared using MANCOVAs with IQ and gender as covariates. Results: Overall, ASD severity scores were highest for the FXS group and lowest for the NF1 group. Compared to nsASD, individuals with an ASD classification in our syndrome groups showed less problems on the instruments' social domains. We found a relative strength in the AS group on the social cognition, communication and motivation domains and a relative challenge in creativity; a relative strength of the NF1 group on the restricted interests and repetitive behavior scale; and a relative challenge in the FXS and TSC groups on the restricted interests and repetitive behavior domain. Conclusion: The syndrome-specific strengths and challenges we found provide a frame of reference to evaluate an individual's symptoms relative to the larger syndromic population and to guide treatment decisions. Our findings support the need for personalized care and a dimensional, symptom-based diagnostic approach, in contrast to a dichotomous ASD diagnosis used as a prerequisite for access to healthcare services. Similarities in ASD symptom profiles between AS and FXS, and between NF1 and TSC may reflect similarities in their neurobiology. Deep phenotyping studies are required to link neurobiological markers to ASD symptomatology.

Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1.

PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance. METHODS: We investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets. RESULTS: Individuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population. CONCLUSIONS: The variance and heritability of IQ in individuals with NF1 are similar to that of the general population, and hence mostly driven by genetic background differences. The only factor that significantly attenuates IQ in NF1 individuals is the NF1 chromosomal microdeletion genotype. Implications for clinical management are that individuals with intragenic NF1 variants that score <1.5-2 SD below the mean of the NF1 population should be screened for additional causes of cognitive disability.

An overview of health issues and development in a large clinical cohort of children with Angelman syndrome.

This study presents a broad overview of health issues and psychomotor development of 100 children with Angelman syndrome (AS), seen at the ENCORE Expertise Center for AS in Rotterdam, the Netherlands. We aimed to further delineate the phenotype of AS, to evaluate the association of the phenotype with genotype and other determinants such as epilepsy and to get insight in possible targets for intervention. We confirmed the presence of a more severe phenotype in the 15q11.2-q13 deletion subtype. Novel findings were an association of (early onset of) epilepsy with a negative effect on development, a high occurrence of nonconvulsive status epilepticus, a high rate of crouch gait in the older children with risk of deterioration of mobility, a relatively low occurrence of microcephaly, a higher mean weight for height in all genetic subtypes with a significant higher mean in the nondeletion children, and a high occurrence of hyperphagia across all genetic subtypes. Natural history data are needed to design future trials. With this large clinical cohort with structured prospective and multidisciplinary follow-up, we provide unbiased data on AS to support further intervention studies to optimize outcome and quality of life of children with AS and their family.

A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex.

OBJECTIVE: To investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC). METHODS: In this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4-17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5-10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems. RESULTS: Thirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect -5.6 IQ points, 95% confidence interval -12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events. CONCLUSIONS: Everolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group. CLINICALTRIALSGOV IDENTIFIER: NCT01730209. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits.

Paediatric population neuroimaging and the Generation R Study: the second wave.

Paediatric population neuroimaging is an emerging field that falls at the intersection between developmental neuroscience and epidemiology. A key feature of population neuroimaging studies involves large-scale recruitment that is representative of the general population. One successful approach for population neuroimaging is to embed neuroimaging studies within large epidemiological cohorts. The Generation R Study is a large, prospective population-based birth-cohort in which nearly 10,000 pregnant mothers were recruited between 2002 and 2006 with repeated measurements in the children and their parents over time. Magnetic resonance imaging was included in 2009 with the scanning of 1070 6-to-9-year-old children. The second neuroimaging wave was initiated in April 2013 with a total of 4245 visiting the MRI suite and 4087 9-to-11-year-old children being scanned. The sequences included high-resolution structural MRI, 35-direction diffusion weighted imaging, and a 6 min and 2 s resting-state functional MRI scan. The goal of this paper is to provide an overview of the imaging protocol and the overlap between the neuroimaging data and metadata. We conclude by providing a brief overview of results from our first wave of neuroimaging, which highlights a diverse array of questions that can be addressed by merging the fields of developmental neuroscience and epidemiology.

Cortical dysplasia and autistic trait severity in children with Tuberous Sclerosis Complex: a clinical epidemiological study.

Tuberous Sclerosis Complex (TSC) is characterized by a high prevalence of autism spectrum disorders (ASD). Little is known about the relation between cortical dysplasia and ASD severity in TSC. We assessed ASD severity (using the Autism Diagnostic Observation Scale), tuber and radial migration line (RML) count and location, and cognitive functioning in 52 children with TSC and performed regression and mediation analyses. Tuber and RML count were strongly positively related to ASD severity. However, when correcting for cognitive functioning, the majority of associations became insignificant and only total tuber count remained associated to the severity of restricted/repetitive behaviors. Occipital RML count remained associated with overall ASD severity, and social communication/interaction deficit severity specifically. This study shows the important explanatory role of cognitive functioning in the association between cortical dysplasia and ASD severity, and the relevance of separately studying the two ASD subdomains.

Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior.

Importance: Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. Objectives: To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Design, Setting, and Participants: Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). Main Outcome and Measures: This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. Results: The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P = .005) was detected. Conclusions and Relevance: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.

Attention and motor deficits index non-specific background liabilities that predict autism recurrence in siblings.

BACKGROUND: Recent research has demonstrated that subclinical autistic traits of parents amplify the effects of deleterious mutations in the causation of autism spectrum disorder (ASD) in their offspring. Here, we examined the extent to which two neurodevelopmental traits that are non-specific to ASD-inattention/hyperactivity and motor coordination-might contribute to ASD recurrence in siblings of ASD probands. METHODS: Data from a quantitative trait study of 114 ASD probands and their brothers, 26% of whom also had ASD, were analyzed. Autistic trait severity was ascertained using the Social Responsiveness Scale-2, attention/hyperactivity problems using the Achenbach System of Empirically Based Assessment, and motor coordination (in a subset of participants) using the Developmental Coordination Disorder Questionnaire. RESULTS: Among siblings (affected and unaffected), both categorical recurrence of ASD (Nagelkerke R 2 = 0.53) and quantitative ASD trait burden (R 2 = 0.55) were predicted by sibling ADHD and motor coordination impairment scores, even though these traits, on average, were not elevated among the unaffected siblings. CONCLUSIONS: These findings in a clinical family cohort confirm observations from general population studies that inattention/hyperactivity and motor impairment-axes of behavioral development that are non-specific to ASD, and often appreciable before ASD is typically diagnosed-jointly account for over 50% of the variation in autistic impairment of siblings, whether ascertained quantitatively or categorically. This finding within a sibling design suggests that background ASD susceptibilities that are inherited but non-specific ("BASINS") may contribute to additive genetic liability in the same manner that ASD-specific susceptibilities (such as parental subclinical ASD traits and deleterious mutations) engender ASD risk.

The association of gender, age, and intelligence with neuropsychological functioning in young typically developing children: The Generation R study.

Although early childhood is a period of rapid neurocognitive development, few studies have assessed neuropsychological functioning in various cognitive domains in young typically developing children. Also, results regarding its association with gender and intelligence are mixed. In 853 typically developing children aged 6 to 10 years old, the association of gender, age, and intelligence with neuropsychological functioning in the domains of attention, executive functioning, language, memory, sensorimotor functioning, and visuospatial processing was explored. Clear positive associations with age were observed. In addition, gender differences were found and showed that girls generally outperformed boys, with the exception of visuospatial tasks. Furthermore, IQ was positively associated with neuropsychological functioning, which was strongest in visuospatial tasks. Performance in different neuropsychological domains was associated with age, gender, and intelligence in young typically developing children, and these factors should be taken into account when assessing neuropsychological functioning in clinical or research settings.

Cortical morphology as a shared neurobiological substrate of attention-deficit/hyperactivity symptoms and executive functioning: a population-based pediatric neuroimaging study.

BACKGROUND: Attention-deficit/hyperactivity symptoms have repeatedly been associated with poor cognitive functioning. Genetic studies have demonstrated a shared etiology of attention-deficit/hyperactivity disorder (ADHD) and cognitive ability, suggesting a common underlying neurobiology of ADHD and cognition. Further, neuroimaging studies suggest that altered cortical development is related to ADHD. In a large population-based sample we investigated whether cortical morphology, as a potential neurobiological substrate, underlies the association between attention-deficit/hyperactivity symptoms and cognitive problems. METHODS: The sample consisted of school-aged children with data on attention-deficit/hyperactivity symptoms, cognitive functioning and structural imaging. First, we investigated the association between attention-deficit/ hyperactivity symptoms and different domains of cognition. Next, we identified cortical correlates of attention-deficit/hyperactivity symptoms and related cognitive domains. Finally, we studied the role of cortical thickness and gyrification in the behaviour-cognition associations. RESULTS: We included 776 children in our analyses. We found that attention-deficit/hyperactivity symptoms were associated specifically with problems in attention and executive functioning (EF; b = -0.041, 95% confidence interval [CI] -0.07 to -0.01, p = 0.004). Cortical thickness and gyrification were associated with both attention-deficit/hyperactivity symptoms and EF in brain regions that have been previously implicated in ADHD. This partly explained the association between attention-deficit/hyperactivity symptoms and EF (bindirect = -0.008, bias-corrected 95% CI -0.018 to -0.001). LIMITATIONS: The nature of our study did not allow us to draw inferences regarding temporal associations; longitudinal studies are needed for clarification. CONCLUSION: In a large, population-based sample of children, we identified a shared cortical morphology underlying attention-deficit/hyperactivity symptoms and EF.

Cognitive functioning in children with internalising, externalising and dysregulation problems: a population-based study.

Psychiatric symptoms in childhood are closely related to neurocognitive deficits. However, it is unclear whether internalising and externalising symptoms are associated with general or distinct cognitive problems. We examined the relation between different types of psychiatric symptoms and neurocognitive functioning in a population-based sample of 1177 school-aged children. Internalising and externalising behaviour was studied both continuously and categorically. For continuous, variable-centred analyses, broadband scores of internalising and externalising symptoms were used. However, these measures are strongly correlated, which may prevent identification of distinct cognitive patterns. To distinguish groups of children with relatively homogeneous symptom patterns, a latent profile analysis of symptoms at age 6 yielded four exclusive groups of children: a class of children with predominantly internalising symptoms, a class with externalising symptoms, a class with co-occurring internalising and externalising symptoms, that resembles the CBCL dysregulation profile and a class with no problems. Five domains of neurocognitive ability were tested: attention/executive functioning, language, memory and learning, sensorimotor functioning, and visuospatial processing. Consistently, these two different modelling approaches demonstrated that children with internalising and externalising symptoms show distinct cognitive profiles. Children with more externalising symptoms performed lower in the attention/executive functioning domain, while children with more internalising symptoms showed impairment in verbal fluency and memory. In the most severely affected class of children with internalising and externalising symptoms, we found specific impairment in the sensorimotor domain. This study illustrates the specific interrelation of internalising and externalising symptoms and cognition in young children.

Relation of infant motor development with nonverbal intelligence, language comprehension and neuropsychological functioning in childhood: a population-based study.

Within a population-based study of 3356 children, we investigated whether infant neuromotor development was associated with cognition in early childhood. Neuromotor development was examined with an adapted version of Touwen's Neurodevelopmental Examination between 9 and 20 weeks. Parents rated their children's executive functioning at 4 years. At age 6 years, children performed intelligence and language comprehension tests, using Dutch test batteries. At age 6-9 years, neuropsychological functioning was assessed in 486 children using the validated NEPSY-II-NL test battery. We showed that less optimal neurodevelopment in infancy may predict poor mental rotation, immediate memory, shifting, and planning; but not nonverbal intelligence or language comprehension.

A Population-Based Imaging Genetics Study of Inattention/Hyperactivity: Basal Ganglia and Genetic Pathways.

OBJECTIVE: Although attention-deficit/hyperactivity disorder (ADHD) is 1 of the most common neurodevelopmental disorders, little is known about the neurobiology. Clinical studies suggest basal ganglia morphology plays a role. Furthermore, hyperactivity/impulsivity symptoms have recently been linked to genetic pathways involved in dopamine/norepinephrine and serotonin neurotransmission and neuritic outgrowth. We aimed to assess the association between ADHD symptoms, basal ganglia volume, and the 3 proposed genetic pathways in a pediatric population-based sample. With this, we aimed to investigate the generalizability of earlier clinical findings to the general population. METHOD: This study included a population-based sample of 1,871 children with data on ADHD symptoms and genetic data, and 344 children with additional neuroimaging data. Regression analyses between ADHD symptom severity and volumetric data of the basal ganglia were performed. Also, gene-set analyses investigating the association between both ADHD symptom severity and basal ganglia volume with the dopamine/norepinephrine, serotonin, and neuritic outgrowth pathways were performed. RESULTS: More inattention and hyperactivity/impulsivity symptoms were associated with a smaller volume of the putamen (ß = -0.13, p = .034), which was regarded as trend-level after correction for multiple testing. Stratified analyses showed a stronger putamen-hyperactivity association in children with clinical scores, although a similar trend was visible in the nonclinical subsample. The genetic pathways were not related to either ADHD symptoms or basal ganglia volume. CONCLUSION: ADHD symptoms were marginally related to putamen volume in our population-based sample. We found no evidence for a role of dopamine/norepinephrine, serotonin, or neuritic outgrowth genetic pathways in ADHD symptom severity.

White matter integrity and cognitive performance in school-age children: A population-based neuroimaging study.

Child and adolescent brain development are typically accompanied by marked improvements in a wide range of cognitive abilities. However, limited information is available surrounding the role of white matter in shaping cognitive abilities in children. The current study examined associations between white matter microstructure and cognitive performance in a large sample (n=778) of 6- to 10-year-old children. Results show white matter microstructure is related to non-verbal intelligence and to visuospatial ability, independent of age. Specificity was demonstrated, as white matter associations with visuospatial ability were independent of general intellectual ability. Associations between white matter integrity and cognition were similar in boys and girls. In summary, results demonstrate white matter structure-function associations are present in children, independent of age and broader cognitive abilities. The presence of such associations in the general population is informative for studies examining child psychopathology.

What twin studies tell us about the heritability of brain development, morphology, and function: a review.

The development of brain structure and function shows large inter-individual variation. The extent to which this variation is due to genetic or environmental influences has been investigated in twin studies using structural and functional Magnetic Resonance Imaging (MRI). The current review presents an overview of twin studies using MRI in children, adults and elderly, and focuses on cross-sectional and longitudinal designs. The majority of the investigated brain measures are heritable to a large extent (60-80%), although spatial differences in heritability are observed as well. Cross-sectional studies suggest that heritability estimates slightly increase from childhood to adulthood. Long-term longitudinal studies are better suited to study developmental changes in heritability, but these studies are limited. Results so far suggest that the heritability of change over time is relatively low or absent, but more studies are needed to confirm these findings. Compared to brain structure, twin studies of brain function are scarce, and show much lower heritability estimates (~40%). The insights from heritability studies aid our understanding of individual differences in brain structure and function. With the recent start of large genetic MRI consortia, the chance of finding genes that explain the heritability of brain morphology increases. Gene identification may provide insight in biological mechanisms involved in brain processes, which in turn will learn us more about healthy and disturbed brain functioning.

Cortical morphology in 6- to 10-year old children with autistic traits: a population-based neuroimaging study.

OBJECTIVE: Recent evidence suggests that symptoms of social impairment in autism spectrum disorder (ASD) form a spectrum that extends into the general population. However, it is unclear whether the neuroanatomy of ASD also shows a similar continuum in the general population. Therefore, the goal of the present study was to investigate the relationship between cortical morphology and autistic traits along a continuum in a large population-based sample of young children. METHOD: The study included 717 children, aged 6-10 years, who are participants in the Generation R Study, a large population-based cohort. Autistic traits were measured using the Social Responsiveness Scale when the children were approximately 6 years old. High-resolution MRI was obtained, and morphological measures of the cortex, including cortical thickness and gyrification, were quantified brain-wide. RESULTS: Children with more autistic traits showed widespread areas of decreased gyrification. After excluding children with the highest autistic traits and confirmed ASD, the association remained present in a large cluster involving the left hemisphere temporal and precuneus regions. Comparable, but nonsignificant, effects when comparing a small sample of confirmed ASD case subjects with age- and gender-matched control subjects were observed. CONCLUSIONS: Differences in cortical morphology related to autistic traits along a continuum in a large population-based sample of school-aged children were found. Part of these differences remained after excluding the most severely affected children. These findings lend support to an extension of the neurobiology of autistic traits to the general population.