Jan Buitelaar

• Radboud University Medical Centre (Radboudumc)

Background: Autism Spectrum Disorder (ASD) is highly heterogeneous in etiology and manifestation. The neurobiological processes underlying ASD development are reflected in multiple features, from behavior and cognition to brain functioning. An integrated analysis of these features may optimize the identification of these processes. Methods: We exam...

Objective: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. Methods: Cortical thickness and surface area (b...

Background The high heterogeneity of autism spectrum disorders (ASD) across multiple domains complicates research and clinical work. Objective To model more homogeneous subgroups within ASD based on early progress of core symptoms and further characterize these subgroups in terms of progression of language, cognition, co-occurring (ADHD-related) t...

Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive...

This chapter reviews sex differences in ADHD, focusing on differences in prevalence, comorbidity, and impairment, and discusses potential mechanisms underlying these differences. ADHD is more common in males than females (sex ratio ~3:1). Males with ADHD show greater comorbidity with comorbid externalizing (conduct) problems, while females with ADH...

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by structural, functional and neurochemical alterations of the fronto-striatal circuits and by deficits in cognitive control. In particular, ADHD has been associated with impairments in top-down fronto-striatal glutamate-signalling. However, it is unknown...

Background: Pregnancy factors have been implicated in offspring oppositional-defiant disorder (ODD) and conduct disorder (CD) symptoms. Literature still holds notable limitations, such as studying only a restricted set of pregnancy factors, use of screening questionnaires which assess broadly defined outcome measures, and lack of control for disru...

Autism spectrum disorder (ASD) and reduced prosocial behaviour are strongly intertwined. However, social interactions with peers may be increasingly practiced over the course of development and may instigate a reduction in ASD symptoms and vice versa. We, therefore, sought to determine if, during adolescence, possible improvements in prosocial beha...

Objective: Research has implicated glutamatergic projections between the various frontal subregions in the pathogenesis of compulsivity and impulsivity. Reducing striatal glutamate release, or antagonising the action of glutamate at its receptors, may therefore represent viable treatment strategies. Several glutamatergic agents with regulatory app...

Additional figures and text. File including Figures A-C (Reward anticipation task; Monoamine precursor biosynthesis pathways; Intestinal microbiome composition) and Text A-F (Cohorts; fMRI parameters and analyses; Microbiome sequencing and analyses; Additional information microbiome; fMRI main effects of reward anticipation; References). (PDF)

Microbiome descriptives. (XLSX)

Relative abundance taxa. (XLSX)

Relative abundance pathways. (XLSX)

Objective: The past decades have seen a surge in stimulant prescriptions for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants acutely alleviate symptoms and cognitive deficits associated with ADHD by modulating striatal dopamine neurotransmission and induce therapeutic changes in brain activation patterns. Long-term fun...

Autism spectrum disorder (ASD) and Attention-deficit/hyperactivity disorder (ADHD) are often comorbid. The purpose of this study is to explore the relationships between ASD and ADHD symptoms by applying causal modeling. We used a large phenotypic data set of 417 children with ASD and/or ADHD, 562 affected and unaffected siblings, and 414 controls,...

Objective To model more homogeneous subgroups within autism spectrum disorder (ASD) based on early trajectories of core symptoms, and further characterize these subgroups in terms of trajectories of language, cognition, co-occurring (attention-deficit/hyperactivity disorder [ADHD]-related) traits and clinical outcome diagnosis. Method Children (N=...

Magnetic resonance imaging (MRI) studies have highlighted subcortical, cortical, and structural connectivity abnormalities associated with attention-deficit/hyperactivity disorder (ADHD). Gyrification investigations of the cortex have been inconsistent and largely negative, potentially due to a lack of sensitivity of the previously used morphologic...

Adolescence is a period of significant brain changes; however, the effects of age and sex on cortical development are yet to be fully characterized. Here, we utilized innovative intrinsic curvature (IC) analysis, along with the traditional cortical measures [cortical thickness (CT), local gyrification index (LGI), and surface area (SA)], to investi...

Objective: The authors sought to explore how conduct, hyperactivity/inattention, and emotional symptoms are associated with neural reactivity to social-emotional stimuli, and the extent to which psychosocial stress modulates these relationships. Method: Participants were community adolescents recruited as part of the European IMAGEN study. Bilat...

Callous-unemotional (CU) traits have mainly been studied in relation to conduct disorder (CD), but can also occur in other disorder groups. However, it is unclear whether there is a clinically relevant cut-off value of levels of CU traits in predicting reduced quality of life (QoL) and clinical symptoms, and whether CU traits better fit a categoric...

Background Many children and adolescents with attention deficit/hyperactivity disorder (ADHD) are treated with stimulant and non-stimulant medication. ADHD medication may be associated with cardiovascular effects. It is important to identify whether mean group effects translate into clinically relevant increases for some individual patients, and/or...

Nutrition plays an important role in neurodevelopment. This insight has led to increasing research into the efficacy of nutrition-related interventions for treating neurodevelopmental disorders. This review discusses an elimination diet as a treatment for attention deficit hyperactivity disorder and autism spectrum disorder, with a focus on the eff...

Purpose of this quasi-experimental trial was to investigate the effect of Pivotal response treatment (PRT) versus treatment as usual (TAU) on autism symptoms. Children with autism spectrum disorder (ASD), aged 3-8 years, received either PRT (n = 11) or TAU (n = 13). Primary outcome measure was the total score on the Autism Diagnostic Observation Sc...

Introduction: Reward processing is a key aspect of cognitive control processes, putatively instantiated by mesolimbic and mesocortical brain circuits. Deficient signaling within these circuits has been associated with psychopathology. We applied a network discovery approach to assess specific functional networks associated with reward processing i...

Background: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size an...

Predictors of dACC self-regulation (within group). Significant effects (p ≤ 0.05) are printed bold and marked with an asterisk. WAIS = Wechsler Adult Intelligence Scale, ADHD = Attention Deficit Hyperactivity Disorder, VC = Vocabulary, BD = Block Design, MSIT = Multi Source Interference task, SA-DOTS = Sustained Attention DOTS task, SART = Sustaine...

Neurofeedback display. Participants in the neurofeedback group were instructed to performed mental calculations at varying levels of difficulty to achieve up-regulation of their activation level within dACC target regions. They were cued to either rest (A), reach a medium (B), or high difficulty level (C) by adapting their mental-calculation task p...

Ethics proposal. The ethics proposal approved by the local Medical Ethics Committee. (PDF)

Behavioral assessment data. This file contains all clinical and neuropsychological data (per individual) from the behavioral assessment administered pre- and post-training, as well as the motivational data collected during each training session. (CSV)

Indices of individual regulation success. To evaluate individual performance three different performance indices were computed: an index of general task performance (mean activation level across sessions (A)), an index of improvement over sessions (increase in activation level over sessions (B)), and an index of improvement in differential modulati...

Motion and data quality during MRI training. Neurofeedback participants (blue bars) showed significantly reduced motion (A), marked with an asterisk) and significantly increased fMRI data quality as measured by tSNR (B), marked with an asterisk) in comparison to control participants (green bars). In both groups worse motion control was linked to co...

Training data. This file contains the activation levels (beta estimates) per individual and functional run during training, derived from the individually defined dACC target regions. (CSV)

Questionnaire of Current motivation. Across all participants, perceived challenge decreased significantly over time (A), with level of interest decreasing significantly as well (B), and mastery confidence increasing over time (C). Incompetence fear did not change over time (D). There were no group differences that developed over time. The only diff...

CONSORT checklist. This list summarizes the information provided regarding how this exploratory randomized, single-blinded study was designed, analyzed and interpreted. (PDF)

dACC target regions. The x, y and z coordinates in Talairach space of the individual dACC target regions are shown per subject and session. SD = standard deviation. (PDF)

Background: Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopa...

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning...

Background: Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive-compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical prob...

Background To create a self-reported, internet-based questionnaire for the assessment of suicide risk in children and adolescents. Methods As part of the EU project ‘Suicidality: Treatment Occurring in Paediatrics’ (STOP project), we developed web-based Patient Reported Outcome Measures (PROMs) for children and adolescents and for proxy reports by...

Supplementary material

A recent Cochrane review assessed the efficacy of methylphenidate for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Notwithstanding the moderate-to-large effect sizes for ADHD symptom reduction found in the meta-analysis, the authors concluded that the quality of the evidence is low and therefore the true magnitude of...

Full data used for all Calculations. (XLS)

The diagnostic algorithm for ADHD in the NeuroIMAGE sample. (DOCX)

A description of the Children's Social and Behavioural Questionnaire (CSBQ). (DOCX)

Distribution of Scanning over Two Sites. (DOCX)

Background: Tourette's disorder and attention-deficit/hyperactivity disorder often co-occur and have both been associated with structural variation of the basal ganglia. However, findings are inconsistent and comorbidity is often neglected. Methods: T1-weighted magnetic resonance images from children (n = 141, 8 to 12 years) with Tourette's diso...

We hypothesize that it is plausible that biologically distinct developmental ASD–ADHD subtypes are present, each characterized by a distinct time of onset of symptoms, progression and combination of symptoms. The aim of the present narrative review was to explore if structural brain imaging studies may shed light on key brain areas that are linked...

Background Compulsivity, the closely linked trait impulsivity and addictive behaviour are associated with several neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive compulsive disorder (OCD). All three disorders show impaired fronto-striatal functioning, which may b...

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 commo...

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using met...

We recently reported that the serotonin transporter polymorphism 5-HTTLPR moderates the relation between stress exposure and attention-deficit/hyperactivity disorder (ADHD) severity. This gene-environment interaction (GxE) has been previously tied to the processing of emotional stimuli, which is increasingly recognized to be a key factor in ADHD-re...

poster from ECNP. Relates to the following publication DOI: 10.1002/mds.26849, http://onlinelibrary.wiley.com/doi/10.1002/mds.26849/full

Cognitive subtyping may be essential for understanding shared mechanisms underlying attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Participants from a population-based sample (n = 360) and an ASD/ADHD clinic-based sample (n = 254), ages 5 to 17 years, were administered a broad cognitive battery. Latent class ana...

The Reactive Proactive Questionnaire (RPQ) was originally developed to assess reactive and proactive aggressive behavior in children. Nevertheless, some studies have used the RPQ in adults. This study examines the reliability of the RPQ within an adult sample by investigating whether reactive and proactive aggression can be distinguished at a varia...

Literature on the co-occurrence between Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) is strongly biased by a focus on childhood age. A review of the adolescent and adult literature was made on core and related symptoms of ADHD and ASD. In addition, an empirical approach was used including 17,173 ASD-ADHD sympto...

Supplementary material

Gilles de la Tourette Syndrome (GTS) is characterized by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency, and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), thus providi...

Background: This meta-analysis evaluates the efficacy of nonpharmacological treatments for conduct disorder (CD) problems in children and adolescents, based on child, parent and teacher report. Methods: PubMed, PsycINFO and EMBASE were searched for peer-reviewed articles published between January 1970 and March 2015. Main inclusion criteria were...

Callous-unemotional (CU) traits, i.e., unconcernedness and lack of prosocial feelings, may manifest in Conduct Disorder (CD), but also in Oppositional Defiant Disorder (ODD) and Attention Deficit Hyperactivity Disorder (ADHD). These disorders have been associated with aberrant reward processing, while the influence of CU traits is unclear. Using fu...

Background: The association of attention-deficit/hyperactivity disorder (ADHD) and tic disorder (TD) is frequent and clinically important. Very few and inconclusive attempts have been made to clarify if and how the combination of ADHD+TD runs in families. Aim: To determine the first time in a large-scale ADHD sample whether ADHD+TD increases the ri...

Background: The association of attention-deficit/hyperactivity disorder (ADHD) and tic disorder (TD) is frequent and clinically important. Very few and inconclusive attempts have been made to clarify if and how the combination of ADHD+TD runs in families. Aim: To determine the first time in a large-scale ADHD sample whether ADHD+TD increases the ri...

Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled...

Demographic and clinical characteristics of matched sample.

Balanced accuracy/ sensitivity/ specificity measures for the predictions described in the results section based on the three activation maps.

Objective: Attention-deficit/hyperactivity disorder (ADHD) has been associated with dopaminergic imbalance and subtle volume decreases in the brain. Stimulants acutely enhance dopaminergic neurotransmission. Long-term effects of prolonged manipulation of the dopaminergic system on brain structure remain poorly understood; they could be beneficial...

This chapter compliments and should be read in conjunction with Chapter D.1 of the IACAPAP Textbook. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood, with an estimated prevalence of about 5% in school-age children. Core symptoms include impaired attention and/or hyperactivity/impulsivity...

Background: Most general practitioners (GPs) do not feel comfortable with diagnosing and treating children with attention deficit hyperactivity disorder (ADHD). This is problematic since ADHD is a prevalent disorder and an active role of GPs is desired. In the Netherlands a collaborative ADHD programme was established, comprising of shortened diagn...

Correlation analyses between environmental measures, maternal or adolescent’s genotype, brain volumes and ADHD severity. Pearson correlation analyses were performed for all variables, except for correlations with peer affiliation and ADHD severity, for which Spearman correlations analyses were performed. a 9-repeat allele present or absent; b short...

Mixed model analyses testing the separate main effects of maternal expressed emotion, peer affiliation and plasticity genes on brain volumes. EE = expressed emotion; PA = peer affiliation. a Reference group: 10/10 absent; b reference group: short allele absent; c reference group: 7-repeat absent. Findings in bold are significant after correction fo...

Mixed model analyses testing interaction effects between plasticity genes and maternal expressed emotion or peer affiliation on brain volumes. PA = peer affiliation. a Reference group: 10/10 absent; b reference group: short allele absent; c reference group: 7-repeat absent. Findings in bold are significant after correction for multiple testing (p <...

Objectives: Impaired inhibitory control is a key feature of attention-deficit/hyperactivity disorder (ADHD). We investigated gene-environment interaction (GxE) as a possible contributing factor to response inhibition variation in context of the differential susceptibility theory. This states individuals carrying plasticity gene variants will be mo...

This study was designed to examine whether proactive and reactive aggression are meaningful distinctions at the variable- and person-based level, and to determine their associated behavioral profiles. Data from 587 adolescents (mean age 15.6; 71.6 % male) from clinical samples of four different sites with differing levels of aggression problems wer...

Background and Aims Individuals with mild or borderline intellectual disability (MBID) are at risk of substance use (SU). At present, it is unclear which strategy is the best for assessing SU in individuals with MBID. This study compares three strategies, namely self-report, collateral-report, and biomarker analysis. Methods and Procedures In a sa...

Personalization of the educational and behavioral training to the developmental stage of the individual child is common practice in educational and therapeutic settings. Research on robot-based education training is only just starting to adopt this approach. We present a pilot study on a behavioral intervention design in which Pivotal Response Trai...

Since Attention-Deficit/Hyperactivity Disorder (ADHD) is presumed to be a risk factor for intimate partner violence (IPV) it is important to screen for the presence of ADHD in this population. Screening instruments for ADHD however have not been tested for use in forensic psychiatry. The aim of the present study was to assess the screening capacity...

Little is known about the causes of individual differences in reward sensitivity. We investigated gene-environment interactions (GxE) on behavioral and neural measures of reward sensitivity, in light of the differential susceptibility theory. This theory states that individuals carrying plasticity gene variants will be more disadvantaged in negativ...

Introduction Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity...

Heterogeneity is a key feature of all psychiatric disorders and manifests on many levels including symptoms, disease course and biological underpinnings. These form a substantial barrier to understanding disease mechanisms and developing effective, personalised treatments. In response, many studies have aimed to stratify psychiatric disorders, aimi...

Appendix S1. Subdimensions of ADHD traits. Appendix S2. ADHD traits (total score).

Objective: There is no questionnaire to specifically monitor perceived adverse events of methylphenidate (MPH) on cognition, motivation, and mood. The current study therefore had two goals. First, to harvest accounts of such putative events from transcripts of interviews in samples enriched for such potential experiences. Second, to use the derive...

Supplementary material.

The dopamine transporter gene, DAT1 (SLC6A3), has been studied extensively as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). Different alleles of variable number of tandem repeats (VNTRs) in this gene have been associated with childhood ADHD (10/10 genotype and haplotype 10-6) and adult ADHD (haplotype 9-6). This suggests a d...

Background: Magnetic resonance imaging (MRI) is able to provide detailed insights into the structural organization of the brain, e.g., by means of mapping brain anatomy and white matter microstructure. Understanding interrelations between MRI modalities, rather than mapping modalities in isolation, will contribute to unraveling the complex neural m...