This dissertation focused on the neural and behavioral mechanisms underlying adolescent learning and mental health in the context of peers and friends. The neuroimaging findings revealed that... Show moreThis dissertation focused on the neural and behavioral mechanisms underlying adolescent learning and mental health in the context of peers and friends. The neuroimaging findings revealed that reward processing for self and peers rely on common reward-related brain regions, whereas a social brain region (TPJ) showed social specificity to observed outcomes for unfamiliar peers compared to friends. Moreover, typically developing adolescents and adolescents with ADHD show neural sensitivity in reward and salience brain regions towards rewards for themselves, friends and peers compared to losses. There were no group differences in neural processing of (vicarious) outcomes between adolescents with and without ADHD, yet a symptom-level approach showed more neural sensitivity for own compared to friends’ losses in individuals with more inattention symptoms. The behavioral findings indicated that adolescents’ learning performance benefitted from observing the choices and outcomes of peers irrespective of the relationship with this peer. The results did not show effects of friendship (quality) and social status on observational and academic learning, but there was a protective effect of friendship quality on internalizing problems. Taken together, these findings highlight adolescence as a period of observational learning opportunities from different types of peers. Adolescence can also serve as a window of opportunity to improve mental health by fostering high-quality friendships. Show less
Langen, M.J.M. van; Hulst, B.M. van; Durston, S. 2023
Psychiatric classifications refer to clusters of behavioral symptoms. We know much about how psychiatric classifications are intended to be used in theory. Yet the scientific study of the practice... Show morePsychiatric classifications refer to clusters of behavioral symptoms. We know much about how psychiatric classifications are intended to be used in theory. Yet the scientific study of the practice of classification to date is limited. We aimed to explore how individuals navigate and make sense of the complexity surrounding an ADHD classification. We used thematic analysis to analyse stakeholder perspectives from seven focus groups: adults classified with ADHD, adolescents classified with ADHD, parents of children classified with ADHD, clinicians, researchers, teachers, and policy makers. We found seven themes in how stakeholders navigate the classification ADHD. Yet, what stood out was an overarching discursive pattern: individual stakeholders expressed highly ambivalent ideas about ADHD but did not address their own ambivalence. We suggest that promoting a social kinds perspective on ADHD may help us navigate the complexity and ambivalence associated with ADHD more competently. Show less
About 1 in 650-1000 children are born with a 47,XXY, 47,XXX or 47,XYY chromosomal pattern (i.e, sex chromosome trisomies, SCT). The presence of SCT is associated with an increased risk for... Show moreAbout 1 in 650-1000 children are born with a 47,XXY, 47,XXX or 47,XYY chromosomal pattern (i.e, sex chromosome trisomies, SCT). The presence of SCT is associated with an increased risk for neurodevelopmental difficulties across the life-span. Studying neurodevelopment in early childhood in children with SCT could signal deviations in development that serve as risk markers to guide clinical care. This thesis explored the development of self-regulation (emotion, cognition, and behavior) in SCT children and population-based controls, aged 1 to 7 years, who participated in the TRIXY Early Childhood Study. Behavioral symptoms were assessed through structured behavioral observation and parental questionnaires. Neurocognition was measured using performance tests and psychophysiological measures of arousal. Outcomes showed behavioral symptoms of psychopathology and neurocognitive vulnerabilities, already from an early age. Difficulties in self-regulation tended to become more pronounced with increasing age and were rather robust; independent of karyotype, pre/postnatal diagnosis, or intelligence-levels. A developmental neurocognitive perspective is key in increasing our knowledge of gene-brain-behavior pathways in SCT as well as advancing clinical care (diagnostics and treatment). Self-regulation amongst other neurocognitive functions may serve as a valuable target for early, tailor-made interventions to minimize the risk for psychopathology later in life and improving quality of life. Show less
The evolving field of multi-omics combines data and provides methods for simultaneous analysis across several omics levels. Here, we integrated genomics (transmitted and non-transmitted polygenic... Show moreThe evolving field of multi-omics combines data and provides methods for simultaneous analysis across several omics levels. Here, we integrated genomics (transmitted and non-transmitted polygenic scores [PGSs]), epigenomics, and metabolomics data in a multi-omics framework to identify biomarkers for Attention-Deficit/Hyperactivity Disorder (ADHD) and investigated the connections among the three omics levels. We first trained single- and next multi-omics models to differentiate between cases and controls in 596 twins (cases = 14.8%) from the Netherlands Twin Register (NTR) demonstrating reasonable in-sample prediction through cross-validation. The multi-omics model selected 30 PGSs, 143 CpGs, and 90 metabolites. We confirmed previous associations of ADHD with glucocorticoid exposure and the transmembrane protein family TMEM, show that the DNA methylation of the MAD1L1 gene associated with ADHD has a relation with parental smoking behavior, and present novel findings including associations between indirect genetic effects and CpGs of the STAP2 gene. However, out-of-sample prediction in NTR participants (N = 258, cases = 14.3%) and in a clinical sample (N = 145, cases = 51%) did not perform well (range misclassification was [0.40, 0.57]). The results highlighted connections between omics levels, with the strongest connections between non-transmitted PGSs, CpGs, and amino acid levels and show that multi-omics designs considering interrelated omics levels can help unravel the complex biology underlying ADHD. Show less
Background: Psychiatric classifications are understood in many different ways. For children with ADHD and their parents, psychoeducation is an important source of information for shaping their... Show moreBackground: Psychiatric classifications are understood in many different ways. For children with ADHD and their parents, psychoeducation is an important source of information for shaping their understanding. Moreover, psychoeducation is often taken by children and parents to represent how their story is understood by the therapist. As a result, the way psychoeducation is formulated may affect the therapeutic alliance, one of the most robust mediators of treatment outcome. In addition, psychoeducation may indirectly influence the way we understand psychological differences as a society. Methods: To better understand how the classification ADHD is given meaning through psychoeducation, we analyzed 41 written psychoeducational materials from four different countries; the USA, UK, Netherlands and Hungary. Results: We identified five patterns of how the materials construct the discourse on ADHD. Notably, tension between biomedical and psychosocial perspectives resulted in conflict within a single thematic stance on ADHD as opposed to a conflict between parties with a different vision on ADHD. There were only few differences between countries in the way they constructed the discourse in the materials. Conclusions: These conflicts cause confusion, misrepresentation and decontextualization of ADHD. Ultimately, for those diagnosed with ADHD and their parents, conflicting information in psychoeducation materials may hamper their ability to understand themselves in the context of their difficulties. Show less
Objective: Previous studies at child and youth mental health services (CYMHS) suggest that children with ADHD have poorer outcomes compared to those with other diagnoses. This study investigates... Show moreObjective: Previous studies at child and youth mental health services (CYMHS) suggest that children with ADHD have poorer outcomes compared to those with other diagnoses. This study investigates this in more detail. Methods: Children with ADHD were compared to those with ASD and those with emotional disorders, on routinely collected outcomes at CYMHS in Australia (N = 2,513) and the Netherlands (N = 844). Results: Where the emotional disorders group reached a similar level of emotional symptoms at the end-of-treatment as the ADHD and ASD groups, the latter two groups still had higher scores on ADHD and ASD symptoms (attention and peer problems). The poorer outcomes were mainly explained by higher severity at baseline. In Australia, an ADHD and/or ASD diagnosis also independently contributed to worse outcomes. Conclusion: Those with neurodevelopmental disorders within both countries had poorer outcomes than those with emotional disorders. Services should aim to optimize treatment to ensure best possible outcomes. Show less
Ozgen, H.; Spijkerman, R.; Noack, M.; Holtmann, M.; Schellekens, A.; Dalsgaard, S.; ... ; Hendriks, V. 2021
Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for the development of substance abuse and substance use disorders (SUD) in adolescence and (early) adulthood. ADHD and... Show moreChildhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for the development of substance abuse and substance use disorders (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment, and is associated with poor treatment outcomes. In this study, we provide a systematic review of controlled studies on the effectiveness of pharmacological, psychosocial, and complementary treatments of ADHD in adolescents with and without comorbid SUD. In addition, we review the longitudinal association between pharmacotherapy for childhood ADHD and the development of SUD in adolescence and early adulthood. We conducted a systematic review of the research literature published since 2000 using Medline, PsycINFO, and the Cochrane Database of Systematic Reviews databases to select randomized clinical trials, observational studies, and meta-analyses. The quality of the evidence from each study was rated using the SIGN grading system. Based on the limited evidence available, strong clinical recommendations are not justified, but provisionally, we conclude that stimulant treatment in children with ADHD may prevent the development of SUD in adolescence or young adulthood, that high-dose stimulant treatment could be an effective treatment for adolescents with ADHD and SUD comorbidity, that cognitive behavior therapy might have a small beneficial effect in these patients, and that alternative treatments are probably not effective. More studies are needed to draw definitive conclusions that will allow for strong clinical recommendations. Show less
Chen, L.M.; Tollenaar, M.S.; Dass, S.H.A.; Bouvette-Turcot, A.A.; Pokhvisneva, I.; Gaudreau, H.; ... ; MAVAN Study Team 2020
Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture... Show moreMaternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture the genotypic influence. We outline a novel approach to describe genomic susceptibility to maternal antenatal depression focusing on child emotional/behavioral difficulties. Two cohorts provided measures of maternal depression, child genetic variation, and child mental health symptoms. We constructed a conventional polygenic risk score (PRS) for attention-deficit/hyperactivity disorder (ADHD) (PRSADHD) that significantly moderated the association between maternal antenatal depression and internalizing problems at 60 months (p = 2.94 x 10(-4), R-2 = .18). We then constructed an interaction PRS (xPRS) based on a subset of those single nucleotide polymorphisms from the PRSADHD that most accounted for the moderation of the association between maternal antenatal depression and child outcome. The interaction between maternal antenatal depression and this xPRS accounted for a larger proportion of the variance in child emotional/behavioral problems than models based on any PRSADHD (p = 5.50 x 10(-9), R-2 = .27), with similar findings in the replication cohort. The xPRS was significantly enriched for genes involved in neuronal development and synaptic function. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health. Show less
Childhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In... Show moreChildhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In children with obesity and respiratory symptoms the diagnosis of asthma was studied and in children with ADHD dosing regimens. Overtreatment as a consequence of overdiagnosis was frequently observed in children with obesity and asthma and undertreatment due to relative underdosing in the ADHD population with obesity. This highlights the necessity for accurate diagnostic processes alongside dosing regimens based on pharmacokinetic changes caused by obesity. The focus in the second part of this thesis was on screening for complications of obesity namely insulin resistance and cardiovascular diseases. Given the high prevalence of insulin resistance and the observed changes of cardiovascular parameters, screening on cardiometabolic complications is warranted in all children with obesity. Pharmacological treatment with metformin in addition to lifestyle intervention was studied in the last part of this thesis. Given the favorable effect on BMI in children and adults and the maintenance of weight loss and reduction in progression towards T2DM in adults, metformin can be considered in children with obesity and insulin resistance in addition to lifestyle intervention. Show less
Stimulant prescription rates for attention deficit hyperactivity disorder (ADHD) are increasing, even though potential long-term effects on the developing brain have not been well-studied. A... Show moreStimulant prescription rates for attention deficit hyperactivity disorder (ADHD) are increasing, even though potential long-term effects on the developing brain have not been well-studied. A previous randomized clinical trial showed short-term age-dependent effects of stimulants on the DA system. We here assessed the long-term modifying effects of age-of-first-stimulant treatment on the human brain and behavior. 81 male adult ADHD patients were stratified into three groups: 1) early stimulant treatment (EST; <16 years of age) 2) late stimulant treatment (LST: ≥23 years of age) and 3) stimulant treatment naive (STN; no history of stimulant treatment). We used pharmacological magnetic resonance imaging (phMRI) to assess the cerebral blood flow (CBF) response to an oral methylphenidate challenge (MPH, 0.5 mg/kg), as an indirect measure of dopamine function in fronto-striatal areas. In addition, mood and anxiety scores, and recreational drug use were assessed. Baseline ACC CBF was lower in the EST than the STN group (p = 0.03), although CBF response to MPH was similar between the three groups (p = 0.23). ADHD symptom severity was higher in the STN group compared to the other groups (p < 0.01). In addition, the EST group reported more depressive symptoms (p = 0.04), but not anxiety (p = 0.26), and less recreational drug use (p = 0.04). In line with extensive pre-clinical data, our data suggest that early, but not late, stimulant treatment long-lastingly affects the human brain and behavior, possibly indicating fundamental changes in the dopamine system. Show less
Stimulant prescription rates for attention deficit hyperactivity disorder (ADHD) are increasing, even though potential long-term effects on the developing brain have not been well-studied. A... Show moreStimulant prescription rates for attention deficit hyperactivity disorder (ADHD) are increasing, even though potential long-term effects on the developing brain have not been well-studied. A previous randomized clinical trial showed short-term age-dependent effects of stimulants on the DA system. We here assessed the long-term modifying effects of age-of-first-stimulant treatment on the human brain and behavior. 81 male adult ADHD patients were stratified into three groups: 1) early stimulant treatment (EST; < 16 years of age) 2) late stimulant treatment (LST: >23 years of age) and 3) stimulant treatment naive (STN; no history of stimulant treatment). We used pharmacological magnetic resonance imaging (phMRI) to assess the cerebral blood flow (CBF) response to an oral methylphenidate challenge (MPH, 0.5 mg/kg), as an indirect measure of dopamine function in fronto-striatal areas. In addition, mood and anxiety scores, and recreational drug use were assessed. Baseline ACC CBF was lower in the EST than the STN group (p = 0.03), although CBF response to MPH was similar between the three groups (p = 0.23). ADHD symptom severity was higher in the STN group compared to the other groups (p < 0.01). In addition, the EST group reported more depressive symptoms (p = 0.04), but not anxiety (p = 0.26), and less recreational drug use (p = 0.04). In line with extensive pre-clinical data, our data suggest that early, but not late, stimulant treatment long-lastingly affects the human brain and behavior, possibly indicating fundamental changes in the dopamine system. Show less
Sleep problems are highly prevalent in ADHD and autism spectrum disorder (ASD). Better insight in the etiology is of clinical importance since intervention and prevention strategies of sleep... Show moreSleep problems are highly prevalent in ADHD and autism spectrum disorder (ASD). Better insight in the etiology is of clinical importance since intervention and prevention strategies of sleep problems are directed at underlying mechanisms. We evaluated the association of sleep problems and sleep patterns with sleep hygiene (behavioral/environmental practices that influence sleep quality, e.g. caffeine use), access to electronic media, chronotype, and anxiety/depression in children aged 6–12 years with ADHD, ASD, or typical development (TD) using parental questionnaires. ANOVA and linear regression analyses were adjusted for age and sex. Children with ADHD and ASD showed more sleep problems (63.6 and 64.7%, vs 25.1% in TD) and shorter sleep duration than controls, while differences between ADHD and ASD were not significant. Sleep hygiene was worse in ADHD and ASD compared to TD, however, the association of worse sleep hygiene with more sleep problems was only significant in ASD and TD. There was a significant association of access to electronic media with sleep problems only in typically developing controls. Chronotype did not differ significantly between groups, but evening types were associated with sleep problems in ADHD and TD. Associations of greater anxiety/depression with more sleep problems were shown in ADHD and TD; however, anxiety/depression did not moderate the effects of chronotype and sleep hygiene. We conclude that sleep problems are highly prevalent in ADHD and ASD, but are differentially related to chronotype and sleep hygiene. In ASD, sleep problems are related to inadequate sleep hygiene and in ADHD to evening chronotype, while in TD both factors are important. Clinical implications are discussed. Show less
Dekkers, T.J.; Agelink van Rentergem, J.A.; Koole, A.; Van den Wildenberg, W.P.M.; Popma, A.; Bexkens, A.; ... ; Huizenga, H.M. 2017
Studies of Attention-Deficit/Hyperactivity Disorder (ADHD) have shown developmental changes in the cortical mantle. Different dimensions of cortical morphology, such as surface area and thickness,... Show moreStudies of Attention-Deficit/Hyperactivity Disorder (ADHD) have shown developmental changes in the cortical mantle. Different dimensions of cortical morphology, such as surface area and thickness, relate to different neurodevelopmental mechanisms. As such, studying multiple dimensions may inform us about the developmental origins of ADHD. Furthermore, results from existing longitudinal samples await replication. Therefore, we conducted a longitudinal study of multiple cortical dimensions in a sizable, independent ADHD sample. We analyzed 297 anatomical MRI scans from two matched groups of 94 subjects with ADHD and 94 controls, aged 6–28 years. We estimated the developmental trajectories of cortical volume, surface, thickness and gyrification for 68 regions using mixed-effects regression analysis. Subjects with ADHD had smaller overall cortical volume, predominantly driven by decreases in frontal lobe volume that were associated with reduced surface area and gyrification. Nearly all decreases were stable across development. Only a few decreases survived stringent Bonferroni correction for multiple comparisons, with the smallest detectable Cohen's d |0.43|. There were no between-group differences in cortical thickness, or in subcortical volumes. Our results suggest that ADHD is associated with developmentally persistent reductions in frontal cortical volume, surface area, and gyrification. This may implicate early neurodevelopmental mechanisms regulating cortical expansion and convolution in ADHD. Show less
Geissler, J.M.; Romanos, M.; Gerlach, M.; Berg, D.; Schulte, C.; Int Parkinson Dis Genomics 2017
