Working memory training in children with neurodevelopmental disorders and intellectual disabilities, the role of coaching: A double-blind randomised controlled trial.

BACKGROUND: Working memory training (WMT) can offer therapeutic benefits to patients with neurodevelopmental disorders (NDD) and mild to borderline intellectual disability (MBID). However, consistent evidence for treatment benefits of WMT over placebo training is missing. So far, participants in double-blind research designs did receive non-specific coaching, whereas active coaching based on individual training results might increase the efficacy of WMT. Furthermore, the intensity and duration of WMT is often too stressful for these children. This study therefore investigated whether a less intensive but more prolonged WMT, with active personalised coaching and feedback, would reduce behavioural symptoms and improve neurocognitive functioning and academic achievements in children with NDD and MBID. METHOD: A double-blind randomised controlled trial in children (aged 10;0-13;11) with MBID (60 < IQ < 85) and ADHD and/or ASD evaluated the effects of a less intensive but prolonged version of the original Cogmed WMT (30 min a day, 4 days a week, 8 weeks in total). Eighteen participants received active, personalised coaching and feedback, based on their actual individual performance during training. Twenty-two received general non-personalised coaching for the same amount of time. Executive functioning, academic achievements and several behavioural measurements were administered, before and after training, with a 6-months follow-up. RESULTS: We observed a significant effect of time on both primary and secondary outcome measures, indicating that all children improved in working memory performance and other neurocognitive and academic outcomes. The interaction between time and group was not significant. DISCUSSION: This study was unable to document superior effects of active personalised coaching and feedback compared with general non-personalised coaching and no feedback in an adaptive WMT in children with MBID and NDD. The objectively documented changes over time suggest that for these vulnerable children, a regular, structured and structural contact with a coach and adapted exercises is enough to develop therapy fidelity, boost motivation and improve neurodevelopmental task performance. Further research is needed to examine which possible subgroups within this heterogenic group of children profit more from WMT compared with other subgroups.

Remote assessment of ADHD in children and adolescents: recommendations from the European ADHD Guidelines Group following the clinical experience during the COVID-19 pandemic.

The COVID-19 pandemic led ADHD services to modify the clinical practice to reduce in-person contact as much as possible to minimise viral spread. This had far-reaching effects on day-to-day clinical practice as remote assessments were widely adopted. Despite the attenuation of the acute threat from COVID, many clinical services are retaining some remote practices. The lack of clear evidence-based guidance about the most appropriate way to conduct remote assessments meant that these changes were typically implemented in a localised, ad hoc, and un-coordinated way. Here, the European ADHD Guidelines Group (EAGG) discusses the strengths and weaknesses of remote assessment methods of children and adolescents with ADHD in a narrative review based on available data and expert opinions to highlight key recommendations for future studies and clinical practice. We conclude that going forward, despite remote working in clinical services functioning adequately during the pandemic, all required components of ADHD assessment should still be completed following national/international guidelines; however, the process may need adaptation. Social restrictions, including changes in education provision, can either mask or exacerbate features associated with ADHD and therefore assessment should carefully chart symptom profile and impairment prior to, as well as during an ongoing pandemic. While remote assessments are valuable in allowing clinical services to continue despite restrictions and may have benefits for routine care in the post-pandemic world, particular attention must be paid to those who may be at high risk but not be able to use/access remote technologies and prioritize these groups for conventional face-to-face assessments.

Evaluation of data imputation strategies in complex, deeply-phenotyped data sets: the case of the EU-AIMS Longitudinal European Autism Project.

An increasing number of large-scale multi-modal research initiatives has been conducted in the typically developing population, e.g. Dev. Cogn. Neur. 32:43-54, 2018; PLoS Med. 12(3):e1001779, 2015; Elam and Van Essen, Enc. Comp. Neur., 2013, as well as in psychiatric cohorts, e.g. Trans. Psych. 10(1):100, 2020; Mol. Psych. 19:659-667, 2014; Mol. Aut. 8:24, 2017; Eur. Child and Adol. Psych. 24(3):265-281, 2015. Missing data is a common problem in such datasets due to the difficulty of assessing multiple measures on a large number of participants. The consequences of missing data accumulate when researchers aim to integrate relationships across multiple measures. Here we aim to evaluate different imputation strategies to fill in missing values in clinical data from a large (total N = 764) and deeply phenotyped (i.e. range of clinical and cognitive instruments administered) sample of N = 453 autistic individuals and N = 311 control individuals recruited as part of the EU-AIMS Longitudinal European Autism Project (LEAP) consortium. In particular, we consider a total of 160 clinical measures divided in 15 overlapping subsets of participants. We use two simple but common univariate strategies-mean and median imputation-as well as a Round Robin regression approach involving four independent multivariate regression models including Bayesian Ridge regression, as well as several non-linear models: Decision Trees (Extra Trees., and Nearest Neighbours regression. We evaluate the models using the traditional mean square error towards removed available data, and also consider the Kullback-Leibler divergence between the observed and the imputed distributions. We show that all of the multivariate approaches tested provide a substantial improvement compared to typical univariate approaches. Further, our analyses reveal that across all 15 data-subsets tested, an Extra Trees regression approach provided the best global results. This not only allows the selection of a unique model to impute missing data for the LEAP project and delivers a fixed set of imputed clinical data to be used by researchers working with the LEAP dataset in the future, but provides more general guidelines for data imputation in large scale epidemiological studies.

Working memory training in children with borderline intellectual functioning and neuropsychiatric disorders: a triple-blind randomised controlled trial.

BACKGROUND: Poor working memory, lower IQ and maladaptive behaviour form a triple disability known to have negative effects on the academic and social development of children with borderline intellectual functioning (BIF; IQ: 70 < IQ < 85) and neuropsychiatric disorders [attention-deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD)]. Treatment possibilities for these children are scarce and hardly evidence based. This study primarily investigated whether adaptive computerised working memory training (WMT) may lead to significantly more improvement on a non-trained visuospatial WM task compared with a non-adaptive control WMT (placebo) in children with BIF and neuropsychiatric disorders. As secondary outcome measures, we used the scores on several non-trained neuropsychological near-transfer and far-transfer tasks as well as behavioural measures. METHOD: We conducted a triple-blind placebo-controlled randomised clinical trial in 72 children (aged 10;0-13;11 years, 53 boys, 19 girls) with BIF and comorbid neuropsychiatric disorders (ADHD = 37, ASD = 21, both = 14) that were referred to child and adolescent psychiatry care, between May 2012 and March 2019. Children completed the Dutch version of Cogmed WMT, either the adaptive training version or the non-adaptive placebo version, 25 sessions (30-45 min a day), for 5 weeks. The primary outcome measure was the score on a non-trained visuospatial working memory task. The primary outcome was measured before and directly after 5 weeks of WMT and again 6 months after training. RESULTS: A total of 375 children were screened for eligibility and 72 were randomised. No significantly higher levels of improvement over time were found on our primary outcome measure in the experimental WMT group compared with the placebo control WMT, nor in the secondary (near-transfer and far-transfer tasks) or tertiary (behavioural measures) outcome measures. However, this study did show changes over time for these measurements for both the experimental and placebo conditions. CONCLUSIONS: This study was unable to document superior training effects over time of an adaptive WMT in children with BIF and neuropsychiatric disorders, compared with a placebo (non-adaptive) WMT. The objectively documented changes over time in the non-adaptive WMT arm suggest that these children with persistent impairments in WM may benefit from a structured learning environment that is associated with improvement of neurocognitive functioning and coping strategies. Further research is needed to examine which elements of cognitive training may be useful for which specific patients and to study long-term effects of training.

Early motor signs of attention-deficit hyperactivity disorder: a systematic review.

ADHD is a common neurodevelopmental disorder with onset of symptoms typically in early childhood. First signs of the disorder, including language delay, motor delay and temperament characteristics, may be evident as early as infancy. The present review describes published evidence about early motor signs of either children with later symptoms of ADHD or a later diagnosis of the disorder. Nine published cohort studies were included after a systematic search of related terms in PubMed and PsycInfo databases. Study eligibility criteria included: (1) report on early motor function or any motor-related signs; (2) the presence of a participants' assessment by/at 12 months of age; (3) report of a later presence of ADHD symptoms. The limited number of reports included suggests an association between mild early neurological markers and later developmental coordination disorder and motor overflow movements. Unfortunately, due to their small sample sizes and focus on group reports rather than individuals, they have limited power to find strong associations. Early motor indicators of ADHD, if present, appear to be non-specific, and therefore not yet useful in clinical screening. Spontaneous motility seems to be a promising measure for early ADHD detection, although further studies with large cohorts are recommended to determine its clinical role in children at risk for ADHD.

Psychosocial risk factors for suicidality in children and adolescents.

Suicidality in childhood and adolescence is of increasing concern. The aim of this paper was to review the published literature identifying key psychosocial risk factors for suicidality in the paediatric population. A systematic two-step search was carried out following the PRISMA statement guidelines, using the terms 'suicidality, suicide, and self-harm' combined with terms 'infant, child, adolescent' according to the US National Library of Medicine and the National Institutes of Health classification of ages. Forty-four studies were included in the qualitative synthesis. The review identified three main factors that appear to increase the risk of suicidality: psychological factors (depression, anxiety, previous suicide attempt, drug and alcohol use, and other comorbid psychiatric disorders); stressful life events (family problems and peer conflicts); and personality traits (such as neuroticism and impulsivity). The evidence highlights the complexity of suicidality and points towards an interaction of factors contributing to suicidal behaviour. More information is needed to understand the complex relationship between risk factors for suicidality. Prospective studies with adequate sample sizes are needed to investigate these multiple variables of risk concurrently and over time.

Development and psychometric properties of the "Suicidality: Treatment Occurring in Paediatrics (STOP) Risk and Resilience Factors Scales" in adolescents.

Suicidality in the child and adolescent population is a major public health concern. There is, however, a lack of developmentally sensitive valid and reliable instruments that can capture data on risk, and clinical and psychosocial mediators of suicidality in young people. In this study, we aimed to develop and assess the validity of instruments evaluating the psychosocial risk and protective factors for suicidal behaviours in the adolescent population. In Phase 1, based on a systematic literature review of suicidality, focus groups, and expert panel advice, the risk factors and protective factors (resilience factors) were identified and the adolescent, parent, and clinician versions of the STOP-Suicidality Risk Factors Scale (STOP-SRiFS) and the Resilience Factors Scale (STOP-SReFS) were developed. Phase 2 involved instrument validation and comprised of two samples (Sample 1 and 2). Sample 1 consisted of 87 adolescents, their parents/carers, and clinicians from the various participating centres, and Sample 2 consisted of three sub-samples: adolescents (n = 259) who completed STOP-SRiFS and/or the STOP-SReFS scales, parents (n = 213) who completed one or both of the scales, and the clinicians who completed the scales (n = 254). The STOP-SRiFS demonstrated a good construct validity-the Cronbach Alpha for the adolescent (α = 0.864), parent (α = 0.842), and clinician (α = 0.722) versions of the scale. Test-retest reliability, inter-rater reliability, and content validity were good for all three versions of the STOP-SRiFS. The sub-scales generated using Exploratory Factor Analysis (EFA) were the (1) anxiety and depression risk, (2) substance misuse risk, (3) interpersonal risk, (4) chronic risk, and (5) risk due to life events. For the STOP-SRiFS, statistically significant correlations were found between the Columbia-Suicide Severity Rating Scale (C-SSRS) total score and the adolescent, parent, and clinical versions of the STOP-SRiFS sub-scale scores. The STOP-SRiFS showed good psychometric properties. This study demonstrated a good construct validity for the STOP-SReFS-the Cronbach Alpha for the three versions were good (adolescent: α = 0.775; parent: α = 0.808; α = clinician: 0.808). EFA for the adolescent version of the STOP-SReFS, which consists of 9 resilience factors domains, generated two factors (1) interpersonal resilience and (2) cognitive resilience. The STOP-SReFS Cognitive Resilience sub-scale for the adolescent was negatively correlated (r = - 0.275) with the C-SSRS total score, showing that there was lower suicidality in those with greater Cognitive Resilience. The STOP-SReFS Interpersonal resilience sub-scale correlations were all negative, but none of them were significantly different to the C-SSRS total scores for either the adolescent, parent, or clinician versions of the scales. This is not surprising, because the items in this sub-scale capture a much larger time-scale, compared to the C-SSRS rating period. The STOP-SReFS showed good psychometric properties. The STOP-SRiFS and STOP-SReFS are instruments that can be used in future studies about suicidality in children and adolescents.

A Potential Role for the STXBP5-AS1 Gene in Adult ADHD Symptoms.

We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10-7) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in "SNAP" (Soluble NSF attachment protein) Receptor" (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r2 = - 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.

Autism spectrum disorders and autistic traits share genetics and biology.

Autism spectrum disorders (ASDs) and autistic traits in the general population may share genetic susceptibility factors. In this study, we investigated such potential overlap based on common genetic variants. We developed and validated a self-report questionnaire of autistic traits in adults. We then conducted genome-wide association studies (GWASs) of six trait scores derived from the questionnaire through exploratory factor analysis in 1981 adults from the general population. Using the results from the Psychiatric Genomics Consortium GWAS of ASDs, we observed genetic sharing between ASDs and the autistic traits 'childhood behavior', 'rigidity' and 'attention to detail'. Gene-set analysis subsequently identified 'rigidity' to be significantly associated with a network of ASD gene-encoded proteins that regulates neurite outgrowth. Gene-wide association with the well-established ASD gene MET reached significance. Taken together, our findings provide evidence for an overlapping genetic and biological etiology underlying ASDs and autistic population traits, which suggests that genetic studies in the general population may yield novel ASD genes.

Revisiting subcortical brain volume correlates of autism in the ABIDE dataset: effects of age and sex.

BACKGROUND: Autism spectrum disorders (ASD) are characterized by substantial clinical, etiological and neurobiological heterogeneity. Despite this heterogeneity, previous imaging studies have highlighted the role of specific cortical and subcortical structures in ASD and have forwarded the notion of an ASD specific neuroanatomy in which abnormalities in brain structures are present that can be used for diagnostic classification approaches. METHOD: A large (N = 859, 6-27 years, IQ 70-130) multi-center structural magnetic resonance imaging dataset was examined to specifically test ASD diagnostic effects regarding (sub)cortical volumes. RESULTS: Despite the large sample size, we found virtually no main effects of ASD diagnosis. Yet, several significant two- and three-way interaction effects of diagnosis by age by gender were found. CONCLUSION: The neuroanatomy of ASD does not exist, but is highly age and gender dependent. Implications for approaches of stratification of ASD into more homogeneous subtypes are discussed.

Autism spectrum disorders and autistic traits share genetics and biology.

This corrects the article DOI: 10.1038/mp.2017.98.

Emotional face recognition in male adolescents with autism spectrum disorder or disruptive behavior disorder: an eye-tracking study.

Autism Spectrum Disorder (ASD), Oppositional Defiant Disorder (ODD), and Conduct Disorder (CD) are often associated with emotion recognition difficulties. This is the first eye-tracking study to examine emotional face recognition (i.e., gazing behavior) in a direct comparison of male adolescents with Autism Spectrum Disorder or Oppositional Defiant Disorder/Conduct Disorder, and typically developing (TD) individuals. We also investigate the role of psychopathic traits, callous-unemotional (CU) traits, and subtypes of aggressive behavior in emotional face recognition. A total of 122 male adolescents (N = 50 ASD, N = 44 ODD/CD, and N = 28 TD) aged 12-19 years (M = 15.4 years, SD= 1.9) were included in the current study for the eye-tracking experiment. Participants were presented with neutral and emotional faces using a Tobii 1750 eye-tracking monitor to record gaze behavior. Our main dependent eye-tracking variables were: (1) fixation duration to the eyes of a face and (2) time to the first fixation to the eyes. Since distributions of eye-tracking variables were not completely Gaussian, non-parametric tests were chosen to investigate gaze behavior across the diagnostic groups with Autism Spectrum Disorder, Oppositional Defiant Disorder/Conduct Disorder, and Typically Developing individuals. Furthermore, we used Spearman correlations to investigate the links with psychopathy, callous, and unemotional traits and subtypes of aggression as assessed by questionnaires. The relative total fixation duration to the eyes was decreased in both the Autism Spectrum Disorder group and the Oppositional Defiant Disorder/Conduct Disorder group for several emotional expressions. In both the Autism Spectrum Disorder and the Oppositional Defiant Disorder/Conduct Disorder group, increased time to first fixation on the eyes of fearful faces only was nominally significant. The time to first fixation on the eyes was nominally correlated with psychopathic traits and proactive aggression. The current findings do not support strong claims for differential cross-disorder eye-gazing deficits and for a role of shared underlying psychopathic traits, callous-unemotional traits, and aggression subtypes. Our data provide valuable and novel insights into gaze timing distributions when looking at the eyes of a fearful face.

Diminished modulation of preparatory sensorimotor mu rhythm predicts attention-deficit/hyperactivity disorder severity.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is characterized by problems in regulating attention and in suppressing disruptive motor activity, i.e. hyperactivity and impulsivity. We recently found evidence that aberrant distribution of posterior α band oscillations (8-12 Hz) is associated with attentional problems in ADHD. The sensorimotor cortex also produces strong 8-12 Hz band oscillations, namely the µ rhythm, and is thought to have a similar inhibitory function. Here, we now investigate whether problems in distributing α band oscillations in ADHD generalize to the µ rhythm in the sensorimotor domain. METHOD: In a group of adult ADHD (n = 17) and healthy control subjects (n = 18; aged 21-40 years) oscillatory brain activity was recorded using magnetoencephalography during a visuo-spatial attention task. Subjects had to anticipate a target with unpredictable timing and respond by pressing a button. RESULTS: Preparing a motor response, the ADHD group failed to increase hemispheric µ lateralization with relatively higher µ power in sensorimotor regions not engaged in the task, as the controls did (F 1,33 = 8.70, p = 0.006). Moreover, the ADHD group pre-response µ lateralization not only correlated positively with accuracy (r s = 0.64, p = 0.0052) and negatively with intra-individual reaction time variability (r s = -0.52, p = 0.033), but it also correlated negatively with the score on an ADHD rating scale (r s = -0.53, p = 0.028). CONCLUSIONS: We suggest that ADHD is associated with an inability to sufficiently inhibit task-irrelevant sensorimotor areas by means of modulating µ oscillatory activity. This could explain disruptive motor activity in ADHD. These results provide further evidence that impaired modulation of α band oscillations is involved in the pathogenesis of ADHD.

Practitioner Review: Psychological treatments for children and adolescents with conduct disorder problems - a systematic review and meta-analysis.

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 nonpharmacological treatment, participants younger than 18 years, clinical CD problems/diagnosis, randomized controlled trials and inclusion of at least one CD problem-related outcome. Treatment efficacy is expressed in effect sizes (ESs) calculated for each rater (parent, teacher, self and blinded observer). RESULTS: Of 1,549 articles retrieved, 17 (published between June 2004 and January 2014) describing 19 interventions met the inclusion criteria. All studies used psychological treatments; only three studies included a blinded observer to rate CD problems. Most studies were of very poor to fair quality. ESs were significant but small for parent-reported outcomes (0.36, 95% CI = 0.27-0.47), teacher-reported outcomes (0.26, 95% CI = 0.12-0.49) and blinded observer outcomes (0.26, 95% CI = 0.06-0.47), and they were nonsignificant for self-reported outcomes (-0.01, 95% CI = -0.25 to 0.23). Comorbidity, gender, age, number of sessions, duration, intervention type, setting, medication use or dropout percentage did not influence the effect of treatment. CONCLUSIONS: Psychological treatments have a small effect in reducing parent-, teacher- and observer-rated CD problems in children and adolescents with clinical CD problems/diagnosis. There is not enough evidence to support one specific psychological treatment over another. Future studies should investigate the influence of participant characteristics (e.g. age of CD onset), use more homogeneous outcome measures and allow better evaluation of study quality. Many reports failed to provide detailed information to allow optimization of psychological treatment strategies.

Development and psychometric properties of the Suicidality: Treatment Occurring in Paediatrics (STOP) Suicidality Assessment Scale (STOP-SAS) in children and adolescents.

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 parents and clinicians in order to assess suicidality. Based on a literature review, expert panels and focus groups of patients, we developed the items of the STOP Suicidality Assessment Scale (STOP-SAS) in Spanish and English, translated it into four more languages, and optimized it for web-based presentation using the HealthTrackerTM platform. Of the total 19 questions developed for the STOP-SAS, four questions that assess low-level suicidality were identified as screening questions (three of them for use with children, and all four for use with adolescents, parents and clinicians). A total of 395 adolescents, 110 children, 637 parents and 716 clinicians completed the questionnaire using the HealthTrackerTM, allowing us to evaluate the internal consistency and convergent validity of the STOP-SAS with the clinician-rated Columbia Suicide Severity Rating Scale (C-SSRS). Validity was also assessed with the receiver operating characteristic (ROC) area of the STOP-SAS with the C-SSRS. RESULTS: The STOP-SAS comprises 19 items in its adolescent, parent, and clinician versions, and 14 items in its children's version. Good internal consistency was found for adolescents (Cronbach's alpha: 0.965), children (Cronbach's alpha: 0.922), parents (Cronbach's alpha: 0.951) and clinicians (Cronbach's alpha: 0.955) versions. A strong correlation was found between the STOP-SAS and the C-SSRS for adolescents (r:0.670), parents (r:0.548), clinicians (r:0.863) and children (r:0.654). The ROC area was good for clinicians' (0.917), adolescents' (0.834) and parents' (0.756) versions but only fair (0.683) for children's version. CONCLUSIONS: The STOP-SAS is a comprehensive, web-based PROM developed on the HealthTrackerTM platform, and co-designed for use by adolescents, children, parents and clinicians. It allows the evaluation of aspects of suicidality and shows good reliability and validity.

Influence of DAT1 and COMT variants on neural activation during response inhibition in adolescents with attention-deficit/hyperactivity disorder and healthy controls.

BACKGROUND: Impairment of response inhibition has been implicated in attention-deficit/hyperactivity disorder (ADHD). Dopamine neurotransmission has been linked to the behavioural and neural correlates of response inhibition. The current study aimed to investigate the relationship of polymorphisms in two dopamine-related genes, the catechol-O-methyltransferase gene (COMT) and the dopamine transporter gene (SLC6A3 or DAT1), with the neural and behavioural correlates of response inhibition. METHOD: Behavioural and neural measures of response inhibition were obtained in 185 adolescents with ADHD, 111 of their unaffected siblings and 124 healthy controls (mean age 16.9 years). We investigated the association of DAT1 and COMT variants on task performance and whole-brain neural activation during response inhibition in a hypothesis-free manner. Additionally, we attempted to explain variance in previously found ADHD effects on neural activation during response inhibition using these DAT1 and COMT polymorphisms. RESULTS: The whole-brain analyses demonstrated large-scale neural activation changes in the medial and lateral prefrontal, subcortical and parietal regions of the response inhibition network in relation to DAT1 and COMT polymorphisms. Although these neural activation changes were associated with different task performance measures, no relationship was found between DAT1 or COMT variants and ADHD, nor did variants in these genes explain variance in the effects of ADHD on neural activation. CONCLUSIONS: These results suggest that dopamine-related genes play a role in the neurobiology of response inhibition. The limited associations between gene polymorphisms and task performance further indicate the added value of neural measures in linking genetic factors and behavioural measures.

Mental health in Dutch adolescents: a TRAILS report on prevalence, severity, age of onset, continuity and co-morbidity of DSM disorders.

BACKGROUND: With psychopathology rising during adolescence and evidence suggesting that adult mental health burden is often due to disorders beginning in youth, it is important to investigate the epidemiology of adolescent mental disorders. METHOD: We analysed data gathered at ages 11 (baseline) and 19 years from the population-based Dutch TRacking Adolescents' Individual Lives Survey (TRAILS) study. At baseline we administered the Achenbach measures (Child Behavior Checklist, Youth Self-Report) and at age 19 years the World Health Organization's Composite International Diagnostic Interview version 3.0 (CIDI 3.0) to 1584 youths. RESULTS: Lifetime, 12-month and 30-day prevalences of any CIDI-DSM-IV disorder were 45, 31 and 15%, respectively. Half were severe. Anxiety disorders were the most common but the least severe whereas mood and behaviour disorders were less prevalent but more severe. Disorders persisted, mostly by recurrence in mood disorders and chronicity in anxiety disorders. Median onset age varied substantially across disorders. Having one disorder increased subjects' risk of developing another disorder. We found substantial homotypic and heterotypic continuity. Baseline problems predicted the development of diagnosable disorders in adolescence. Non-intact families and low maternal education predicted externalizing disorders. Most morbidity concentrated in 5-10% of the sample, experiencing 34-55% of all severe lifetime disorders. CONCLUSIONS: At late adolescence, 22% of youths have experienced a severe episode and 23% only mild episodes. This psychopathology is rather persistent, mostly due to recurrence, showing both monotypic and heterotypic continuity, with family context affecting particularly externalizing disorders. High problem levels at age 11 years are modest precursors of incident adolescent disorders. The burden of mental illness concentrates in 5-10% of the adolescent population.

Combined stimulant and antipsychotic treatment in adolescents with attention-deficit/hyperactivity disorder: a cross-sectional observational structural MRI study.

Meta-analyses suggest normalizing effects of methylphenidate on structural fronto-striatal abnormalities in patients with attention-deficit/hyperactivity disorder (ADHD). A subgroup of patients receives atypical antipsychotics concurrent with methylphenidate. Long-term safety and efficacy of combined treatment are unknown. The current study provides an initial investigation of structural brain correlates of combined methylphenidate and antipsychotic treatment in patients with ADHD. Structural magnetic resonance imaging was obtained in 31 patients who had received combined methylphenidate and antipsychotic treatment, 31 matched patients who had received methylphenidate but not antipsychotics, and 31 healthy controls (M age 16.7 years). We analyzed between-group effects in total cortical and subcortical volume, and in seven frontal cortical and eight subcortical-limbic volumes of interest, each involved in dopaminergic neurotransmission. Patients in the combined treatment group, but not those in the methylphenidate only group, showed a reduction in total cortical volume compared to healthy controls (Cohen's d = 0.69, p < 0.004), which was apparent in most frontal volumes of interest. Further, the combined treatment group, but not the methylphenidate group, showed volume reduction in bilateral ventral diencephalon (Left Cohen's d = 0.48, p < 0.04; Right Cohen's d = 0.46, p < 0.05) and the left thalamus (Cohen's d = 0.47, p < 0.04). These findings may indicate antipsychotic treatment counteracting the normalizing effects of methylphenidate on brain structure. However, it cannot be ruled out that pre-existing clinical differences between both patient groups may have resulted in anatomical differences at the time of scanning. The absence of an untreated ADHD group hinders unequivocal interpretation and implications of our findings.

[Neural activation and connectivity during response inhibition in adolescents with ADHD]. / Neurale activatie en connectiviteit tijdens responsinhibitie bij adolescenten met ADHD.

BACKGROUND: We studied the neural correlates of response inhibition in a large cohort of adolescents with ADHD, their unaffected siblings and controls. Response inhibition is a key executive function deficit of attentiondeficit/hyperactivity disorder (ADHD). AIM: To obtain new insight into the biological nature of response inhibition deficits in adolescents with ADHD. METHOD: We studied the neural correlates of response inhibition in a large cohort of adolescents with ADHD (n = 185), their siblings unaffected by ADHD (n = 111) and controls (n = 126). We took fmri measurement while the subjects performed the stop-task; this allowed us to investigate neural activation and neural connectivity. RESULTS: Our results indicate that adolescents with ADHD show reduced brain activation and reduced connectivity in their response inhibition network. Our neural measurements correlated with subjects' performance on the stop-task and with the number of ADHD symptoms in the adolescents with ADHD. Unaffected siblings showed similar but less severe neural deviations but no cognitive deficits; unaffected siblings also showed unique patterns of compensatory connectivity. CONCLUSION: These results provide new insights into the biological background of response inhibition and of ADHD. Neural measurements can give us a better understanding of the familial patterns of biological alterations, even if no behavioral deficits could be detected in the unaffected siblings. These neural correlates can also help to explain part of the ADHD phenotype.

[Efficacy of frequency-neurofeedback and Cogmed JM-working memory training in children with ADHD]. / Effectiviteit van frequentieneurofeedback en Cogmed JM-werkgeheugentraining bij kinderen met ADHD.

BACKGROUND: The need for and the interest in non-pharmacological treatments for children with ADHD are increasing. The treatments include electro-encephalogram (EEG) frequency-neurofeedback and Cogmed working memory training. AIM: To investigate the efficacy of frequency-neurofeedback and Cogmed working memory training in children with ADHD. METHOD: Forty-one children with ADHD (aged 8-15 years) were assigned to frequency-neurofeedback or to placebo-neurofeedback in a randomized double-blind trial. We took measurements to find out whether frequency-neurofeedback had reduced the severity of the ADHD-symptoms, and/or had improved neurocognitive ability and global clinical functioning. Fifty-one children with ADHD (aged 5-7 years) were assigned to the active Cogmed JM-working memory training or to the placebo working memory training in a randomised double-blind trial. We took measurements to find out whether Cogmed JM-working memory training had reduced the ADHD symptoms, and/or had improved neurocognitive ability, daily performance and global clinical functioning. RESULTS: The ADHD symptoms and global clinical functioning of the children in both neurofeedback groups improved. However, frequency-neurofeedback did nor produce any significantly better treatment results than did the placebo neurofeedback. At the neurocognitive level, frequency-neurofeedback did not yield any measurements that were significantly superior to those achieved with placebo feedback. Various outcome measurements improved in both groups with memory training. However, the active working memory training was not found to have produced significantly better results than the placebo training with regards to the ADHD symptoms, neurocognitive ability and daily and global functioning. Children from the active working memory training group showed improvements in trained working memory tasks but not on untrained tasks. CONCLUSION: Neither study produced any conclusive evidence for the efficacy of the investigated treatments in children with ADHD. However, both types of treatments can be further improved. Furthermore, the controlled designs may have restricted the embedding of the treatments. Because of possible improvements in the treatments in the future and because of the design restrictions affecting the treatments in their present form, it is still too early to draw any definitive conclusions about the validity and advantages of the two treatment methods.