Publications by authors named "Tobias Banaschewski"

502 Publications

The management of ADHD in children and adolescents: bringing evidence to the clinic: perspective from the European ADHD Guidelines Group (EAGG).

Eur Child Adolesc Psychiatry 2021 Oct 22. Epub 2021 Oct 22.

LWL-University Hospital for Child and Adolescent Psychiatry, Ruhr-University Bochum, Hamm, Germany.

ADHD is the most common neurodevelopmental disorder presenting to child and adolescent mental health, paediatric, and primary care services. Timely and effective interventions to address core ADHD symptoms and co-occurring problems are a high priority for healthcare and society more widely. While much research has reported on the benefits and adverse effects of different interventions for ADHD, these individual research reports and the reviews, meta-analyses and guidelines summarizing their findings are sometimes inconsistent and difficult to interpret. We have summarized the current evidence and identified several methodological issues and gaps in the current evidence that we believe are important for clinicians to consider when evaluating the evidence and making treatment decisions. These include understanding potential impact of bias such as inadequate blinding and selection bias on study outcomes; the relative lack of high-quality data comparing different treatments and assessing long-term effectiveness, adverse effects and safety for both pharmacological and non-pharmacological treatments; and the problems associated with observational studies, including those based on large national registries and comparing treatments with each other. We highlight key similarities across current international clinical guidelines and discuss the reasons for divergence where these occur. We discuss the integration of these different perspective into a framework for person/family-centered evidence-based practice approach to care that aims to achieve optimal outcomes that prioritize individual strengths and impairments, as well as the personal treatment targets of children and their families. Finally, we consider how access to care for this common and impairing disorder can be improved in different healthcare systems.
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http://dx.doi.org/10.1007/s00787-021-01871-xDOI Listing
October 2021

Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model.

Front Syst Neurosci 2021 30;15:725413. Epub 2021 Sep 30.

University of Paris, CNRS, INCC, Paris, France.

Adolescence is a period of vulnerability for the maturation of gray matter (GM) and also for the onset of psychiatric disorders such as major depressive disorder (MDD), bipolar disorder and schizophrenia. Chronic neuroinflammation is considered to play a role in the etiology of these illnesses. However, the involvement of neuroinflammation in the observed link between regional GM volume reductions and psychiatric symptoms is not established yet. Here, we investigated a possible common immune-related genetic link between these two phenomena in european adolescents recruited from the community. Hippocampal and medial prefrontal cortex (mPFC) were defined as regions of interest (ROIs). Their GM volumes were extracted in 1,563 14-year-olds from the IMAGEN database. We found a set of 26 SNPs that correlated with the hippocampal volumes and 29 with the mPFC volumes at age 14. We formed two ROI-Related Immune-gene scores (RRI) with the inflammation SNPs that correlated to hippocampal GM volume and to mPFC GM volume. The predictive ability of both RRIs with regards to the presence of psychiatric symptoms at age 18 was investigated by correlating the RRIs with psychometric questionnaires obtained at age 18. The RRIs (but not control scores constructed with random SNPs) correlated with the presence of depressive symptoms, positive psychotic symptoms, and externalizing symptoms in later adolescence. In addition, the effect of childhood maltreatment, one of the major environmental risk factors for depression and other mental disorders, interacted with the RRI effect. We next sought to validate this finding by investigating our set of inflammatory genes in a translational animal model of early life adversity. Mice were subjected to a protocol of maternal separation at an early post-natal age. We evaluated depressive behaviors in separated and non-separated mice at adolescence and their correlations with the concomitant expression of our genes in whole blood samples. We show that in mice, early life adversity affected the expression of our set of genes in peripheral blood, and that levels of expression correlated with symptoms of negative affect in adolescence. Overall, our translational findings in adolescent mice and humans provide a novel validated gene-set of immune-related genes for further research in the early stages of mood disorders.
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http://dx.doi.org/10.3389/fnsys.2021.725413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514661PMC
September 2021

Headache in ADHD as comorbidity and a side effect of medications: a systematic review and meta-analysis.

Psychol Med 2021 Oct 12:1-12. Epub 2021 Oct 12.

Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research; Department of Women's and Children's Health, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.

There is mixed evidence on the association between headache and attention-deficit/hyperactivity disorder (ADHD), as well as headache and ADHD medications. This systematic review and meta-analysis investigated the co-occurrence of headache in children with ADHD, and the effects of ADHD medications on headache. Embase, Medline and PsycInfo were searched for population-based and clinical studies comparing the prevalence of headache in ADHD and controls through January 26, 2021. In addition, we updated the search of a previous systematic review and network meta-analysis of double-blind randomized controlled trials (RCTs) on ADHD medications on June 16, 2020. Trials of amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with a placebo arm and reporting data on headache as an adverse event, were included. Thirteen epidemiological studies and 58 clinical trials were eligible for inclusion. In epidemiological studies, a significant association between headache and ADHD was found [odds ratio (OR) = 2.01, 95% confidence interval (CI) = 1.63-2.46], which remained significant when limited to studies reporting ORs adjusted for possible confounders. The pooled prevalence of headaches in children with ADHD was 26.6%. In RCTs, three ADHD medications were associated with increased headache during treatment periods, compared to placebo: atomoxetine (OR = 1.29, 95% CI = 1.06-1.56), guanfacine (OR = 1.43, 95% CI = 1.12-1.82), and methylphenidate (OR = 1.33, 95% CI = 1.09-1.63). The summarized evidence suggests that headache is common in children with ADHD, both as part of the clinical presentation as such and as a side effect of some standard medications. Monitoring and clinical management strategies of headache in ADHD, in general, and during pharmacological treatment are recommended.
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http://dx.doi.org/10.1017/S0033291721004141DOI Listing
October 2021

Assessing anger and irritability in children: psychometric evaluation and normative data for the German version of the PROMIS® Parent Proxy Anger Scale.

Qual Life Res 2021 Sep 29. Epub 2021 Sep 29.

Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose: Anger and irritability are common and impairing symptoms in children. The PROMIS Anger scales assess self- and parent-reported irritable and angry mood over the past 7 days. The aim of this study was to evaluate the psychometric properties of the German version of the PROMIS Parent Proxy Short Form v1.0-Anger and to provide normative data.

Methods: To evaluate the psychometric properties, data from the study ADOPT Epidemiology were used. In this study, the PROMIS Anger Scale was administered to a population-based sample of n = 8746 parents of children aged 8-12 years. Psychometric analyses were carried out including the investigation of distribution characteristics, factor structure, model fit, internal consistency, and congruent validity. Normative data were calculated as percentile ranks and T-scores.

Results: The PROMIS Anger Scale demonstrated good psychometric properties, including satisfactory distribution characteristics, unidimensionality, good internal consistency as well as congruent validity. German normative data for the PROMIS Anger Scale are presented.

Conclusion: Based on first psychometric analyses, the German version of the PROMIS Anger Scale can be recommended for use in research and practice; however, further investigations using clinical data are needed. The normative data will allow researchers and clinicians an interpretation of the test scores in future applications.
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http://dx.doi.org/10.1007/s11136-021-03001-1DOI Listing
September 2021

Similarity and stability of face network across populations and throughout adolescence and adulthood.

Neuroimage 2021 Sep 21;244:118587. Epub 2021 Sep 21.

Department of Psychology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Departments of Psychiatry and Neuroscience, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Centre hospitalier universitaire Sainte-Justine, University of Montreal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada. Electronic address:

The ability to extract cues from faces is fundamental for social animals, including humans. An individual's profile of functional connectivity across a face network can be shaped by common organizing principles, stable individual traits, and time-varying mental states. In the present study, we used data obtained with functional magnetic resonance imaging in two cohorts, IMAGEN (N = 534) and ALSPAC (N = 465), to investigate - both at group and individual levels - the consistency of the regional profile of functional connectivity across populations (IMAGEN, ALSPAC) and time (Visits 1 to 3 in IMAGEN; age 14 to 22 years). At the group level, we found a robust canonical profile of connectivity both across populations and time. At the individual level, connectivity profiles deviated from the canonical profile, and the magnitude of this deviation related to the presence of psychopathology. These findings suggest that the brain processes faces in a highly stereotypical manner, and that the deviations from this normative pattern may be related to the risk of mental illness.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118587DOI Listing
September 2021

Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder.

Am J Psychiatry 2021 Sep 10:appiajp202120050630. Epub 2021 Sep 10.

Department of Child and Adolescent Psychiatry, University Hospital, Goethe University, Frankfurt am Main, Germany (Ecker, Bletsch, Mann, Schaefer, Yousaf, Chiocchetti, Bast, Freitag).

Objective: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions.

Methods: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features.

Results: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission.

Conclusions: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.
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http://dx.doi.org/10.1176/appi.ajp.2021.20050630DOI Listing
September 2021

Practice Tools for Screening and Monitoring Insomnia in Children and Adolescents with Autism Spectrum Disorder.

J Autism Dev Disord 2021 Aug 31. Epub 2021 Aug 31.

Department of Child and Adolescent Psychiatry & Excellence Centre for Autism and Neurodevelopmental Disorders STRAS&ND, Strasbourg University Hospitals & University of Strasbourg Medical School, 67000, Strasbourg, France.

Between 50-80% of children with autism spectrum disorder (ASD) have insomnia, which adversely affects their mental and physical health. However, there is no consensus to-date on suitable tools for insomnia screening and monitoring in daily clinical practice. An expert panel of child neuropsychiatry and sleep specialists, with expertise in children with neurodevelopmental disabilities, recommends: (1) performing insomnia screening of all children with ASD; (2) considering discussion or referral to a sleep specialist when comorbid sleep disorders are suspected. The panel further developed structured, brief screening and monitoring tools to facilitate insomnia screening and management in daily practice, monitor treatment effectiveness and standardize and compare outcomes across clinical settings to improve care and well-being of children with ASD and their families.
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http://dx.doi.org/10.1007/s10803-021-05236-wDOI Listing
August 2021

Disentangling symptoms of externalizing disorders in children using multiple measures and informants.

Psychol Assess 2021 Nov 26;33(11):1065-1079. Epub 2021 Aug 26.

School of Child and Adolescent Cognitive Behavior Therapy (AKiP).

The trait impulsivity theory suggests that a single, highly heritable externalizing liability factor, expressed as temperamental trait impulsivity, represents the core vulnerability for externalizing disorders. The present study sought to test the application of latent factor models derived from this theory to a clinical sample of children. Participants were 474 German children (age 6-12 years, 81% male) with symptoms of attention-deficit/hyperactivity disorder and externalizing behavior problems participating in an ongoing multicenter intervention study. Using confirmatory factor analyses (CFA) and exploratory structural equation modeling (ESEM), we evaluated several factor models of externalizing spectrum disorders (unidimensional; first-order correlated factors; higher-order factor; fully symmetrical bifactor; bifactor S-1 model). Furthermore, we assessed our prevailing factor models for measurement invariance across raters (clinicians, parents, teachers) and assessment modes (interview, questionnaires). While both CFA and ESEM approaches provided valuable insights into the multidimensionality, ESEM solutions were generally superior since they showed a substantially better model fit and less biased factor loadings. Among the models tested, the bifactor S-1 CFA/ESEM models, with a general hyperactivity-impulsivity reference factor, displayed a statistically sound factor structure and allowed for straightforward interpretability. Furthermore, these models showed the same organization of factors and loading patterns, but not equivalent item thresholds across raters and assessment modes, highlighting cross-situational variability in child behavior. Our findings are consistent with the assumption of the trait impulsivity theory that a common trait, presented as hyperactivity-impulsivity symptoms, underlies all externalizing disorders. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0001053DOI Listing
November 2021

Can neurophysiological markers of anticipation and attention predict ADHD severity and neurofeedback outcomes?

Biol Psychol 2021 Aug 18;165:108169. Epub 2021 Aug 18.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zürich, Zürich, Switzerland; Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Neuroscience Center Zürich, Swiss Federal Institute of Technology and University of Zürich, Zürich, Switzerland.

Neurophysiological measures of preparation and attention are often atypical in ADHD. Still, replicated findings that these measures predict which patients improve after Neurofeedback (NF), reveal neurophysiological specificity, and reflect ADHD-severity are limited.

Methods: We analyzed children's preparatory (CNV) and attentional (Cue-P3) brain activity and behavioral performance during a cued Continuous Performance Task (CPT) before and after slow cortical potential (SCP)-NF or semi-active control treatment (electromyogram biofeedback). Mixed-effects models were performed with 103 participants at baseline and 77 were assessed for pre-post comparisons focusing on clinical outcome prediction, specific neurophysiological effects of NF, and associations with ADHD-severity.

Results: Attentional and preparatory brain activity and performance were non-specifically reduced after treatment. Preparatory activity in the SCP-NF group increased with clinical improvement. Several performance and brain activity measures predicted non-specific treatment outcome.

Conclusion: Specific neurophysiological effects after SCP-NF were limited to increased neural preparation associated with improvement on ADHD-subscales, but several performance and neurophysiological measures of attention predicted treatment outcome and reflected symptom severity in ADHD. The results may help to optimize treatment.
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http://dx.doi.org/10.1016/j.biopsycho.2021.108169DOI Listing
August 2021

[International Consensus Statement for the Screening, Diagnosis, and Treatment of Adolescents with Concurrent Attention-Deficit/Hyperactivity Disorder and Substance Use Disorder].

Z Kinder Jugendpsychiatr Psychother 2021 Aug 16. Epub 2021 Aug 16.

Klinik für Abhängiges Verhalten und Suchtmedizin, Zentralinstitut für seelische Gesundheit, Mannheim, Deutschland.

International Consensus Statement for the Screening, Diagnosis, and Treatment of Adolescents with Concurrent Attention-Deficit/Hyperactivity Disorder and Substance Use Disorder Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance misuse and substance use disorder (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. Research on the effect of treatment of childhood ADHD on the prevention of adolescent SUD is inconclusive, and studies on the diagnosis and treatment of adolescents with ADHD and SUD are scarce. Thus, the available evidence is generally not sufficient to justify robust treatment recommendations. The aim of the study was to obtain a consensus statement based on a combination of scientific data and clinical experience. A modified Delphi study to reach consensus based upon the combination of scientific data and clinical experience with a multidisciplinary group of 55 experts from 17 countries. The experts were asked to rate a set of statements on the effect of treatment of childhood ADHD on adolescent SUD and on the screening, diagnosis, and treatment of adolescents with comorbid ADHD and SUD. After 3 iterative rounds of rating and adapting 37 statements, consensus was reached on 36 of these statements representing 6 domains: general ( = 4), risk of developing SUD ( = 3), screening and diagnosis ( = 7), psychosocial treatment ( = 5), pharmacological treatment ( = 11), and complementary treatments ( = 7). Routine screening is recommended for ADHD in adolescent patients in substance abuse treatment and for SUD in adolescent patients with ADHD in mental healthcare settings. Long-acting stimulants are recommended as the first-line treatment of ADHD in adolescents with concurrent ADHD and SUD, and pharmacotherapy should preferably be embedded in psychosocial treatment. The only remaining no-consensus statement concerned the requirement of abstinence before starting pharmacological treatment in adolescents with ADHD and concurrent SUD. In contrast to the majority, some experts required full abstinence before starting any pharmacological treatment, some were against the use of stimulants in the treatment of these patients (independent of abstinence), while some were against the alternative use of bupropion. This international consensus statement can be used by clinicians and patients together in a shared decision-making process to select the best interventions and to reach optimal outcomes in adolescent patients with concurrent ADHD and SUD.
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http://dx.doi.org/10.1024/1422-4917/a000828DOI Listing
August 2021

Pediatric prolonged-release melatonin for insomnia in children and adolescents with autism spectrum disorders.

Expert Opin Pharmacother 2021 Aug 9:1-10. Epub 2021 Aug 9.

Department of Developmental and Social Psychology, Sapienza University, Rome, Italy.

: Insomnia is common among children and adolescents with Autism spectrum disorder (ASD). The first drug licensed for insomnia in this population, a pediatric-appropriate prolonged-release melatonin (PedPRM) formulation is described.: Literature search on  PedPRM efficacy and safety profile in clinical trials, and a proposed decision-making algorithm to optimize outcome  in the treatment of insomnia in children and adolescents with ASD.: PedPRM treatment effectively improves sleep onset, duration and consolidation, and daytime externalizing behaviors in children and adolescents with ASD and subsequently caregivers' quality of life and satisfaction with their children's sleep. The coated, odorless and taste-free mini-tablets are well-accepted in this population who often have sensory hypersensitivity and problems swallowing standard tablet preparations. The most frequent long-term treatment-related adverse events were fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%) with no evidence of delay in height, BMI, or pubertal development, or withdrawal effects. The starting dose is 2 mg once daily independent of age or weight, escalated to 5-10 mg/day if predefined treatment success criteria are unmet. Slow melatonin metabolizers (~10% of children), may require lower doses. Given its long-term efficacy, safety and acceptance, PedPRM may ameliorate long-term consequences of insomnia in this population.
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http://dx.doi.org/10.1080/14656566.2021.1959549DOI Listing
August 2021

Prediction Along a Developmental Perspective in Psychiatry: How Far Might We Go?

Front Syst Neurosci 2021 6;15:670404. Epub 2021 Jul 6.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Most mental disorders originate in childhood, and once symptoms present, a variety of psychosocial and cognitive maladjustments may arise. Although early childhood problems are generally associated with later mental health impairments and psychopathology, pluripotent transdiagnostic trajectories may manifest. Possible predictors range from behavioral and neurobiological mechanisms, genetic predispositions, environmental and social factors, and psychopathological comorbidity. They may manifest in altered neurodevelopmental trajectories and need to be validated capitalizing on large-scale multi-modal epidemiological longitudinal cohorts. Moreover, clinical and etiological variability between patients with the same disorders represents a major obstacle to develop effective treatments. Hence, in order to achieve stratification of patient samples opening the avenue of adapting and optimizing treatment for the individual, there is a need to integrate data from multi-dimensionally phenotyped clinical cohorts and cross-validate them with epidemiological cohort data. In the present review, we discuss these aspects in the context of externalizing and internalizing disorders summarizing the current state of knowledge, obstacles, and pitfalls. Although a large number of studies have already increased our understanding on neuropsychobiological mechanisms of mental disorders, it became also clear that this knowledge might only be the tip of the Eisberg and that a large proportion still remains unknown. We discuss prediction strategies and how the integration of different factors and methods may provide useful contributions to research and at the same time may inform prevention and intervention.
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http://dx.doi.org/10.3389/fnsys.2021.670404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290854PMC
July 2021

Ambulatory assessment for precision psychiatry: Foundations, current developments and future avenues.

Exp Neurol 2021 Nov 3;345:113807. Epub 2021 Jul 3.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, 68159 Mannheim, Baden-Wuerttemberg, Germany. Electronic address:

Precision psychiatry stands to benefit from the latest digital technologies for assessment and analyses to tailor treatment towards individuals. Insights into dynamic psychological processes as they unfold in humans' everyday life can critically add value in understanding symptomatology and environmental stressors to provide individualized treatment where and when needed. Towards this goal, ambulatory assessment encompasses methodological approaches to investigate behavioral, physiological, and biological processes in humans' everyday life. It combines repeated assessments of symptomatology over time, e.g., via Ecological Momentary Assessment (e.g., smartphone-diaries), with monitoring of physical behavior, environmental characteristics (such as geolocations, social interactions) and physiological function via sensors, e.g., mobile accelerometers, global-positioning-systems, and electrocardiography. In this review, we expand on promises of ambulatory assessment in the investigation of mental states (e.g., real-life, dynamical and contextual perspective), on chances for precision psychiatry such as the prediction of courses of psychiatric disorders, detection of tipping points and critical windows of relapse, and treatment effects as exemplified by ongoing projects, and on future avenues of how ambulatory interventions can benefit personalized care for psychiatric patients (e.g., through real-time feedback in everyday life). Ambulatory assessment is a key contributor to precision psychiatry, opening up promising avenues in research, diagnoses, prevention and treatment.
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http://dx.doi.org/10.1016/j.expneurol.2021.113807DOI Listing
November 2021

Evidence-based pharmacological treatment options for ADHD in children and adolescents.

Pharmacol Ther 2021 Jun 23:107940. Epub 2021 Jun 23.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, causing functional impairment. Its prevalence lies at approximately 5% in children and adolescents and at approximately 2.5% in adults. The disorder follows a multifactorial etiology and shows a high heritability. Patients show a high interindividual and intraindividual variability of symptoms, with executive deficits in several cognitive domains. Overall, ADHD is associated with high rates of psychiatric comorbidities, and insufficient treatment is linked to adverse long-term outcomes. Current clinical guidelines recommend an individualized multimodal treatment approach including psychoeducation, pharmacological interventions, and non-pharmacological interventions. Available medications include stimulants (methylphenidate, amphetamines) and non-stimulants (atomoxetine, guanfacine, clonidine). While available pharmacological treatment options for ADHD show relatively large effect sizes (in short-term trials) and overall good tolerability, there is still a need for improvement of current pharmacotherapeutic strategies and for the development of novel medications. This review summarizes available pharmacological treatment options for ADHD in children and adolescents, identifies current issues in research and evidence gaps, and provides an overview of ongoing efforts to develop new medications for the treatment of ADHD in children and adolescents by means of a systematic cross-sectional analysis of the clinical trials registry www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107940DOI Listing
June 2021

Personalized at-home neurofeedback compared to long-acting methylphenidate in children with ADHD: NEWROFEED, a European randomized noninferiority trial.

J Child Psychol Psychiatry 2021 Jun 24. Epub 2021 Jun 24.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

Background: Neurofeedback is considered a promising intervention for the treatment of attention-deficit hyperactivity disorder (ADHD). NEWROFEED is a prospective, multicentre, randomized (3:2), reference drug-controlled trial in children with ADHD aged between 7 and 13 years. The main objective of NEWROFEED was to demonstrate the noninferiority of personalized at-home neurofeedback (NF) training versus methylphenidate in the treatment of children with ADHD.

Methods: The NF group (n = 111) underwent eight visits and two treatment phases of 16 to 20 at-home sessions with down-training of the theta/beta ratio (TBR) for children with high TBR and enhancing the sensorimotor rhythm (SMR) for the others. The control group (n = 67) received optimally titrated long-acting methylphenidate. The primary endpoint was the change between baseline and endpoint in the Clinician ADHD-RS-IV total score in the per-protocol population (90 NF/59 controls).

Trial Registration: US National Institute of Health, ClinicalTrials.gov #NCT02778360.

Results: Our study failed to demonstrate noninferiority of NF versus methylphenidate (mean between-group difference 8.09 90% CI [8.09; 10.56]). However, both treatment groups showed significant pre-post improvements in core ADHD symptoms and in a broader range of problems. Reduction in the Clinician ADHD-RS-IV total score between baseline and final visit (D90) was 26.7% (SMD = 0.89) in the NF and 46.9% (SMD = 2.03) in the control group. NF effects increased whereas those of methylphenidate were stable between intermediate and final visit.

Conclusions: Based on clinicians' reports, the effects of at-home NF were inferior to those of methylphenidate as a stand-alone treatment.
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http://dx.doi.org/10.1111/jcpp.13462DOI Listing
June 2021

[Treatment of disorders of emotion regulation in the Adolescents Center at the Central Intitute of Mental Health].

Nervenarzt 2021 Jul 17;92(7):670-678. Epub 2021 Jun 17.

Klinik für Psychosomatik und Psychotherapeutische Medizin, Zentralinstitut für Seelische Gesundheit, Medizinische Fakultät Mannheim, Universität Heidelberg, J5, 68159, Mannheim, Deutschland.

Severe disorders of emotion regulation, e.g. in the context of mental illnesses, such as borderline disorders, attention deficit hyperactivity disorder (ADHD) and complex posttraumatic stress disorder (PTSD), often begin in childhood and adolescence and influence the psychosocial development of those affected, often into adulthood. Professional treatment therefore often requires longer term planning, if possible from a single source. The sectorized structure of the current psychiatric healthcare system, however, makes this process more difficult or is even a hindrance and promotes high hospitalization rates and chronification. The concept of the Adolescents Center for Disorders of Emotion Regulation at the Central Institute of Mental Health functions as a model concept for long-term, cross-sectoral treatment structures. A constant treatment team from child, adolescent and adult psychiatry and psychotherapy provides evidence-based psychotherapy according to the guidelines of dialectical behavior therapy (DBT) for those affected between the ages of 16 and 24 years. Conceptually, inpatient, day care and staged outpatient treatment modules complement each other in order to not only provide psychotherapy to the young patients in this important phase of life but also to accompany and support them in completing school and training, in partnership and independent living.
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http://dx.doi.org/10.1007/s00115-021-01152-7DOI Listing
July 2021

Association of Cannabis Use During Adolescence With Neurodevelopment.

JAMA Psychiatry 2021 Jun 16. Epub 2021 Jun 16.

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.

Importance: Animal studies have shown that the adolescent brain is sensitive to disruptions in endocannabinoid signaling, resulting in altered neurodevelopment and lasting behavioral effects. However, few studies have investigated ties between cannabis use and adolescent brain development in humans.

Objective: To examine the degree to which magnetic resonance (MR) imaging-assessed cerebral cortical thickness development is associated with cannabis use in a longitudinal sample of adolescents.

Design, Setting, And Participants: Data were obtained from the community-based IMAGEN cohort study, conducted across 8 European sites. Baseline data used in the present study were acquired from March 1, 2008, to December 31, 2011, and follow-up data were acquired from January 1, 2013, to December 31, 2016. A total of 799 IMAGEN participants were identified who reported being cannabis naive at study baseline and had behavioral and neuroimaging data available at baseline and 5-year follow-up. Statistical analysis was performed from October 1, 2019, to August 31, 2020.

Main Outcomes And Measures: Cannabis use was assessed at baseline and 5-year follow-up with the European School Survey Project on Alcohol and Other Drugs. Anatomical MR images were acquired with a 3-dimensional T1-weighted magnetization prepared gradient echo sequence. Quality-controlled native MR images were processed through the CIVET pipeline, version 2.1.0.

Results: The study evaluated 1598 MR images from 799 participants (450 female participants [56.3%]; mean [SD] age, 14.4 [0.4] years at baseline and 19.0 [0.7] years at follow-up). At 5-year follow-up, cannabis use (from 0 to >40 uses) was negatively associated with thickness in left prefrontal (peak: t785 = -4.87, cluster size = 1558 vertices; P = 1.10 × 10-6, random field theory cluster corrected) and right prefrontal (peak: t785 = -4.27, cluster size = 1551 vertices; P = 2.81 × 10-5, random field theory cluster corrected) cortices. There were no significant associations between lifetime cannabis use at 5-year follow-up and baseline cortical thickness, suggesting that the observed neuroanatomical differences did not precede initiation of cannabis use. Longitudinal analysis revealed that age-related cortical thinning was qualified by cannabis use in a dose-dependent fashion such that greater use, from baseline to follow-up, was associated with increased thinning in left prefrontal (peak: t815.27 = -4.24, cluster size = 3643 vertices; P = 2.28 × 10-8, random field theory cluster corrected) and right prefrontal (peak: t813.30 = -4.71, cluster size = 2675 vertices; P = 3.72 × 10-8, random field theory cluster corrected) cortices. The spatial pattern of cannabis-related thinning was associated with age-related thinning in this sample (r = 0.540; P < .001), and a positron emission tomography-assessed cannabinoid 1 receptor-binding map derived from a separate sample of participants (r = -0.189; P < .001). Analysis revealed that thinning in right prefrontal cortices, from baseline to follow-up, was associated with attentional impulsiveness at follow-up.

Conclusions And Relevance: Results suggest that cannabis use during adolescence is associated with altered neurodevelopment, particularly in cortices rich in cannabinoid 1 receptors and undergoing the greatest age-related thickness change in middle to late adolescence.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.1258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209561PMC
June 2021

Early maternal care and amygdala habituation to emotional stimuli in adulthood.

Soc Cogn Affect Neurosci 2021 09;16(10):1100-1110

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Baden-Württemberg 68159, Germany.

Evidence suggests that maternal care constitutes a protective factor for psychopathology which may be conditional on the level of family adversity. Given that psychopathology is frequently linked with social deficits and the amygdala with social functioning, we investigated the impact of early maternal care on amygdala function under high vs low familial risk for psychopathology. Amygdala activity and habituation during an emotional face-matching paradigm was analyzed in participants of an epidemiological cohort study followed since birth (n = 172, 25 years). Early mother-infant interaction was assessed during a standardized nursing and play setting at the age of 3 months. Information on familial risk during the offspring's childhood and on the participants' lifetime psychopathology was obtained with diagnostic interviews. An interaction between maternal stimulation and familial risk was found on amygdala habituation but not on activation, with higher maternal stimulation predicting stronger amygdala habituation in the familial risk group only. Furthermore, amygdala habituation correlated inversely with Attention Deficit Hyperactivity Disorder (ADHD) diagnoses. The findings underline the long-term importance of early maternal care on the offspring's socioemotional neurodevelopment and of interventions targeting maternal sensitivity early in life, particularly by increasing maternal interactive behavior in those with familial risk.
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http://dx.doi.org/10.1093/scan/nsab059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483279PMC
September 2021

Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts.

Front Psychiatry 2021 20;12:645746. Epub 2021 Apr 20.

Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada.

Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14-18 years old) followed in the IMAGEN study ( = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) ( = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher's exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 ( < 0.05; OR<1). Two SNPs remain significant after correction by false discovery rate (FDR): rs9343525 in (p =0.042, OR = 0.73) and rs507961 in (p = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 () and rs507961 () remained significantly associated with positive AUDIT screens ( < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction ( = 0.006) involving rs484061 (), rs4963307 (), and rs7766029 () predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.
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http://dx.doi.org/10.3389/fpsyt.2021.645746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093566PMC
April 2021

Reward Processing in Novelty Seekers: A Transdiagnostic Psychiatric Imaging Biomarker.

Biol Psychiatry 2021 Oct 30;90(8):529-539. Epub 2021 Jan 30.

Centre for Population Neuroscience and Stratified Medicine, Institute for Science and Technology of Brain-Inspired Intelligence, Fudan University, Shanghai, China.

Background: Dysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues.

Methods: A subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS-associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels.

Results: Multimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%.

Conclusions: Adolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS-associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.
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http://dx.doi.org/10.1016/j.biopsych.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322149PMC
October 2021

Orbitofrontal control of conduct problems? Evidence from healthy adolescents processing negative facial affect.

Eur Child Adolesc Psychiatry 2021 Apr 16. Epub 2021 Apr 16.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159, Mannheim, Germany.

Conduct problems (CP) in patients with disruptive behavior disorders have been linked to impaired prefrontal processing of negative facial affect compared to controls. However, it is unknown whether associations with prefrontal activity during affective face processing hold along the CP dimension in a healthy population sample, and how subcortical processing is affected. We measured functional brain responses during negative affective face processing in 1444 healthy adolescents [M = 14.39 years (SD = 0.40), 51.5% female] from the European IMAGEN multicenter study. To determine the effects of CP, we applied a two-step approach: (a) testing matched subgroups of low versus high CP, extending into the clinical range [N = 182 per group, M = 14.44 years, (SD = 0.41), 47.3% female] using analysis of variance, and (b) considering (non)linear effects along the CP dimension in the full sample and in the high CP group using multiple regression. We observed no significant cortical or subcortical effect of CP group on brain responses to negative facial affect. In the full sample, regression analyses revealed a significant linear increase of left orbitofrontal cortex (OFC) activity with increasing CP up to the clinical range. In the high CP group, a significant inverted u-shaped effect indicated that left OFC responses decreased again in individuals with high CP. Left OFC activity during negative affective processing which is increasing with CP and decreasing in the highest CP range may reflect on the importance of frontal control mechanisms that counteract the consequences of severe CP by facilitating higher social engagement and better evaluation of social content in adolescents.
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http://dx.doi.org/10.1007/s00787-021-01770-1DOI Listing
April 2021

Affective Dysregulation in Children Is Associated With Difficulties in Response Control in Emotional Ambiguous Situations.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Apr 17. Epub 2021 Apr 17.

Department of Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. Electronic address:

Background: Affective dysregulation (AD), or synonymously "irritability," is a transdiagnostic construct that serves as a diagnostic criterion in various childhood mental disorders. It is characterized by severe or persistent outbursts of anger and aggression. Emotional self-regulation is highly dependent on the ability to process relevant and ignore conflicting emotional information. Understanding neurophysiological mechanisms underlying impairment in AD may provide a starting point for research on pharmacological treatment options and evaluation of psychotherapeutic intervention.

Methods: A total of 120 children 8 to 12 years of age (63 with AD and 57 typically developing) were examined using an emotional Stroop task. Signal-decomposed electroencephalographic recordings providing information about the affected sensory-perceptual, response selection, or motor information processing stage were combined with source localization.

Results: Behavioral performance revealed dysfunctional cognitive-emotional conflict monitoring in children with AD, suggesting difficulties in differentiating between conflicting and nonconflicting cognitive-emotional information. This was confirmed by the electroencephalographic data showing that they cannot intensify response selection processes during conflicting cognitive-emotional situations. Typically developing children were able to do so and activated a functional-neuroanatomical network comprising the left inferior parietal cortex (Brodmann area 40), right middle frontal (Brodmann area 10), and right inferior/orbitofrontal (Brodmann area 47) regions. Purely sensory-perceptual selection and motor execution processes were not modulated in AD, as evidenced by Bayesian analyses.

Conclusions: Behavioral and electroencephalogram data suggest that children with AD cannot adequately modulate controlled response selection processes given emotionally ambiguous information. Which neurotransmitter systems underlie these deficits and how they can be improved are important questions for future research.
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http://dx.doi.org/10.1016/j.bpsc.2021.03.014DOI Listing
April 2021

The interaction of child abuse and rs1360780 of the FKBP5 gene is associated with amygdala resting-state functional connectivity in young adults.

Hum Brain Mapp 2021 Jul 5;42(10):3269-3281. Epub 2021 Apr 5.

Department of Psychiatry and Psychotherapy CCM, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Extensive research has demonstrated that rs1360780, a common single nucleotide polymorphism within the FKBP5 gene, interacts with early-life stress in predicting psychopathology. Previous results suggest that carriers of the TT genotype of rs1360780 who were exposed to child abuse show differences in structure and functional activation of emotion-processing brain areas belonging to the salience network. Extending these findings on intermediate phenotypes of psychopathology, we examined if the interaction between rs1360780 and child abuse predicts resting-state functional connectivity (rsFC) between the amygdala and other areas of the salience network. We analyzed data of young European adults from the general population (N = 774; mean age = 18.76 years) who took part in the IMAGEN study. In the absence of main effects of genotype and abuse, a significant interaction effect was observed for rsFC between the right centromedial amygdala and right posterior insula (p < .025, FWE-corrected), which was driven by stronger rsFC in TT allele carriers with a history of abuse. Our results suggest that the TT genotype of rs1360780 may render individuals with a history of abuse more vulnerable to functional changes in communication between brain areas processing emotions and bodily sensations, which could underlie or increase the risk for psychopathology.
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http://dx.doi.org/10.1002/hbm.25433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193540PMC
July 2021

Neuroimaging evidence for structural correlates in adolescents resilient to polysubstance use: A five-year follow-up study.

Eur Neuropsychopharmacol 2021 Aug 24;49:11-22. Epub 2021 Mar 24.

School of Psychology and Global Brain Health Institute, University College Dublin, Dublin, Ireland.

Early initiation of polysubstance use (PSU) is a strong predictor of subsequent addiction, however scarce individuals present resilience capacity. This neuroimaging study aimed to investigate structural correlates associated with cessation or reduction of PSU and determine the extent to which brain structural features accounted for this resilient outcome. Participants from a European community-based cohort self-reported their alcohol, tobacco and cannabis use frequency at ages 14, 16 and 19 and had neuroimaging sessions at ages 14 and 19. We included three groups in the study: the resilient-to-PSU participants showed PSU at 16 and/or 14 but no more at 19 (n = 18), the enduring polysubstance users at 19 displayed PSU continuation from 14 or 16 (n = 193) and the controls were abstinent or low drinking participants (n = 460). We conducted between-group comparisons of grey matter volumes on whole brain using voxel-based morphometry and regional fractional anisotropy using tract-based spatial statistics. Random-forests machine-learning approach generated individual-level PSU-behavior predictions based on personality and neuroimaging features. Adolescents resilient to PSU showed significant larger grey matter volumes in the bilateral cingulate gyrus compared with enduring polysubstance users and controls at ages 19 and 14 (p<0.05 corrected) but no difference in fractional anisotropy. The larger cingulate volumes and personality trait "openness to experience" were the best precursors of resilience to PSU. Early in adolescence, a larger cingulate gyrus differentiated adolescents resilient to PSU, and this feature was critical in predicting this outcome. This study encourages further research into the neurobiological bases of resilience to addictive behaviors.
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http://dx.doi.org/10.1016/j.euroneuro.2021.03.001DOI Listing
August 2021

Sex differences in neural correlates of common psychopathological symptoms in early adolescence.

Psychol Med 2021 Mar 26:1-11. Epub 2021 Mar 26.

Centre for Population Neuroscience and Stratified Medicine (PONS) and Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.

Background: Sex-related differences in psychopathology are known phenomena, with externalizing and internalizing symptoms typically more common in boys and girls, respectively. However, the neural correlates of these sex-by-psychopathology interactions are underinvestigated, particularly in adolescence.

Methods: Participants were 14 years of age and part of the IMAGEN study, a large (N = 1526) community-based sample. To test for sex-by-psychopathology interactions in structural grey matter volume (GMV), we used whole-brain, voxel-wise neuroimaging analyses based on robust non-parametric methods. Psychopathological symptom data were derived from the Strengths and Difficulties Questionnaire (SDQ).

Results: We found a sex-by-hyperactivity/inattention interaction in four brain clusters: right temporoparietal-opercular region (p < 0.01, Cohen's d = -0.24), bilateral anterior and mid-cingulum (p < 0.05, Cohen's d = -0.18), right cerebellum and fusiform (p < 0.05, Cohen's d = -0.20) and left frontal superior and middle gyri (p < 0.05, Cohen's d = -0.26). Higher symptoms of hyperactivity/inattention were associated with lower GMV in all four brain clusters in boys, and with higher GMV in the temporoparietal-opercular and cerebellar-fusiform clusters in girls.

Conclusions: Using a large, sex-balanced and community-based sample, our study lends support to the idea that externalizing symptoms of hyperactivity/inattention may be associated with different neural structures in male and female adolescents. The brain regions we report have been associated with a myriad of important cognitive functions, in particular, attention, cognitive and motor control, and timing, that are potentially relevant to understand the behavioural manifestations of hyperactive and inattentive symptoms. This study highlights the importance of considering sex in our efforts to uncover mechanisms underlying psychopathology during adolescence.
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http://dx.doi.org/10.1017/S0033291720005140DOI Listing
March 2021

Developmental changes in fronto-striatal glutamate and their association with functioning during inhibitory control in autism spectrum disorder and obsessive compulsive disorder.

Neuroimage Clin 2021 10;30:102622. Epub 2021 Mar 10.

Department of Cognitive Neuroscience, Donders Institute of Brain, Cognition and Behaviour, Radboud University Medical Center, the Netherlands; Donders Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, the Netherlands. Electronic address:

Autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) show overlapping symptomatology and deficits in inhibitory control, which are associated with altered functioning and glutamatergic signaling in fronto-striatal circuitry. These parameters have never been examined together. The purpose of the current study was to investigate functioning during inhibitory control and its association with fronto-striatal glutamate concentrations across these disorders using a multi-center, longitudinal approach. Adolescents with ASD (n = 24), OCD (n = 15) and controls (n = 35) underwent two magnetic resonance imaging (MRI) sessions with a one-year interval. This included proton magnetic resonance spectroscopy (H-MRS; n = 74) and functional MRI during an inhibitory control task (n = 53). We investigated H-MRS data and fMRI data separately as well as integrated in a multimodal analysis using linear models focusing on diagnosis and continuous measures of overlapping compulsivity symptoms. ACC glutamate was reduced over time in the ASD group compared with controls, while striatal glutamate decreased over time independent of diagnosis. Increased compulsive behavior seemed to be associated with increased striatal activity during failed inhibitory control. The integrated analyses showed differential involvement of increased striatal glutamate during failed but decreased striatal glutamate during successful inhibitory control in the OCD group compared to controls and ASD, suggesting different underlying mechanisms for OCD compared to ASD.
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http://dx.doi.org/10.1016/j.nicl.2021.102622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022251PMC
July 2021

Predicting Depression Onset in Young People Based on Clinical, Cognitive, Environmental, and Neurobiological Data.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Mar 19. Epub 2021 Mar 19.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: Adolescent onset of depression is associated with long-lasting negative consequences. Identifying adolescents at risk for developing depression would enable the monitoring of risk factors and the development of early intervention strategies. Using machine learning to combine several risk factors from multiple modalities might allow prediction of depression onset at the individual level.

Methods: A subsample of a multisite longitudinal study in adolescents, the IMAGEN study, was used to predict future (subthreshold) major depressive disorder onset in healthy adolescents. Based on 2-year and 5-year follow-up data, participants were grouped into the following: 1) those developing a diagnosis of major depressive disorder or subthreshold major depressive disorder and 2) healthy control subjects. Baseline measurements of 145 variables from different modalities (clinical, cognitive, environmental, and structural magnetic resonance imaging) at age 14 years were used as input to penalized logistic regression (with different levels of penalization) to predict depression onset in a training dataset (n = 407). The features contributing the highest to the prediction were validated in an independent hold-out sample (three independent IMAGEN sites; n = 137).

Results: The area under the receiver operating characteristic curve for predicting depression onset ranged between 0.70 and 0.72 in the training dataset. Baseline severity of depressive symptoms, female sex, neuroticism, stressful life events, and surface area of the supramarginal gyrus contributed most to the predictive model and predicted onset of depression, with an area under the receiver operating characteristic curve between 0.68 and 0.72 in the independent validation sample.

Conclusions: This study showed that depression onset in adolescents can be predicted based on a combination multimodal data of clinical characteristics, life events, personality traits, and brain structure variables.
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http://dx.doi.org/10.1016/j.bpsc.2021.03.005DOI Listing
March 2021

[Cohorts in psychiatric research].

Nervenarzt 2021 03 9;92(3):197-198. Epub 2021 Mar 9.

Sozial- und Präventivmedizin, Department Sport- und Gesundheitswissenschaften, Strukturbereich Kognitionswissenschaften, und Fakultät für Gesundheitswissenschaften Brandenburg, Profilbereich für Versorgungsforschung mit Schwerpunkt eHealth, Universität Potsdam, Potsdam, Deutschland.

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http://dx.doi.org/10.1007/s00115-020-01043-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943493PMC
March 2021

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

J Child Psychol Psychiatry 2021 10 22;62(10):1202-1219. Epub 2021 Mar 22.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.

Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.

Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.

Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing.

Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
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http://dx.doi.org/10.1111/jcpp.13396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455726PMC
October 2021

Differential predictors for alcohol use in adolescents as a function of familial risk.

Transl Psychiatry 2021 03 4;11(1):157. Epub 2021 Mar 4.

Social and Preventive Medicine, Department of Sports and Health Sciences, Intra-faculty unit "Cognitive Sciences", Faculty of Human Science, and Faculty of Health Sciences Brandenburg, Research Area Services Research and e-Health, University of Potsdam, Potsdam, Germany.

Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions.
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http://dx.doi.org/10.1038/s41398-021-01260-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933140PMC
March 2021
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