Publications by authors named "Daniel Brandeis"

217 Publications

Neurotherapeutics for Attention Deficit/Hyperactivity Disorder (ADHD): A Review.

Cells 2021 Aug 21;10(8). Epub 2021 Aug 21.

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

This review focuses on the evidence for neurotherapeutics for attention deficit/hyperactivity disorder (ADHD). EEG-neurofeedback has been tested for about 45 years, with the latest meta-analyses of randomised controlled trials (RCT) showing small/medium effects compared to non-active controls only. Three small studies piloted neurofeedback of frontal activations in ADHD using functional magnetic resonance imaging or near-infrared spectroscopy, finding no superior effects over control conditions. Brain stimulation has been applied to ADHD using mostly repetitive transcranial magnetic and direct current stimulation (rTMS/tDCS). rTMS has shown mostly negative findings on improving cognition or symptoms. Meta-analyses of tDCS studies targeting mostly the dorsolateral prefrontal cortex show small effects on cognitive improvements with only two out of three studies showing clinical improvements. Trigeminal nerve stimulation has been shown to improve ADHD symptoms with medium effect in one RCT. Modern neurotherapeutics are attractive due to their relative safety and potential neuroplastic effects. However, they need to be thoroughly tested for clinical and cognitive efficacy across settings and beyond core symptoms and for their potential for individualised treatment.
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http://dx.doi.org/10.3390/cells10082156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394071PMC
August 2021

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

Psychol Assess 2021 Aug 26. 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
August 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

Early neurophysiological stimulus processing during a performance-monitoring task differentiates women with bipolar disorder from women with ADHD.

Psychiatry Res 2021 Sep 29;303:114088. Epub 2021 Jun 29.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, UK. Electronic address:

Adults with attention-deficit/hyperactivity disorder (ADHD) or bipolar disorder (BD) may display similar cognitive impairments and clinical symptoms, which might reflect shared mechanisms. Initial evidence indicates disorder-specific and overlapping neurophysiological alterations using event-related potentials (ERPs) in individuals with BD or ADHD during attentional tasks, but it is unknown whether impairments generalize across other processes and tasks. We conduct the first comparison between women with ADHD (n = 20), women with BD (n = 20) and control women (n = 20) on ERPs from a performance-monitoring flanker task. The BD group showed a significantly attenuated frontal ERP of conflict monitoring (N2) compared to the ADHD group across both low-conflict (congruent) and high-conflict (incongruent) task conditions, and compared to controls in the high-conflict condition. However, when controlling for an earlier attentional ERP (frontal N1), which was significantly reduced in participants with BD compared to participants with ADHD and controls, N2 group differences were no longer significant. These results indicate that ERP differences in conflict monitoring may be attributable to differences in earlier attentional processes. These findings identify neural differences in early attention between BD and ADHD which precede conflict monitoring processes, potentially pointing to distinct neural mechanisms implicated in the two disorders.
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http://dx.doi.org/10.1016/j.psychres.2021.114088DOI Listing
September 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

The rise and fall of rapid occipito-temporal sensitivity to letters: Transient specialization through elementary school.

Dev Cogn Neurosci 2021 06 11;49:100958. Epub 2021 May 11.

Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland; MR-Center of the Department of Psychiatry, Psychotherapy and Psychosomatics and the Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Switzerland. Electronic address:

Letters, foundational units of alphabetic writing systems, are quintessential to human culture. The ability to read, indispensable to perform in today's society, necessitates a reorganization of visual cortex for fast letter recognition, but the developmental course of this process has not yet been characterized. Here, we show the emergence of visual sensitivity to letters across five electroencephalography measurements from kindergarten and throughout elementary school and relate this development to emerging reading skills. We examined the visual N1, the electrophysiological correlate of ventral occipito-temporal cortex activation in 65 children at varying familial risk for dyslexia. N1 letter sensitivity emerged in first grade, when letter sound knowledge gains were most pronounced and decayed shortly after when letter knowledge is consolidated, showing an inverted U-shaped development. This trajectory can be interpreted within an interactive framework that underscores the influence of top-down predictions. While the N1 amplitudes to letters correlated with letter sound knowledge at the beginning of learning, no association between the early N1 letter response and later reading skills was found. In summary, the current findings provide an important reference point for our neuroscientific understanding of learning trajectories and the process of visual specialization during skill learning.
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http://dx.doi.org/10.1016/j.dcn.2021.100958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141525PMC
June 2021

Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis.

Mol Psychiatry 2021 May 10. Epub 2021 May 10.

Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life sciences & Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK.

The nature and magnitude of placebo and nocebo responses to ADHD medications and the extent to which response to active medications and placebo are inter-correlated is unclear. To assess the magnitude of placebo and nocebo responses to ADHD and their association with active treatment response. We searched literature until June 26, 2019, for published/unpublished double-blind, randomised placebo-controlled trials (RCTs) of ADHD medication. Authors were contacted for additional data. We assessed placebo effects on efficacy and nocebo effects on tolerability using random effects meta-analysis. We assessed the association of study design and patient features with placebo/nocebo response. We analysed 128 RCTs (10,578 children/adolescents and 9175 adults) and found significant and heterogenous placebo effects for all efficacy outcomes, with no publication bias. The placebo effect was greatest for clinician compared with other raters. We found nocebo effects on tolerability outcomes. Efficacy outcomes from most raters showed significant positive correlations between the baseline to endpoint placebo effects and the baseline to endpoint drug effects. Placebo and nocebo effects did not differ among drugs. Baseline severity and type of rating scale influenced the findings. Shared non-specific factors influence response to both placebo and active medication. Although ADHD medications are superior to placebo, and placebo treatment in clinical practice is not feasible, clinicians should attempt to incorporate factors associated with placebo effects into clinical care. Future studies should explore how such effects influence response to medication treatment. Upon publication, data will be available in Mendeley Data: PROSPERO (CRD42019130292).
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http://dx.doi.org/10.1038/s41380-021-01134-wDOI Listing
May 2021

Early Maternal Care and Amygdala Habituation to Emotional Stimuli in Adulthood.

Soc Cogn Affect Neurosci 2021 May 8. Epub 2021 May 8.

Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Baden-Württemberg, 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 versus 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 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
May 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

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

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

J Child Psychol Psychiatry 2021 Mar 22. 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
March 2021

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 17. Epub 2021 Feb 17.

Laboratory of Psychiatric Neuroimaging, Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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http://dx.doi.org/10.1002/hbm.25364DOI Listing
February 2021

Reward and Punishment Sensitivity are Associated with Cross-disorder Traits.

Psychiatry Res 2021 04 8;298:113795. Epub 2021 Feb 8.

Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud University, Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, Nijmegen, The Netherlands.

Reversal learning deficits following reward and punishment processing are observed across disruptive behaviors (DB) and attention-deficit/hyperactivity disorder (ADHD), and have been associated with callous-unemotional (CU) traits. However, it remains unknown to what extent these altered reinforcement sensitivities are linked to the co-occurrence of oppositional traits, ADHD symptoms, and CU traits. Reward and punishment sensitivity and perseverative behavior were therefore derived from a probabilistic reversal learning task to investigate reinforcement sensitivity in participants with DB (n=183, ODD=62, CD=10, combined=57, age-range 8-18), ADHD (n=144, age-range 11-28), and controls (n=191, age-range 8-26). The SNAP-IV and Conners rating scales were used to assess oppositional and ADHD traits. The Inventory of CU traits was used to assess CU traits. Decreased reward sensitivity was associated with ADHD symptom severity (p=0.018) if corrected for oppositional symptoms. ADHD symptomatology interacted with oppositional behavior on perseveration (p=0.019), with the former aggravating the effect of oppositional behavior on perseveration and vice versa. Within a pooled sample, reversal learning alterations were associated with the severity of ADHD symptoms, underpinned by hyposensitivity to reward and increased perseveration. These results show ADHD traits, as opposed to oppositional behavior and CU traits, is associated with decreased reward-based learning in adolescents and adults.
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http://dx.doi.org/10.1016/j.psychres.2021.113795DOI Listing
April 2021

EEG Data Quality: Determinants and Impact in a Multicenter Study of Children, Adolescents, and Adults with Attention-Deficit/Hyperactivity Disorder (ADHD).

Brain Sci 2021 Feb 10;11(2). Epub 2021 Feb 10.

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

Electroencephalography (EEG) represents a widely established method for assessing altered and typically developing brain function. However, systematic studies on EEG data quality, its correlates, and consequences are scarce. To address this research gap, the current study focused on the percentage of artifact-free segments after standard EEG pre-processing as a data quality index. We analyzed participant-related and methodological influences, and validity by replicating landmark EEG effects. Further, effects of data quality on spectral power analyses beyond participant-related characteristics were explored. EEG data from a multicenter ADHD-cohort (age range 6 to 45 years), and a non-ADHD school-age control group were analyzed (n = 305). Resting-state data during eyes open, and eyes closed conditions, and task-related data during a cued Continuous Performance Task (CPT) were collected. After pre-processing, general linear models, and stepwise regression models were fitted to the data. We found that EEG data quality was strongly related to demographic characteristics, but not to methodological factors. We were able to replicate maturational, task, and ADHD effects reported in the EEG literature, establishing a link with EEG-landmark effects. Furthermore, we showed that poor data quality significantly increases spectral power beyond effects of maturation and symptom severity. Taken together, the current results indicate that with a careful design and systematic quality control, informative large-scale multicenter trials characterizing neurophysiological mechanisms in neurodevelopmental disorders across the lifespan are feasible. Nevertheless, results are restricted to the limitations reported. Future work will clarify predictive value.
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http://dx.doi.org/10.3390/brainsci11020214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916500PMC
February 2021

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 11. Epub 2021 Feb 11.

Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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http://dx.doi.org/10.1002/hbm.25320DOI Listing
February 2021

Subgrouping children and adolescents with disruptive behaviors: symptom profiles and the role of callous-unemotional traits.

Eur Child Adolesc Psychiatry 2020 Nov 4. Epub 2020 Nov 4.

Department of Child and Adolescent Psychiatry and Psychology, Clinic Institute of Neurosciences, Hospital Clínic de Barcelona, 2017SGR881, University of Barcelona, CIBERSAM, IDIBAPS, Barcelona, Spain.

Disruptive behavior during childhood and adolescence is heterogeneous and associated with several psychiatric disorders. The identification of more homogeneous subgroups might help identify different underlying pathways and tailor treatment strategies. Children and adolescents (aged 8-18) with disruptive behaviors (N = 121) and healthy controls (N = 100) were included in a European multi-center cognition and brain imaging study. They were assessed via a battery of standardized semi-structured interviews and questionnaires. K-means cluster-model analysis was carried out to identify subgroups within the group with disruptive behaviors, based on clinical symptom profiles, callous-unemotional (CU) traits, and proactive and reactive aggression. The resulting subgroups were then compared to healthy controls with regard to these clinical variables. Three distinct subgroups were found within the group with disruptive behaviors. The High CU Traits subgroup presented elevated scores for CU traits, proactive aggression and conduct disorder (CD) symptoms, as well as a higher proportion of comorbidities (CD + oppositional defiant disorder + attention deficit hyperactivity disorder (ADHD). The ADHD and Affective Dysregulation subgroup showed elevated scores for internalizing and ADHD symptoms, as well as a higher proportion of females. The Low Severity subgroup had relatively low levels of psychopathology and aggressive behavior compared to the other two subgroups. The High CU Traits subgroup displayed more antisocial behaviors than the Low Severity subgroup, but did not differ when compared to the ADHD and Affective Dysregulation subgroup. All three subgroups differed significantly from the healthy controls in all the variables analyzed. The present study extends previous findings on subgrouping children and adolescents with disruptive behaviors using a multidimensional approach and describes levels of anxiety, affective problems, ADHD, proactive aggression and CU traits as key factors that differentiate conclusively between subgroups.
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http://dx.doi.org/10.1007/s00787-020-01662-wDOI Listing
November 2020

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Mol Psychiatry 2020 Oct 14. Epub 2020 Oct 14.

Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience and Maastricht Brain Imaging Center (M-BIC), Maastricht University, Maastricht, The Netherlands.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at p = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10), educational attainment (0.86[0.82; 0.91]; p = 2 × 10), and intelligence (0.72[0.68; 0.76]; p = 9 × 10). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
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http://dx.doi.org/10.1038/s41380-020-00898-xDOI Listing
October 2020

Greater male than female variability in regional brain structure across the lifespan.

Hum Brain Mapp 2020 Oct 12. Epub 2020 Oct 12.

FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
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http://dx.doi.org/10.1002/hbm.25204DOI Listing
October 2020

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

The experience-dependent increase in deep sleep activity is reduced in children with attention-deficit/hyperactivity disorder.

Sleep Med 2020 11 4;75:50-53. Epub 2019 Oct 4.

Child Development Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland; Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, 8032, Zurich, Switzerland. Electronic address:

Objective/background: Learning of a visuomotor adaptation task during wakefulness leads to a local increase in slow-wave activity (SWA, EEG power between 1 and 4.5 Hz) during subsequent deep sleep. Here, we examined this relationship between learning and SWA in children with attention-deficit/hyperactivity disorder (ADHD).

Patients/methods: Participants were 15 children with ADHD (9.7-14.8 y, one female) and 15 age-matched healthy controls (9.6-15.7 y, three female). After the completion of a visuomotor adaptation task in the evening, participants underwent an all-night high-density (HD, 128 electrodes) sleep-EEG measurement.

Results: Healthy control children showed the expected right-parietal increase in sleep SWA after visuomotor learning. Despite no difference in visuomotor learning, the local up-regulation during sleep was significantly reduced in ADHD patients compared to healthy controls.

Conclusions: Our results indicate that the local, experience-dependent regulation of SWA is different in ADHD patients. Because the customarily observed heightened regulation in children was related to sensitive period maturation, ADHD patients may lack certain sensitive periods or show a developmental delay.
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http://dx.doi.org/10.1016/j.sleep.2019.09.018DOI Listing
November 2020

Toward a Dimensional Assessment of Externalizing Disorders in Children: Reliability and Validity of a Semi-Structured Parent Interview.

Front Psychol 2020 24;11:1840. Epub 2020 Jul 24.

School of Child and Adolescent Cognitive Behavior Therapy (AKiP), Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.

Objective: This study assesses the reliability and validity of the DSM-5-based, semi-structured (ILF-EXTERNAL).

Method: Participant data were drawn from the ongoing ESCAschool intervention study. The ILF-EXTERNAL was evaluated in a clinical sample of 474 children and adolescents (aged 6-12 years, 92 females) with symptoms of attention-deficit/hyperactivity disorder (ADHD). To obtain interrater reliability, the one-way random-effects, absolute agreement models of the intraclass correlation (ICC) for single ICC(1,1) and average measurements ICC(1,3) were computed between the interviewers and two independent raters for 45 randomly selected interviews involving ten interviewers. Overall agreement on DSM-5 diagnoses was assessed using Fleiss' kappa. Further analyses evaluated internal consistencies, item-total correlations as well as correlations between symptom severity and the degree of functional impairment. Additionally, parents completed the German version of the (CBCL) and two DSM-5-based parent questionnaires for the assessment of ADHD symptoms and symptoms of disruptive behavior disorders (FBB-ADHS; FBB-SSV), which were used to evaluate convergent and divergent validity.

Results: ICC coefficients demonstrated very good to excellent interrater reliability on the item and scale level of the ILF-EXTERNAL [scale level: ICC(1,1) = 0.83-0.95; ICC(1,3) = 0.94-0.98]. Overall kappa agreement on DSM-5 diagnoses was substantial to almost perfect for most disorders (0.38 ≤ κ ≤ 0.94). With some exceptions, internal consistencies (0.60 ≤ α ≤ 0.86) and item-total correlations (0.21 ≤ ≤ 0.71) were generally satisfactory to good. Furthermore, higher symptom severity was associated with a higher degree of functional impairment. The evaluation of convergent validity revealed positive results regarding clinical judgment and parent ratings (FBB-ADHS; FBB-SSV). Correlations between the ILF-EXTERNAL scales and the CBCL were moderate to high. Finally, the ILF-EXTERNAL scales were significantly more strongly associated with the CBCL than with the , indicating divergent validity.

Conclusion: In clinically referred, school-age children, the ILF-EXTERNAL demonstrates sound psychometric properties. The ILF-EXTERNAL is a promising clinical interview and contributes to high-quality diagnostics of externalizing disorders in children and adolescents.
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http://dx.doi.org/10.3389/fpsyg.2020.01840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396521PMC
July 2020

Aggression subtypes relate to distinct resting state functional connectivity in children and adolescents with disruptive behavior.

Eur Child Adolesc Psychiatry 2021 Aug 13;30(8):1237-1249. Epub 2020 Aug 13.

Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón School of Medicine, IiSGM, CIBERSAM, Universidad Complutense, Madrid, Spain.

There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02-18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala-precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control.
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http://dx.doi.org/10.1007/s00787-020-01601-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310860PMC
August 2021

Specific cortical and subcortical alterations for reactive and proactive aggression in children and adolescents with disruptive behavior.

Neuroimage Clin 2020 11;27:102344. Epub 2020 Jul 11.

Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Department of Cognitive Neuroscience, Nijmegen, the Netherlands; Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands.

Maladaptive aggression, as present in conduct disorder (CD) and, to a lesser extent, oppositional defiant disorder (ODD), has been associated with structural alterations in various brain regions, such as ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), amygdala, insula and ventral striatum. Although aggression can be subdivided into reactive and proactive subtypes, no neuroimaging studies have yet investigated if any structural brain alterations are associated with either of the subtypes specifically. Here we investigated associations between aggression subtypes, CU traits and ADHD symptoms in predefined regions of interest. T1-weighted magnetic resonance images were acquired from 158 children and adolescents with disruptive behavior (ODD/CD) and 96 controls in a multi-center study (aged 8-18). Aggression subtypes were assessed by questionnaires filled in by participants and their parents. Cortical volume and subcortical volumes and shape were determined using Freesurfer and the FMRIB integrated registration and segmentation tool. Associations between volumes and continuous measures of aggression were established using multilevel linear mixed effects models. Proactive aggression was negatively associated with amygdala volume (b = -10.7, p = 0.02), while reactive aggression was negatively associated with insula volume (b = -21.7, p = 0.01). No associations were found with CU traits or ADHD symptomatology. Classical group comparison showed that children and adolescents with disruptive behavior had smaller volumes than controls in (bilateral) vmPFC (p = 0.003) with modest effect size and a reduced shape in the anterior part of the left ventral striatum (p = 0.005). Our study showed negative associations between reactive aggression and volumes in a region involved in threat responsivity and between proactive aggression and a region linked to empathy. This provides evidence for aggression subtype-specific alterations in brain structure which may provide useful insights for clinical practice.
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http://dx.doi.org/10.1016/j.nicl.2020.102344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374596PMC
June 2021

The effects of callous-unemotional traits and aggression subtypes on amygdala activity in response to negative faces.

Psychol Med 2020 Jul 6:1-9. Epub 2020 Jul 6.

Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.

Background: Brain imaging studies have shown altered amygdala activity during emotion processing in children and adolescents with oppositional defiant disorder (ODD) and conduct disorder (CD) compared to typically developing children and adolescents (TD). Here we aimed to assess whether aggression-related subtypes (reactive and proactive aggression) and callous-unemotional (CU) traits predicted variation in amygdala activity and skin conductance (SC) response during emotion processing.

Methods: We included 177 participants (n = 108 cases with disruptive behaviour and/or ODD/CD and n = 69 TD), aged 8-18 years, across nine sites in Europe, as part of the EU Aggressotype and MATRICS projects. All participants performed an emotional face-matching functional magnetic resonance imaging task.

Results: Differences between cases and TD in affective processing, as well as specificity of activation patterns for aggression subtypes and CU traits, were assessed. Simultaneous SC recordings were acquired in a subsample (n = 63). Cases compared to TDs showed higher amygdala activity in response to negative faces (fearful and angry) v. shapes. Subtyping cases according to aggression-related subtypes did not significantly influence on amygdala activity; while stratification based on CU traits was more sensitive and revealed decreased amygdala activity in the high CU group. SC responses were significantly lower in cases and negatively correlated with CU traits, reactive and proactive aggression.

Conclusions: Our results showed differences in amygdala activity and SC responses to emotional faces between cases with ODD/CD and TD, while CU traits moderate both central (amygdala) and peripheral (SC) responses. Our insights regarding subtypes and trait-specific aggression could be used for improved diagnostics and personalized treatment.
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http://dx.doi.org/10.1017/S0033291720002111DOI Listing
July 2020

ADHD: Current Concepts and Treatments in Children and Adolescents.

Neuropediatrics 2020 10 19;51(5):315-335. Epub 2020 Jun 19.

Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry, University of Zurich, Zurich, Switzerland.

Attention deficit hyperactivity disorder (ADHD) is among the most frequent disorders within child and adolescent psychiatry, with a prevalence of over 5%. Nosological systems, such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and the International Classification of Diseases, editions 10 and 11 (ICD-10/11) continue to define ADHD according to behavioral criteria, based on observation and on informant reports. Despite an overwhelming body of research on ADHD over the last 10 to 20 years, valid neurobiological markers or other objective criteria that may lead to unequivocal diagnostic classification are still lacking. On the contrary, the concept of ADHD seems to have become broader and more heterogeneous. Thus, the diagnosis and treatment of ADHD are still challenging for clinicians, necessitating increased reliance on their expertise and experience. The first part of this review presents an overview of the current definitions of the disorder (DSM-5, ICD-10/11). Furthermore, it discusses more controversial aspects of the construct of ADHD, including the dimensional versus categorical approach, alternative ADHD constructs, and aspects pertaining to epidemiology and prevalence. The second part focuses on comorbidities, on the difficulty of distinguishing between "primary" and "secondary" ADHD for purposes of differential diagnosis, and on clinical diagnostic procedures. In the third and most prominent part, an overview of current neurobiological concepts of ADHD is given, including neuropsychological and neurophysiological researches and summaries of current neuroimaging and genetic studies. Finally, treatment options are reviewed, including a discussion of multimodal, pharmacological, and nonpharmacological interventions and their evidence base.
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http://dx.doi.org/10.1055/s-0040-1701658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508636PMC
October 2020

Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups.

Am J Psychiatry 2020 09 16;177(9):834-843. Epub 2020 Jun 16.

The full list of authors in the ENIGMA working groups, author affiliations, author disclosures, and acknowledgments are provided in online supplements.

Objective: Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data.

Methods: Structural T-weighted whole-brain MRI data from healthy control subjects (N=5,827) and from patients with ADHD (N=2,271), ASD (N=1,777), and OCD (N=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. The authors examined subcortical volume, cortical thickness, and cortical surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults, using linear mixed-effects models adjusting for age, sex, and site (and intracranial volume for subcortical and surface area measures).

Results: No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood.

Conclusions: The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.
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http://dx.doi.org/10.1176/appi.ajp.2020.19030331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296070PMC
September 2020

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Hum Brain Mapp 2020 May 18. Epub 2020 May 18.

Division of Psychological & Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technischen Universität Dresden, Dresden, Germany.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
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http://dx.doi.org/10.1002/hbm.25029DOI Listing
May 2020
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