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Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique gaining more attention in neurodevelopmental disorders (NDDs). Due to the phenotypic heterogeneity of NDDs, tDCS is unlikely to be equally effective in all individuals. The present study aimed to establish neuroanatomical markers in typically developing (TD) individuals that may be used for the prediction of individual responses to tDCS. Fifty-seven male and female children received 2â mA anodal and sham tDCS, targeting the left dorsolateral prefrontal cortex (DLPFCleft), right inferior frontal gyrus, and bilateral temporoparietal junction. Response to tDCS was assessed based on task performance differences between anodal and sham tDCS in different neurocognitive tasks (N-back, flanker, Mooney faces detection, attentional emotional recognition task). Measures of cortical thickness (CT) and surface area (SA) were derived from 3 Tesla structural MRI scans. Associations between neuroanatomy and task performance were assessed using general linear models (GLM). Machine learning (ML) algorithms were employed to predict responses to tDCS. Vertex-wise estimates of SA were more closely linked to differences in task performance than measures of CT. Across ML algorithms, highest accuracies were observed for the prediction of N-back task performance differences following stimulation of the DLPFCleft, where 65% of behavioral variance was explained by variability in SA. Lower accuracies were observed for all other tasks and stimulated regions. This suggests that it may be possible to predict individual responses to tDCS for some behavioral measures and target regions. In the future, these models might be extended to predict treatment outcome in individuals with NDDs.
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Imageamento por Ressonância Magnética , Estimulação Transcraniana por Corrente Contínua , Humanos , Masculino , Estimulação Transcraniana por Corrente Contínua/métodos , Feminino , Criança , Adolescente , Cognição/fisiologia , Desempenho Psicomotor/fisiologiaRESUMO
Cooperative action involves the simulation of actions and their co-representation by two or more people. This requires the involvement of two complex brain systems: the mirror neuron system (MNS) and the mentalizing system (MENT), both of critical importance for successful social interaction. However, their internal organization and the potential synergy of both systems during joint actions (JA) are yet to be determined. The aim of this study was to examine the role and interaction of these two fundamental systems-MENT and MNS-during continuous interaction. To this hand, we conducted a multiple-brain connectivity analysis in the source domain during a motor cooperation task using high-density EEG dual-recordings providing relevant insights into the roles of MNS and MENT at the intra- and interbrain levels. In particular, the intra-brain analysis demonstrated the essential function of both systems during JA, as well as the crucial role played by single brain regions of both neural mechanisms during cooperative activities. Specifically, our intra-brain analysis revealed that both neural mechanisms are essential during Joint Action (JA), showing a solid connection between MNS and MENT and a central role of the single brain regions of both mechanisms during cooperative actions. Additionally, our inter-brain study revealed increased inter-subject connections involving the motor system, MENT and MNS. Thus, our findings show a mutual influence between two interacting agents, based on synchronization of MNS and MENT systems. Our results actually encourage more research into the still-largely unknown realm of inter-brain dynamics and contribute to expand the body of knowledge in social neuroscience.
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Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals' adaptive skills naturally improve or remain stable, while others' decrease. To pave the way for 'precision-medicine' approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6-30 years), with two assessment time points separated by ~12-24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful "Increasers", "No-changers", and "Decreasers" in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup's neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences' potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.
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Transtorno do Espectro Autista , Transtorno Autístico , Humanos , Seguimentos , Neuroanatomia , Estudos TransversaisRESUMO
BACKGROUND: Conduct disorder (CD) and oppositional defiant disorder (ODD) both convey a high risk for maladjustment later in life and are understudied in girls. Here, we aimed at confirming the efficacy of START NOW, a cognitive-behavioral, dialectical behavior therapy-oriented skills training program aiming to enhance emotion regulation skills, interpersonal and psychosocial adjustment, adapted for female adolescents with CD or ODD. METHODS: A total of 127 girls were included in this prospective, cluster randomized, multi-center, parallel group, quasi-randomized, controlled phase III trial, which tested the efficacy of START NOW (n = 72) compared with standard care (treatment as usual, TAU, n = 55). All female adolescents had a clinical diagnosis of CD or ODD, were 15.6 (±1.5) years on average (range: 12-20 years), and were institutionalized in youth welfare institutions. The two primary endpoints were the change in number of CD/ODD symptoms between (1) baseline (T1) and post-treatment (T3), and (2) between T1 and 12-week follow-up (T4). RESULTS: Both treatment groups showed reduced CD/ODD symptoms at T3 compared with T1 (95% CI: START NOW = -4.87, -2.49; TAU = -4.94, -2.30). There was no significant mean difference in CD/ODD symptom reduction from T1 to T3 between START NOW and TAU (-0.056; 95% CI = -1.860, 1.749; Hedge's g = -0.011). However, the START NOW group showed greater mean symptom reduction from T1 to T4 (-2.326; 95% CI = -4.274, -0.378; Hedge's g = -0.563). Additionally, secondary endpoint results revealed a reduction in staff reported aggression and parent-reported irritability at post assessment. CONCLUSIONS: Although START NOW did not result in greater symptom reduction from baseline to post-treatment compared with TAU, the START NOW group showed greater symptom reduction from baseline to follow-up with a medium effect size, which indicates a clinically meaningful delayed treatment effect.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno da Conduta , Adolescente , Feminino , Humanos , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/terapia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Cognição , Transtorno da Conduta/terapia , Transtorno da Conduta/psicologia , Transtorno Desafiador Opositor , Estudos Prospectivos , Criança , Adulto JovemRESUMO
Depression is common in attention-deficit/hyperactivity disorder (ADHD), but preventive behavioural interventions are lacking. This randomised controlled, pilot phase-IIa trial aimed to study a physical exercise intervention (EI) and bright light therapy (BLT)-both implemented and monitored in an individual, naturalistic setting via a mobile health (m-health) system-for feasibility of trial design and interventions, and to estimate their effects on depressive symptoms in young people with ADHD. Two hundred seven participants aged 14-45 years were randomised to 10-week add-on intervention of either BLT (10,000 lx; daily 30-min sessions) (n = 70), EI (aerobic and muscle-strengthening activities 3 days/ week) (n = 69), or treatment-as-usual (TAU) (n = 68), of whom 165 (80%) were retained (BLT: n = 54; EI: n = 52; TAU: n = 59). Intervention adherence (i.e. ≥ 80% completed sessions) was very low for both BLT (n = 13, 22%) and EI (n = 4, 7%). Usability of the m-health system to conduct interventions was limited as indicated by objective and subjective data. Safety was high and comparable between groups. Changes in depressive symptoms (assessed via observer-blind ratings, Inventory of Depressive Symptomatology) between baseline and end of intervention were small (BLT: -0.124 [95% CI: -2.219, 1.971], EI: -2.646 [95% CI: -4.777, -0.515], TAU: -1.428 [95% CI: -3.381, 0.526]) with no group differences [F(2,153) = 1.45, p = 0.2384]. These findings suggest that the m-health approach did not achieve feasibility of EI and BLT in young people with ADHD. Prior to designing efficacy studies, strategies how to achieve high intervention adherence should be specifically investigated in this patient group. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03371810, 13 December 2017.
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The S3 Guideline on the Treatment of Language Development Disorders: Summary of Recommendations Abstract: The German S3 Guidelines on the Treatment of Developmental Speech and Language Disorders (AWMF: No. 049-015) were published on the AWMF homepage at the end of 2022. The German Society for Phoniatrics and Paedaudiologie coordinated the work and developed the guideline text together with linguists and speech and language therapists. Many scientific medical societies consented to the respective recommendations. For the first time in the German-speaking area, the guideline group reviewed international research results on the treatment of various speech and language disorders and formulated evidence- or consensus-based recommendations for clinical care. The present article summarizes these recommendations and evaluates the guidelines from the perspective of child and adolescent psychiatry and psychotherapy.
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Transtornos do Desenvolvimento da Linguagem , Humanos , Transtornos do Desenvolvimento da Linguagem/terapia , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Criança , Alemanha , Adolescente , Medicina Baseada em Evidências , Terapia da Linguagem , Fonoterapia , Pré-Escolar , Psicoterapia , Psiquiatria Infantil , Psiquiatria do AdolescenteRESUMO
Social phobia (SP) is a common mental disorder in youth often accompanied by absence from school, which may require daycare or inpatient intervention (DC/IN). Objective: The present explorative study investigates changes in anxiety-specific implicit assumptions and interpretation bias following DC/IN. Methods: The study included 16 youths with SP (M age = 15.8 [SD = 1.24], females: 62.5 %) participating in DC/IN. We assessed the main outcomes using the Implicit Association Test and Affective Misattribution Procedure. Results: A large effect was shown for reducing implicit assumptions of feeling anxious (p = .142; η2p = .171) and for reducing the implicit interpretation bias (p = .137; η2p = .162). No change was indicated by effect size in implicit assumptions of feeling socially rejected (p = .649; η2p = .016). Social phobia symptoms initially correlated with changes in implicit assumptions of feeling anxious (r = .45). Conclusion: Effect sizes indicate that implicit anxiety-specific assumptions and interpretation bias descriptively improved following DC/IN. Thus, DC/IN may lead to meaningful improvements of anxiety-specific cognition in some individuals with high SP symptoms, emphasizing the relevance of cognitive behavioral approaches in the treatment of SP. Several limitations are discussed.
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Fobia Social , Feminino , Adolescente , Humanos , Fobia Social/diagnóstico , Fobia Social/terapia , Fobia Social/psicologia , Absenteísmo , Pacientes Internados , Ansiedade/terapia , Cognição , Instituições AcadêmicasRESUMO
Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.
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Transtorno do Espectro Autista/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Transtorno do Espectro Autista/patologia , Criança , Metilação de DNA/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Epigênese Genética/genética , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Transcriptoma/genéticaRESUMO
Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium's ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.
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Transtorno do Espectro Autista , Encéfalo , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Vias NeuraisRESUMO
The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March-December 2019 and March-December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.
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COVID-19 , Tentativa de Suicídio , Humanos , Tentativa de Suicídio/psicologia , Pandemias , Estudos Longitudinais , COVID-19/epidemiologia , Controle de Doenças TransmissíveisRESUMO
There is increasing evidence that resilience in youth may have a neurobiological basis. However, the existing literature lacks a consistent way of operationalizing resilience, often relying on arbitrary judgments or narrow definitions (e.g., not developing PTSD) to classify individuals as resilient. Therefore, this study used data-driven, continuous resilience scores based on adversity and psychopathology to investigate associations between resilience and brain structure in youth. Structural MRI data from 298 youth aged 9-18 years (Mage = 13.51; 51% female) who participated in the European multisite FemNAT-CD study were preprocessed using SPM12 and analyzed using voxel-based morphometry. Resilience scores were derived by regressing data on adversity exposure against current/lifetime psychopathology and quantifying each individual's distance from the regression line. General linear models tested for associations between resilience and gray matter volume (GMV) and examined whether associations between resilience and GMV differed by sex. Resilience was positively correlated with GMV in the right inferior frontal and medial frontal gyri. Sex-by-resilience interactions were observed in the middle temporal and middle frontal gyri. These findings demonstrate that resilience in youth is associated with volume in brain regions implicated in executive functioning, emotion regulation, and attention. Our results also provide evidence for sex differences in the neurobiology of resilience.
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Resiliência Psicológica , Adolescente , Humanos , Feminino , Masculino , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Córtex Pré-Frontal/patologia , Lobo Frontal/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
Due to modern technological innovations, aggressive behaviors have expanded into the cyberspace, creating a new matter of public concern: cyberbullying. Antisocial and aggressive behaviors, including bullying are characteristic for children and adolescents diagnosed with conduct disorder (CD), raising the question whether these youths are highly involved in cyberbullying experiences, too. 206 participants with CD versus typically developing controls (TDCs) aged 9-19 years (57% girls) were included in the study. Individuals completed several self-report measures investigating cyber- and traditional bullying experiences, and hierarchical multiple regression analyses were conducted to explain the relationship between cyberbullying victimization and perpetration with demographic and clinical variables. Experiences of cyberbullying victimization and perpetration were significantly higher among youth with CD compared to TDCs, and this was accompanied by significantly higher scores on a measure of traditional bullying in CD versus TDCs. CD diagnosis, female sex and higher levels of callous-unemotional (CU) traits were each uniquely associated with increased experiences of cyberbullying victimization, whereas CD diagnosis, higher levels of CU traits and older age were each uniquely associated with increased experiences of cyberbullying perpetration. Individuals with CD, compared to TDCs are at higher risk of becoming cyberbully victims and perpetrators, hence representing an important novel aspect in the assessment and treatment of these youths.
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Transtorno da Conduta , Cyberbullying , Adolescente , Criança , Humanos , Adulto Jovem , Transtorno da Conduta/psicologia , Cyberbullying/psicologia , Masculino , FemininoRESUMO
Interpretation bias and dysfunctional social assumptions are proposed to play a pivotal role in the development and maintenance of social phobia (SP), especially in youth. In this study, we aimed to investigate disorder-specific implicit assumptions of rejection and implicit interpretation bias in youth with severe, chronic SP and healthy controls (CG). Twenty-seven youth with SP in inpatient/day-care treatment (M age = 15.6 years, 74% female) and 24 healthy controls (M age = 15.7 years, 54% female) were included. The Implicit Association Test (IAT) and the Affect Misattribution Procedure (AMP) were completed to assess implicit assumptions and interpretation bias related to the processing of social and affective stimuli. No group differences were observed for the IAT controlling for depressive symptoms in the analyses. However, group differences were found regarding interpretation bias (p = .017, η2p = .137). Correlations between implicit scores and explicit questionnaire results were medium to large in the SP group (r =|.28| to |.54|, pall ≤ .05), but lower in the control group (r =|.04| to |.46|, pall ≤ .05). Our results confirm the finding of an interpretation bias in youth SP, especially regarding the implicit processing of faces, whereas implicit dysfunctional social assumptions of being rejected do not seem to be specific for SP. Future research should investigate the causal relationship of assumptions/interpretation bias and SP.
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Fobia Social , Humanos , Feminino , Adolescente , Masculino , Inquéritos e QuestionáriosRESUMO
Evidence of alterations in emotion processing in maltreated youth has been hypothesized to reflect latent vulnerability for psychopathology. However, previous studies have not systematically examined the influence of psychopathology on the results. Here, we examined emotion recognition and learning in youth who differed in terms of presence vs. absence of maltreatment and psychopathology and tested for potential sex effects. Maltreatment and psychopathology were assessed in 828 youth (514 females) aged 9-18 years using diagnostic interviews and self- and parent-report questionnaires. Emotion recognition was assessed via identification of morphed facial expressions of six universal emotions. For emotion learning, reward and punishment values were assigned to novel stimuli and participants had to learn to correctly respond/withhold response to stimuli to maximize points. A three-way interaction of maltreatment by psychopathology by emotion indicated that when psychopathology was low, maltreated youth were less accurate than non-maltreated youth for happy, fear and disgust. A three-way interaction of sex, maltreatment and emotion indicated that maltreated girls and boys were impaired for fear, but girls showed an impairment for happy, while boys for disgust. There were no effects of maltreatment, psychopathology, or sex on reward learning. However, a two-way interaction between sex and maltreatment showed that maltreated girls were worse at learning from punishment relative to non-maltreated girls, while maltreated boys were better than non-maltreated boys. The study provides the first clear evidence of latent-vulnerability in emotion recognition in maltreated youth and suggests that girls and boys might be characterized by distinct profiles of emotion recognition and learning following maltreatment.
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Maus-Tratos Infantis , Masculino , Criança , Feminino , Adolescente , Humanos , Maus-Tratos Infantis/psicologia , Emoções , Medo , Expressão Facial , PsicopatologiaRESUMO
Conduct disorder (CD) with high levels of callous-unemotional traits (CD/HCU) has been theoretically linked to specific difficulties with fear and sadness recognition, in contrast to CD with low levels of callous-unemotional traits (CD/LCU). However, experimental evidence for this distinction is mixed, and it is unclear whether these difficulties are a reliable marker of CD/HCU compared to CD/LCU. In a large sample (N = 1263, 9-18 years), we combined univariate analyses and machine learning classifiers to investigate whether CD/HCU is associated with disproportionate difficulties with fear and sadness recognition over other emotions, and whether such difficulties are a reliable individual-level marker of CD/HCU. We observed similar emotion recognition abilities in CD/HCU and CD/LCU. The CD/HCU group underperformed relative to typically developing (TD) youths, but difficulties were not specific to fear or sadness. Classifiers did not distinguish between youths with CD/HCU versus CD/LCU (52% accuracy), although youths with CD/HCU and CD/LCU were reliably distinguished from TD youths (64% and 60%, respectively). In the subset of classifiers that performed well for youths with CD/HCU, fear and sadness were the most relevant emotions for distinguishing them from youths with CD/LCU and TD youths, respectively. We conclude that non-specific emotion recognition difficulties are common in CD/HCU, but are not reliable individual-level markers of CD/HCU versus CD/LCU. These findings highlight that a reduced ability to recognise facial expressions of distress should not be assumed to be a core feature of CD/HCU.
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Transtorno da Conduta , Reconhecimento Facial , Adolescente , Humanos , Transtorno da Conduta/diagnóstico , Transtorno da Conduta/psicologia , Emoções , Medo , Reconhecimento PsicológicoRESUMO
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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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Encéfalo , Neuroimagem , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Estudos Multicêntricos como Assunto , NeurociênciasRESUMO
BACKGROUND: Conduct disorder (CD) rarely occurs alone but is typically accompanied by comorbid psychiatric disorders, which complicates the clinical presentation and treatment of affected youths. The aim of this study was to investigate sex differences in comorbidity pattern in CD and to systematically explore the 'gender paradox' and 'delayed-onset pathway' hypotheses of female CD. METHODS: As part of the FemNAT-CD multisite study, semistructured clinical interviews and rating scales were used to perform a comprehensive phenotypic characterization of 454 girls and 295 boys with CD (9-18 years), compared to 864 sex- and age-matched typically developing controls. RESULTS: Girls with CD exhibited higher rates of current major depression, anxiety disorders, post-traumatic stress disorder and borderline personality disorder, whereas boys with CD had higher rates of current attention-deficit/hyperactivity disorder. In line with the 'gender paradox' hypothesis, relative to boys, girls with CD showed significantly more lifetime psychiatric comorbidities (incl. Alcohol Use Disorder), which were accompanied by more severe CD symptoms. Female and male youths with CD also differed significantly in their CD symptom profiles and distribution of age-of-onset subtypes of CD (i.e. fewer girls with childhood-onset CD). In line with the 'delayed-onset pathway' hypothesis, girls with adolescent-onset CD showed similar levels of dimensional psychopathology like boys with childhood-onset CD, while boys with adolescent-onset CD had the lowest levels of internalizing psychopathology. CONCLUSIONS: Within the largest study of CD in girls performed to date, we found compelling evidence for sex differences in comorbidity patterns and clinical presentation of CD. Our findings further support aspects of the 'gender paradox' and 'delayed-onset pathway' hypotheses by showing that girls with CD had higher rates of comorbid lifetime mental disorders and functional impairments, and they usually developed CD during adolescence. These novel data on sex-specific clinical profiles of CD will be critical in informing intervention and prevention programmes.
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Transtorno da Conduta , Fatores Sexuais , Adolescente , Transtornos de Ansiedade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Comorbidade , Transtorno da Conduta/epidemiologia , Depressão/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Feminino , Humanos , Masculino , Transtornos da Personalidade/epidemiologia , Transtornos de Estresse Pós-Traumáticos/epidemiologiaRESUMO
Youth with attention-deficit/hyperactivity disorder (ADHD) are at increased risk to develop co-morbid depression. Identifying factors that contribute to depression risk may allow early intervention and prevention. Poor emotion regulation, which is common in adolescents, is a candidate risk factor. Impaired cognitive emotion regulation is a fundamental characteristic of depression and depression risk in the general population. However, little is known about cognitive emotion regulation in youth with ADHD and its link to depression and depression risk. Using explicit and implicit measures, this study assessed cognitive emotion regulation in youth with ADHD (N = 40) compared to demographically matched healthy controls (N = 40) and determined the association with depressive symptomatology. As explicit measure, we assessed the use of cognitive emotion regulation strategies via self-report. As implicit measure, performance in an ambiguous cue-conditioning task was assessed as indicator of affective bias in the processing of information. Compared to controls, patients reported more frequent use of maladaptive (i.e., self-blame, catastrophizing, and rumination) and less frequent use of adaptive (i.e., positive reappraisal) emotion regulation strategies. This pattern was associated with the severity of current depressive symptoms in patients. In the implicit measure of cognitive bias, there was no significant difference in response of patients and controls and no association with depression. Our findings point to depression-related alterations in the use of cognitive emotion regulation strategies in youth with ADHD. The study suggests those alterations as a candidate risk factor for ADHD-depression comorbidity that may be used for risk assessment and prevention strategies.
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Transtorno do Deficit de Atenção com Hiperatividade , Regulação Emocional , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Cognição , Comorbidade , Depressão/etiologia , Depressão/psicologia , Emoções/fisiologia , HumanosRESUMO
RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.
Assuntos
Transtorno Autístico/genética , Ataxia Cerebelar/genética , Genes Dominantes , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Adolescente , Adulto , Idoso de 80 Anos ou mais , Alelos , Animais , Transtorno Autístico/complicações , Encéfalo/patologia , Ataxia Cerebelar/complicações , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Modelos Animais de Doenças , Feminino , Teste de Complementação Genética , Humanos , Deficiência Intelectual/complicações , Larva/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Síndrome , Peixe-Zebra/genéticaRESUMO
BACKGROUND: Visual exploration in autism spectrum disorder (ASD) is characterized by attenuated social attention. The underlying oculomotor function during visual exploration is understudied, whereas oculomotor function during restricted viewing suggested saccade dysmetria in ASD by altered pontocerebellar motor modulation. METHODS: Oculomotor function was recorded using remote eye tracking in 142 ASD participants and 142 matched neurotypical controls during free viewing of naturalistic videos with and without human content. The sample was heterogenous concerning age (6-30 years), cognitive ability (60-140 IQ), and male/female ratio (3:1). Oculomotor function was defined as saccade, fixation, and pupil-dilation features that were compared between groups in linear mixed models. Oculomotor function was investigated as ASD classifier and features were correlated with clinical measures. RESULTS: We observed decreased saccade duration (∆M = -0.50, CI [-0.21, -0.78]) and amplitude (∆M = -0.42, CI [-0.12, -0.72]), which was independent of human video content. We observed null findings concerning fixation and pupil-dilation features (POWER = .81). Oculomotor function is a valid ASD classifier comparable to social attention concerning discriminative power. Within ASD, saccade features correlated with measures of restricted and repetitive behavior. CONCLUSIONS: We conclude saccade dysmetria as ASD oculomotor phenotype relevant to visual exploration. Decreased saccade amplitude and duration indicate spatially clustered fixations that attenuate visual exploration and emphasize endogenous over exogenous attention. We propose altered pontocerebellar motor modulation as underlying mechanism that contributes to atypical (oculo-)motor coordination and attention function in ASD.