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    Christine Freitag

    Background Despite the increasing interest in cardiac autonomic nervous activity, the normal development is not fully understood. The main aim was to determine the maturation of different cardiac sympathetic‐(SNS) and parasympathetic... more
    Background Despite the increasing interest in cardiac autonomic nervous activity, the normal development is not fully understood. The main aim was to determine the maturation of different cardiac sympathetic‐(SNS) and parasympathetic nervous system (PNS) activity parameters in healthy patients aged 0.5 to 20 years. A second aim was to determine potential sex differences. Methods and Results Five studies covering the 0.5‐ to 20‐year age range provided impedance‐ and electrocardiography recordings from which heart rate, different PNS‐parameters (eg, respiratory sinus arrhythmia) and an SNS‐parameter (pre‐ejection period) were collected. Age trends were computed in the mean values across 12 age‐bins and in the age‐specific variances. Age was associated with changes in mean and variance of all parameters. PNS‐activity followed a cubic trend, with an exponential increase from infancy, a plateau phase during middle childhood, followed by a decrease to adolescence. SNS‐activity showed a mo...
    Compassion is a particular form of empathic reaction to harm that befalls others and is accompanied by a desire to alleviate their suffering. This altruistic behavior is often manifested through altruistic punishment, wherein individuals... more
    Compassion is a particular form of empathic reaction to harm that befalls others and is accompanied by a desire to alleviate their suffering. This altruistic behavior is often manifested through altruistic punishment, wherein individuals penalize a deprecated human’s actions, even if they are directed toward strangers. By adopting a dual approach, we provide empirical evidence that compassion is a multifaceted prosocial behavior and can predict altruistic punishment. In particular, in this multiple-brain connectivity study in an EEG hyperscanning setting, compassion was examined during real-time social interactions in a third-party punishment (TPP) experiment. We observed that specific connectivity patterns were linked to behavioral and psychological intra- and interpersonal factors. Thus, our results suggest that an ecological approach based on simultaneous dual-scanning and multiple-brain connectivity is suitable for analyzing complex social phenomena.
    BackgroundLeft-right asymmetry is an important organizing feature of the healthy brain. Various studies have reported altered structural brain asymmetry in autism spectrum disorder (ASD). However, findings have been inconsistent, likely... more
    BackgroundLeft-right asymmetry is an important organizing feature of the healthy brain. Various studies have reported altered structural brain asymmetry in autism spectrum disorder (ASD). However, findings have been inconsistent, likely due to limited sample sizes and low statistical power.MethodsWe investigated 1,774 subjects with ASD and 1,809 controls, from 54 datasets, for differences in the asymmetry of thickness and surface area of 34 cerebral cortical regions. We also examined global hemispheric measures of cortical thickness and area asymmetry, and volumetric asymmetries of subcortical structures. Data were obtained via the ASD Working Group of the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas.ResultsASD was significantly associated with reduced leftward asymmetry of total hemispheric average cortical thickness, compared to controls. Eight r...
    Assessment of selective mutism (SM) is hampered by the lack of diagnostic measures. The Frankfurt Scale of Selective Mutism was developed for kindergarteners, schoolchildren, and adolescents, including the diagnostic scale (DS) and the... more
    Assessment of selective mutism (SM) is hampered by the lack of diagnostic measures. The Frankfurt Scale of Selective Mutism was developed for kindergarteners, schoolchildren, and adolescents, including the diagnostic scale (DS) and the severity scale (SS). The objective of this study was to evaluate this novel, parent-rated questionnaire among individuals aged 3 to 18 years ( n = 334) with SM, social phobia, internalizing disorders, and a control group. Item analysis resulted in high item-total correlations, and internal consistency in both scales was excellent with Cronbach’s α = .90-.98. Exploratory factor analysis of the SS consistently yielded a one-factor solution. Mean sum scores of the DS differed significantly between the diagnostic groups, and the receiver operating characteristic analysis resulted in optimal cutoffs for distinguishing SM from all other groups with the area under the curves of 0.94-1.00. The SS sum scores correlated significantly with SM’s clinician-rated s...
    Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To... more
    Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To investigate whether common variants in ASTN2 contribute to ADHD disorder risk, we tested 63 SNPs spanning ASTN2 for association with ADHD and specific comorbid disorders in two samples: 171 families of children with ADHD and their parents (N = 592), and an adult sample comprising 604 adult ADHD cases and 974 controls. The C-allele of rs12376789 in ASTN2 nominally increased the risk for ADHD in the trio sample (p = 0.025). This was not observed in the adult case-control sample alone, but retained in the combined sample (nominal p = 0.030). Several other SNPs showed nominally significant association with comorbid disorders, especially anxiety disorder, in the childhood and adult ADHD samples. Some ASTN2 variants were nominally associated with personality ...
    The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism... more
    The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR)…
    In recent years, findings from genetic and other biological studies are starting to reveal the role of various molecular mechanisms that contribute to the etiology of ASD [...]
    Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in early childhood [...]
    Additional file 2. Model consent form.
    Results from DESeq2 analysis and count data from RNA-Seq (MACE analysis). (XLSX 5308 kb)
    Supplementary methods, supplementary results, supplementary table S1, supplementary figures S1-S6. (DOCX 555 kb)
    SPIRIT Checklist. (DOC 122 kb)
    This article is accompanied by an online supplement containing additional information regarding the analysis. (PDF 376 kb)
    Autism spectrum disorders (ASDs) are phenotypically as well as genetically heterogeneous developmental disorders with a strong heritability. Clinical and basic science research has described many replicated genetic risk factors. Many... more
    Autism spectrum disorders (ASDs) are phenotypically as well as genetically heterogeneous developmental disorders with a strong heritability. Clinical and basic science research has described many replicated genetic risk factors. Many findings can well be translated into clinical human genetic practice. The current article summarizes results of genetic studies in ASD, provides a diagnostic algorithm for the clinical human genetic work-up reflecting the German health care system options and gives information with regard to the obligatory genetic counselling after a clinical genetic assessment.
    Zusammenfassung. Sprach- und Sprechstörungen kommen bei zahlreichen Kindern vor und werden in der ICD-11 analog zur ICD-10 als Entwicklungsstörungen im Kapitel 6 (Psychische, Verhaltens- und Entwicklungsstörungen) klassifiziert.... more
    Zusammenfassung. Sprach- und Sprechstörungen kommen bei zahlreichen Kindern vor und werden in der ICD-11 analog zur ICD-10 als Entwicklungsstörungen im Kapitel 6 (Psychische, Verhaltens- und Entwicklungsstörungen) klassifiziert. International sind bislang die ICD-10-Kriterien nicht von allen Professionen, die sich mit Sprach- und Sprechstörungen klinisch oder im Rahmen der Forschung beschäftigen, akzeptiert. Sie werden einerseits als zu wenig differenziert hinsichtlich der unterschiedlichen Sprachkomponenten vonseiten der Linguistik, Sprachtherapie oder Logopädie erlebt. Zum anderen wird die unklare Abgrenzung organisch bedingter Sprach- und Sprechprobleme von der Sprachentwicklungsstörung vonseiten der Medizin teilweise kritisch bewertet. In dem vorliegenden Artikel wird deshalb einerseits die Klassifikation von Sprach- und Sprechproblemen und -störungen in der ICD-11 im Vergleich zur ICD-10 vorgenommen. Wesentlich erscheint hier die in der ICD-11 neu eingeführte Differenzierung in...
    Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A2A receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product,... more
    Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A2A receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A2A receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expr...
    Zusammenfassung. Die Ätiologie der Autismus-Spektrum-Störungen (ASS) ist in genetischen Risikofaktoren sowie der Interaktion von genetischen und biologisch wirksamen Umweltrisikofaktoren begründet. ASS werden aufgrund von... more
    Zusammenfassung. Die Ätiologie der Autismus-Spektrum-Störungen (ASS) ist in genetischen Risikofaktoren sowie der Interaktion von genetischen und biologisch wirksamen Umweltrisikofaktoren begründet. ASS werden aufgrund von Verhaltensmerkmalen, nämlich bleibend eingeschränkter sozialer Kommunikation, sowie durch stereotypes Verhalten, sensorische und Sonderinteressen diagnostiziert. Hinsichtlich des genetischen Hintergrundes besteht eine hohe genetische Heterogenität, d. h., die genetischen Ursachen sind vielfältig und individuell oft sehr unterschiedlich ausgeprägt. Allerdings konvergieren diese Ursachen in bestimmten biologischen Mechanismen und überlappenden biologischen Endstrecken, deren Veränderung sehr wahrscheinlich den autismusspezifischen Verhaltensmerkmalen zugrunde liegt. Die vorliegende, selektive Literaturübersicht summiert die genetischen Befunde und fokusiert sich insbesondere auf Mechanismen und Endstrecken, die aufgrund der neueren Forschung immer besser charakterisi...
    Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher... more
    Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. We analyzed genome-wide common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish population-registry data (N=77,905 cases, N=1,874,637 population controls). We find strong genetic correlation for ADHD across sex and no mean difference in polygenic burden across sex. In contrast, siblings of female probands are at an increased risk of ADHD, compared to siblings of male probands. The results also suggest that females with ADHD are at especially high risk of comorbid developmental conditions. Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity. However, autosomal common variants ...
    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... more
    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 we...
    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... more
    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 (ntotal = 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...
    The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a... more
    The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Ge...
    Zusammenfassung. Der vorliegende systematische Überblicksartikel basiert auf Vorarbeiten im Rahmen der Erstellung der AWMF-S3-Leitlinien zur Therapie von Autismus-Spektrum-Störungen (ASS). Das Ziel ist, den aktuellen Stand... more
    Zusammenfassung. Der vorliegende systematische Überblicksartikel basiert auf Vorarbeiten im Rahmen der Erstellung der AWMF-S3-Leitlinien zur Therapie von Autismus-Spektrum-Störungen (ASS). Das Ziel ist, den aktuellen Stand evidenzbasierter Interventionen zur Behandlung der Kernsymptomatik sowie sprachlichen Förderung im Kleinkind- und Vorschulalter für Kinder mit ASS darzustellen. Einschlusskriterien: entwicklungsorientierte oder verhaltenstherapeutisch basierte, manualisierte Intervention für Kinder mit ASS nach DSM-III (R), DSM-IV (TR), DSM-5 oder ICD-10, Alter < 7 Jahre, Publikationsdatum 1.1.2011 bis 31.8.2018. Iterativ-hierarchischer Prozess für den Studieneinschluss: systematisches Review > randomisiert kontrollierte > kontrollierte klinische Studie. Zielgrößen der eingeschlossenen Studien: zentrale autismusspezifische Symptomatik oder entwicklungspsychologisch belegte Vorläuferfertigkeiten oder Verbesserung der sprachlichen Fertigkeiten. Die Interventionen wurden (1)...
    Background Naturalistic developmental behavioural interventions (NDBI) have been shown to improve autism-specific symptoms in young children with Autism Spectrum Disorder (ASD). NDBI approaches, such as the ASD-specific Frankfurt Early... more
    Background Naturalistic developmental behavioural interventions (NDBI) have been shown to improve autism-specific symptoms in young children with Autism Spectrum Disorder (ASD). NDBI approaches, such as the ASD-specific Frankfurt Early Intervention Programme for ASD (A-FFIP), are based on ASD-specific developmental and learning aspects. A-FFIP is a low-intensity intervention which can easily be implemented in the local health care/social welfare system. The aim of the present study is to establish 1-year efficacy of the manualised early intervention programme A-FFIP in toddlers and preschool children with ASD. It is hypothesised that A-FFIP will result in improved ASD-specific symptoms compared to early intervention as usual (EIAU). Child- and family-specific secondary outcomes, as well as moderators and mediators of outcome, will be explored. Methods/design A prospective, multi-centre, parallel-group, randomised controlled, phase-III trial comparing A-FFIP versus EIAU. A total of 1...
    Traits of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are strongly associated in children and adolescents, largely due to genetic factors. Less is known about the phenotypic and aetiological overlap... more
    Traits of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are strongly associated in children and adolescents, largely due to genetic factors. Less is known about the phenotypic and aetiological overlap between ADHD and ASD traits in adults. We studied 6866 individuals aged 20-28 years from the Swedish Study of Young Adult Twins. Inattention (IA) and hyperactivity/impulsivity (HI) were assessed using the WHO Adult ADHD Self-Report Scale-V1.1. Repetitive and restricted behaviours (RRB) and social interaction and communication (SIC) were assessed using the Autism-Tics, ADHD, and other Comorbidities inventory. We used structural equation modelling to decompose covariance between these ADHD and ASD trait dimensions into genetic and shared/non-shared environmental components. At the phenotypic level, IA was similarly correlated with RRB (r = 0.33; 95% Confidence Interval (CI) 0.31-0.36) and with SIC (r = 0.32; 95% CI 0.29-0.34), whereas HI was more stro...
    The diagnostics of autism spectrum disorder in children, adolescents and adults: Overview of the key questions and main results of the first part of the German AWMF-S3-clinical guideline Abstract. Autism spectrum disorders (ASD) include... more
    The diagnostics of autism spectrum disorder in children, adolescents and adults: Overview of the key questions and main results of the first part of the German AWMF-S3-clinical guideline Abstract. Autism spectrum disorders (ASD) include ICD-10 diagnoses of childhood autism, Asperger syndrome, and atypical autism; there is a lifetime prevalence of ~1 %. The aim of the evidence-based clinical guideline (AWMF-S3-Guideline) is to summarize the current evidence concerning diagnostic and therapeutic processes for professionals working in healthcare and social welfare and to provide consensus on clinical recommendations. The present study summarizes the most important results of the diagnostic part of this guideline. The guideline group comprised 14 clinical and scientific expert associations from the German healthcare system, in addition to representatives of relatives and patients. Recommendations were based on results of a systematic literature search, data extraction, the evaluation of study quality, and, if possible, meta-analytic aggregation of included data in combination with the clinical expertise of the respective representatives. Consensus-based recommendations were determined via nominal group technique. The AWMF-S3-Clinical Guideline, Diagnostic Part, summarizes current research on this topic. The main focus is put on the question of obligatory versus redundant diagnostic procedures. After a general introduction to the clinical picture of ASD, essential aspects like obtaining the medical history, the effective use of screening and diagnostic instruments, medical examination, the full diagnostic work-up as well as communicating the diagnostic results to relatives and patients are described in detail. We also conducted a meta-analysis on the stability of early diagnosis. This first part of the ASD guideline offers users the opportunity to inform themselves about the background of ASD as well as evidence-based and broadly consented information on the correct diagnostic process of ASD from infancy to adulthood.
    We examined predictors and moderators of treatment outcome in mothers and children diagnosed with ADHD in a large multicentre RCT. In total, 144 mother-child dyads with ADHD were randomly assigned to either a maternal ADHD treatment... more
    We examined predictors and moderators of treatment outcome in mothers and children diagnosed with ADHD in a large multicentre RCT. In total, 144 mother-child dyads with ADHD were randomly assigned to either a maternal ADHD treatment (group psychotherapy and open methylphenidate medication, TG) or to a control treatment (individual counselling without psycho- or pharmacotherapy, CG). After maternal ADHD treatment, parent-child training (PCT) for all mother-child dyads was added. The final analysis set was based on 123 dyads with completed primary outcome assessments (TG: n = 67, CG: n = 56). The primary outcome was the change in each child's externalizing symptoms. Multiple linear regression analyses were performed. The severity of the child's externalizing problem behaviour in the family at baseline predicted more externalizing symptoms in the child after PCT, independent of maternal treatment. When mothers had a comorbid depression, TG children showed more externalizing sym...
    Conduct disorder (CD) is a common and highly impairing psychiatric disorder of childhood and adolescence that frequently leads to poor physical and mental health outcomes in adulthood. The prevalence of CD is substantially higher in males... more
    Conduct disorder (CD) is a common and highly impairing psychiatric disorder of childhood and adolescence that frequently leads to poor physical and mental health outcomes in adulthood. The prevalence of CD is substantially higher in males than females, and partly due to this, most research on this condition has used all-male or predominantly male samples. Although the number of females exhibiting CD has increased in recent decades, the majority of studies on neurobiological measures, neurocognitive phenotypes, and treatments for CD have focused on male subjects only, despite strong evidence for sex differences in the aetiology and neurobiology of CD. Here, we selectively review the existing literature on CD and related phenotypes in females, focusing in particular on sex differences in CD symptoms, patterns of psychiatric comorbidity, and callous-unemotional personality traits. We also consider studies investigating the neurobiology of CD in females, with a focus on studies using ge...
    Multimodal treatment of children with ADHD often includes parent-child training (PCT). However, due to the high heritability, parents of children with ADHD are frequently also affected by the disorder, which is likely to constitute a... more
    Multimodal treatment of children with ADHD often includes parent-child training (PCT). However, due to the high heritability, parents of children with ADHD are frequently also affected by the disorder, which is likely to constitute a significant barrier to successful treatment of the child. This secondary analysis of our randomized controlled multicentre AIMAC trial (ADHD in mothers and children) investigates whether children's outcomes following parent-child training in combination with maternal ADHD treatment depend on maternal symptom improvement. In a first step focusing on treatment of maternal ADHD, 144 mothers of mother-child dyads were randomized to multimodal ADHD treatment (group psychotherapy plus methylphenidate) or clinical management (mainly supportive counselling). After 12 weeks (T2), a 12-week PCT program (T2-T3) for all mother-child dyads was added to treat children's ADHD. Maternal symptomatology (CAARS-O:L; SCL-90-R) and children's externalizing sympt...

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