[Show abstract][Hide abstract] ABSTRACT: Traditionally, adversity was defined as the accumulation of environmental events (allostatic load). Recently however, a mismatch between the early and the later (adult) environment (mismatch) has been hypothesized to be critical for disease-development, a hypothesis that has not yet been tested explicitly in humans.We explored the impact of timing of life adversity (childhood and past year) on anxiety and depression levels (N=833) and brain morphology (N= 129).Both remote (childhood) and proximal (recent) adversities were differentially mirrored in morphometric changes in areas critically involved in emotional processing (i.e. amygdala/hippocampus, dorsal anterior cingulate cortex respectively). The effect of adversity on affect acted in an additive way with no evidence for interactions (mismatch). Structural equation modelling demonstrated a direct effect of adversity on morphometric estimates and anxiety/depression without evidence of brain morphology functioning as a mediator.Our results highlight that adversity manifests as pronounced changes in brain morphometric and affective temperament even though these seem to represent distinct mechanistic pathways. A major goal of future studies should be to define critical time periods for the impact of adversity and strategies for intervening to prevent or reverse the effects of adverse childhood life experiences.
Social Cognitive and Affective Neuroscience 11/2015; DOI:10.1093/scan/nsv137 · 7.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Contactin Associated Protein-like 2 (CNTNAP2) gene has been discussed to be associated with different symptoms of autism spectrum disorders (ASDs) and other neurodevelopmental disorders. We aimed to elucidate the genetic association of CNTNAP2 within high functioning ASD (HFA), focusing on autism specific symptoms and reducing intelligence related factors. Furthermore, we compared our findings conducting a meta-analysis in patients with ASD and HFA only. A case-control association study was performed for HFA (HFA, n = 105; controls, n = 133). Moreover, we performed a family-based association study (DFAM) analysis (HFA, n = 44; siblings, n = 57). Individuals were genotyped for the two most frequently reported single nucleotide polymorphisms (SNPs) in the CNTNAP2 gene (rs2710102, rs7794745). Furthermore, a meta-analysis using the MIX2 software integrated our results with previously published data. A significant association for the carriers of the T-allele of the rs7794745 with HFA was found in the case-control sample [OR = 1.547; (95 % CI 1.056-2.266); p = 0.025]. No association could be found by DFAM with any of the CNTNAP2 SNPs with HFA. The meta-analysis of both SNPs did not show a significant association with either ASD or with HFA. Overall, including case-control, sibs, and meta-analysis, we could not detect any significant association with the CNTNAP2 gene and HFA. Our results point in the direction that CNTNAP2 may not play a major role in HFA, but rather seems to have a significance in neurodevelopmental disorders or in individuals displaying intellectual delays.
Journal of Neural Transmission 11/2015; DOI:10.1007/s00702-015-1458-5 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The neuropeptide S (NPS) system contributes to the pathogenesis of anxiety. The more active T allele of the functional rs324981 variant in the neuropeptide S receptor gene (NPSR1) is associated with panic disorder (PD) and distorted cortico-limbic activity during emotion processing in healthy adults and PD patients. This study investigated the influence of NPSR1 genotype on fronto-limbic effective connectivity within the developing brain. Sixty healthy subjects (8-21 years) were examined using an emotional go-nogo task and fMRI. Fronto-limbic connectivity was determined using Dynamic Causal Modeling. In A allele carriers, connectivity between the right middle frontal gyrus (MFG) and the right amygdala was higher in older (≥14 years) than that in younger (<14 years) probands, whereas TT homozygotes ≥14 years showed a reduction of fronto-limbic connectivity between the MFG and both the amygdala and the insula. Fronto-limbic connectivity varied between NPSR1 genotypes in the developing brain suggesting a risk-increasing effect of the NPSR1T allele for anxiety-related traits via impaired top-down control of limbic structures emerging during adolescence. Provided robust replication in longitudinal studies, these findings may constitute valuable biomarkers for early targeted prevention of anxiety disorders.
[Show abstract][Hide abstract] ABSTRACT: Rational pharmacotherapy is a challenging task in child and adolescent psychiatry. Increasing prescription numbers contrast with the uncertainties of safety and efficacy issues. The lack of clinical (authorization) trials often implies a non- age-specific use of drugs. However, young patients show particular metabolic conditions and a higher vulnerability for adverse drug reactions. Thus it seems mandatory to create age-specific pharmacological data about efficacy and safety of psychotropic drug use in minors. Legislation authorities became aware of this situation and introduced European and national scientific pharmacovigilance regulations and programmes accordingly in order to continuously evaluate the benefit-risk-ratio, detect, collect, minimize, and prevent adverse effects of drugs by appropriate measures, e.g., therapeutic drug monitoring. In this paper the principles and needs of pharmacovigilance in child and adolescent psychiatry are discussed. Furthermore a large multicenter clinical trial («TDM-VIGIL»), funded by the German Federal Institute for Drugs and Medical Devices, is presented, which appeals to collect epidemiological prescription and safety data of psychotropic drugs in children and adolescents using an internet-based data infrastructure (patient registry).
Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie 01/2015; 43(1):21-8. DOI:10.1024/1422-4917/a000329 · 0.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypoarousal as indicated by skin conductance and electroencephalography (EEG) has been discussed as a pathogenetic factor in attention-deficit/hyperactivity disorder (ADHD). The aim of this paper was to review these arousal-related pathogenetic concepts and to present the more recently proposed vigilance regulation model of affective disorders and ADHD. The latter builds on methodological advances in classifying short EEG segments into vigilance stages (Vigilance Algorithm Leipzig, VIGALL), indicating different states of global brain function ("brain arousal"). VIGALL allows the objective assessment of vigilance regulation under defined conditions, e.g. how fast vigilance declines to lower vigilance stages associated with drowsiness during 15-20-min EEG recordings under resting conditions with eyes closed. According to the vigilance regulation model, the hyperactivity and sensation seeking observed in overtired children, ADHD and mania may be interpreted as an autoregulatory attempt to create a stimulating environment in order to stabilize vigilance. The unstable regulation of vigilance observed in both mania and ADHD may thus explain the attention deficits, which become especially prominent in monotonous sustained attention tasks. Among the arguments supporting the vigilance regulation model are the facts that destabilizing vigilance (e.g. via sleep deprivation) can trigger or exacerbate symptoms of ADHD or mania, whereas stabilizing vigilance (e.g. via psychostimulants, reducing sleep deficits) alleviates these symptoms. The potential antimanic effects of methylphenidate are presently being studied in an international randomized controlled trial. We propose vigilance regulation as a converging biomarker, which could be useful for identifying treatment responders to psychostimulants and forming pathophysiologically more homogeneous ADHD subgroups for research purposes.
ADHD Attention Deficit and Hyperactivity Disorders 09/2014; 6(3). DOI:10.1007/s12402-014-0144-z
[Show abstract][Hide abstract] ABSTRACT: Findings from research in animal models and humans have shown a clear role for the neuropeptide oxytocin (OT) on complex social behaviors. This is also true in the context of autism spectrum disorder (ASD). Previous studies on peripheral OT concentrations in children and young adults have reported conflicting results with the initial studies presenting mainly decreased OT plasma levels in ASD compared to healthy controls. Our study therefore aimed to further investigate changes in peripheral OT concentrations as a potential surrogate for the effects observed in the central nervous system (CNS) in ASD. OT plasma concentrations were assessed in 19 male children and adolescents with ASD, all with an IQ > 70 (age 10.7 ± 3.8 years), 17 healthy male children (age 13.6 ± 2.1 years) and 19 young male patients with attention deficit hyperactivity disorder (ADHD) as a clinical control group (age 10.4 ± 1.9 years) using a validated radioimmunoassay. Analysis of covariance revealed significant group differences in OT plasma concentrations (F(2, 48) = 9.574, p
ADHD Attention Deficit and Hyperactivity Disorders 07/2014; 6(3). DOI:10.1007/s12402-014-0145-y
[Show abstract][Hide abstract] ABSTRACT: AIM: We investigated whether objectively measured access to urban green spaces is associated with behavioural problems in 10-year old children living in Munich and its surrounding areas.
METHODS: Behavioural problems were assessed in the GINIplus and LISAplus 10-year follow-up between 2006 and 2009 using the Strengths and Difficulties Questionnaire. Access to green spaces was defined using the distance from a child's residence to the nearest urban green space. Associations between access to urban green spaces and behavioural problems were assessed using proportional odds and logistic regression models in 1932 children with complete exposure, outcome and covariate data.
RESULTS: The distance between a child's residence and the nearest urban green space was positively associated with the odds of hyperactivity/inattention, especially among children with abnormal values compared to children with borderline or normal values (odds ratio (OR)=1.20 (95% confidence interval (CI)=1.01-1.42) per 500m increase in distance). When stratified by sex, this association was only statistically significant among males. Children living further than 500m away from urban green spaces had more overall behavioural problems than those living within 500m of urban green spaces (proportional OR=1.41 (95% CI=1.06-1.87)). Behavioural problems were not associated with the distance to forests or with residential surrounding greenness.
CONCLUSION: Poor access to urban green spaces was associated with behavioural problems in 10-year old children. Results were most consistent with hyperactivity/inattention problems.
Environment International 06/2014; 71C:29-35. DOI:10.1016/j.envint.2014.06.002 · 5.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diagnosing childhood depression can pose a challenge, even for mental health specialists. Screening tools can aid clinicians within the initial step of the diagnostic process. For the first time, the Children׳s Depression Screener (ChilD-S) is validated in a mental health setting as a novel field of application beyond the previously examined pediatric setting. Based on a structured interview, DSM-IV-TR diagnoses of depression were made for 79 psychiatric patients aged 9-12, serving as the gold standard for validation. For assessing criterion validity, receiver operating characteristic (ROC) curves were calculated. Point prevalence of major depression and dysthymia was 28%. Diagnostic accuracy in terms of the area under the ROC curve was high (0.97). At the optimal cut-off point ≥12 according to the Youden׳s index, sensitivity was 0.91 and specificity was 0.81. The findings suggest that the ChilD-S is not only a valid screening instrument for childhood depression in pediatric care but also in mental health settings. As a brief tool it can easily be implemented into daily clinical practice of mental health professionals facilitating the diagnostic process, especially in case of comorbid depression.
[Show abstract][Hide abstract] ABSTRACT: Objective: Despite growing awareness of adult ADHD and its comorbidity with personality disorders (PDs), little is known about sex- and subtype-related differences. Method: In all, 910 patients (452 females, 458 males) affected with persistent adult ADHD were assessed for comorbid PDs with the Structured Clinical Interview of DSM-IV and for personality traits with the revised NEO personality inventory, and the Tridimensional Personality Questionnaire. Results: The most prevalent PDs were narcissistic PD in males and histrionic PD in females. Affected females showed higher Neuroticism, Openness to Experience, and Agreeableness scores as well as Harm Avoidance and Reward Dependence scores. Narcissistic PD and antisocial PD have the highest prevalence in the H-type, while Borderline PD is more frequent in the C-type. Conclusion: Sex- and subtype-related differences in Axis II disorder comorbidity as well as impairment-modifying personality traits have to be taken into account in epidemiological studies of persistent ADHD. (J. of Att. Dis. XXXX; XX(X) XX-XX).
Journal of Attention Disorders 02/2014; DOI:10.1177/1087054714521293 · 3.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Findings from molecular genetic studies and analyses of postmortem and peripheral tissue led to the hypothesis that neurotrophins—as crucial moderators of neuroplasticity—impact on the pathophysiology of autism spectrum disorder (ASD). The study projects aimed to complement former results on the role of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family with fundamental impact on brain development and function. The purpose of this work was to investigate peripheral BDNF mRNA expression and BDNF protein concentrations in ASD as potential surrogates for the effects observed in the central nervous system. In a BDNF protein quantification study, serum concentrations were analyzed using Enzyme-Linked Immunosorbent Assays in 24 male patients with ASD, all with an IQ > 70 (age 13.9 ± 3.0 years) and 20 age- and gender-matched healthy control subjects (age 14.4 ± 2.1 years; p = 0.522). In a further independent project, a BDNF mRNA expression analysis, mRNA levels from total blood were assessed by quantitative real-time polymerase chain reaction in a sample of 16 male ASD patients (age 10.8 ± 2.2), 15 age- and gender-matched healthy controls (age 12.1 ± 2.2) and 15 patients with attention deficit hyperactivity disorder as a clinical control group (age 11.8 ± 2.2; p = 0.207). In the protein quantification project, significantly decreased BDNF serum concentrations were found in ASD cases compared to healthy control children (t = −2.123, df = 42, p
[Show abstract][Hide abstract] ABSTRACT: A deficit in emotion recognition has been suggested to underlie conduct problems. Although several studies have been conducted on this topic so far, most concentrated on male participants. The aim of the current study was to compare recognition of morphed emotional faces in girls with conduct problems (CP) with elevated or low callous-unemotional (CU+ vs. CU-) traits and a matched healthy developing control group (CG). Sixteen girls with CP-CU+, 16 girls with CP-CU- and 32 controls (mean age: 13.23 years, SD = 2.33 years) were included. Video clips with morphed faces were presented in two runs to assess emotion recognition. Multivariate analysis of variance with the factors group and run was performed. Girls with CP-CU- needed more time than the CG to encode sad, fearful, and happy faces and they correctly identified sadness less often. Girls with CP-CU+ outperformed the other groups in the identification of fear. Learning effects throughout runs were the same for all groups except that girls with CP-CU- correctly identified fear less often in the second run compared to the first run. Results need to be replicated with comparable tasks, which might result in subgroup-specific therapeutic recommendations.
[Show abstract][Hide abstract] ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development, has persisted for at least 6 months to a degree that is inconsistent with expected developmental Ievels and that negatively impacts directly on social and academic/occupational activities. Manifestations of the disorder must be present in more than one setting (e.g., home, school, or work). Typically, symptoms vary depending on context within a given setting. According to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition DSM-5 criteria, several inattentive or hyperactive-impulsive symptoms must have been present prior to the age of 12 years.
[Show abstract][Hide abstract] ABSTRACT: Abstract Objectives. This study investigates an overall autonomic hypoactivity reflecting hypoarousal as important aetiological factor in ADHD at baseline during rest and in response towards stimuli. In addition, effects of methylphenidate (MPH) are examined. We further assessed whether this hypoarousal is a stable characteristic or ameliorated by arousing emotional stimuli. Methods. Boys with ADHD were examined with (n = 35) or without MPH (n = 45) and compared with healthy boys (n = 22) regarding skin conductance level (SCL) during rest and skin conductance responses (SCRs) as well as valence and arousal ratings in response to positive, neutral, and negative pictures. Results. ADHD children without MPH were characterized by reduced baseline SCL and overall reduced SCRs. ADHD children with MPH never differed from control children. All groups displayed normal valence and arousal ratings of the stimuli and enhanced SCRs to emotional in comparison to neutral pictures. Conclusions. This is the first study to unravel (1) a general autonomic hypoactivity in ADHD children at baseline and in response to low arousing neutral and highly arousing emotional stimuli, and (2) hints that MPH normalizes this hypoactivity. Results contribute to the understanding of ADHD aetiology and MPH functionality, and are consistent with the cognitive-energetic model of ADHD.
The World Journal of Biological Psychiatry 01/2014; 15(1):56-65. DOI:10.3109/15622975.2013.829584 · 4.18 Impact Factor