Publications by authors named "Tobias J Renner"

42 Publications

How Do Children with Autism Spectrum Disorder Form Gist Memory During Sleep? - A Study of Slow Oscillation-Spindle Coupling.

Sleep 2020 Dec 26. Epub 2020 Dec 26.

Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Germany.

Sleep is assumed to support memory through an active systems consolidation process that does not only strengthen newly encoded representations but also facilitates the formation of more abstract gist memories. Studies in humans and rodents indicate a key role of the precise temporal coupling of sleep slow oscillations (SO) and spindles in this process. The present study aimed at bolstering these findings in typically developing (TD) children, and at dissecting particularities in SO-spindle coupling underlying signs of enhanced gist memory formation during sleep found in a foregoing study in children with autism spectrum disorder (ASD) without intellectual impairment. Sleep data from 19 boys with ASD and 20 TD boys (9-12 years) were analyzed. Children performed a picture-recognition task and the Deese-Roediger-McDermott (DRM) task before nocturnal sleep (encoding) and in the next morning (retrieval). Sleep-dependent benefits for visual-recognition memory were comparable between groups but were greater for gist abstraction (recall of DRM critical lure words) in ASD than TD children. Both groups showed a closely comparable SO-spindle coupling, with fast spindle activity nesting in SO-upstates, suggesting that a key mechanism of memory processing during sleep is fully functioning already at childhood. Picture-recognition at retrieval after sleep was positively correlated to frontocortical SO-fast-spindle coupling in TD children, and less in ASD children. Critical lure recall did not correlate with SO-spindle coupling in TD children but showed a negative correlation (r=-.64, p=.003) with parietal SO-fast-spindle coupling in ASD children, suggesting other mechanisms specifically conveying gist abstraction, that may even compete with SO-spindle coupling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsaa290DOI Listing
December 2020

Times are changing: digitalisation in child and adolescent psychotherapy.

Eur Child Adolesc Psychiatry 2020 Jul 31. Epub 2020 Jul 31.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Psychiatry and Psychotherapy Tübingen, Center of Mental Health Tübingen, Osianderstraße 14, 72074, Tübingen, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00787-020-01610-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393619PMC
July 2020

Age dependency of body mass index distribution in childhood and adolescent inpatients with anorexia nervosa with a focus on DSM-5 and ICD-11 weight criteria and severity specifiers.

Eur Child Adolesc Psychiatry 2020 Jul 14. Epub 2020 Jul 14.

Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatics, University Hospital Essen (AöR), University of Duisburg-Essen, Wickenburgstrasse 21, 45147, Essen, Germany.

Both DSM-5 and ICD-11 have provided weight cut-offs and severity specifiers for the diagnosis of anorexia nervosa (AN) in childhood, adolescence and adulthood. The aims of the current study focusing on inpatients aged < 19 years were to assess (1) the relationship between age and body mass index (BMI; kg/m), BMI-centiles, BMI-standard deviation scores (BMI-SDS) and body height-SDS at referral, (2) the percentages of patients fulfilling the DSM-5 and ICD-11 weight criteria and severity categories for AN, and (3) the validity of the AN severity specifiers via analysis of both weight related data at discharge and inpatient treatment duration. The German Registry for Anorexia Nervosa encompassed complete data sets for 469 female patients (mean age = 15.2 years; range 8.9-18.9 years) with a diagnosis of AN (n = 404) or atypical AN (n = 65), who were ascertained at 16 German child and adolescent psychiatric hospitals. BMI at referral increased up to age 15 to subsequently plateau. Approximately one tenth of all patients with AN had a BMI above the fifth centile. The ICD-11 specifier based on a BMI-centile of 0.3 for childhood and adolescent AN entailed two equally sized groups of patients. Discharge data revealed limited validity of the specifiers. Height-SDS was not correlated with age thus stunting had no impact on our data. We corroborate the evidence to use the tenth instead of the fifth BMI-centile as the weight criterion in children and adolescents. Weight criteria should not entail major diagnostic shifts during the transition from adolescence to adulthood. The severity specifiers based on BMI or BMI-centiles do not seem to have substantial clinical validity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00787-020-01595-4DOI Listing
July 2020

Attention allocation to illness-compatible information discriminates women with active versus weight-recovered anorexia nervosa.

Int J Eat Disord 2020 08 16;53(8):1270-1279. Epub 2019 Dec 16.

Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital Tübingen, Tübingen, Germany.

Objective: Biased attention for disorder-relevant information plays a crucial role in the maintenance of different mental disorders including eating disorders and might be of use to define recovery beyond symptom-related criteria.

Method: We assessed attention deployment using eye tracking in a cued choice viewing paradigm to two different categories of disorder-relevant stimuli in 24 individuals with acute anorexia nervosa (AN), 20 weight-recovered individuals with a history of AN (WRAN) and 23 healthy control participants (CG). Picture pairs consisted of a food stimulus or a picture depicting physical activity and a matched control stimulus (household item/physical inactivity). Participants rated the valence of stimuli afterwards.

Results: The groups did not differ in initial attention deployment. In later processing stages, AN patients showed a generalized attentional avoidance of food and control pictures as compared to CG, while WRAN individuals were in between. AN patients showed an attentional bias toward physical activity pictures as compared to WRAN individuals, but not the CG. AN individuals rated the food pictures and the pictures showing physical inactivity as less pleasant than the CG, while WRAN individuals were in between.

Discussion: Attention deployment is partly changed in WRAN as compared to the acute AN group, especially with regard to a shift away from illness-compatible stimuli (physical activity), and this might be a useful recovery criterion. Valence rating of food stimuli might be an additional useful tool to distinguish between acutely ill and weight-recovered individuals. Attentional biases for illness-compatible stimuli might qualify as a valuable approach to defining recovery in AN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eat.23209DOI Listing
August 2020

Clinical Characteristics of Inpatients with Childhood vs. Adolescent Anorexia Nervosa.

Nutrients 2019 Oct 28;11(11). Epub 2019 Oct 28.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, RWTH Aachen, 52074 Aachen, Germany.

We aimed to compare the clinical data at first presentation to inpatient treatment of children (<14 years) vs. adolescents (≥14 years) with anorexia nervosa (AN), focusing on duration of illness before hospital admission and body mass index (BMI) at admission and discharge, proven predictors of the outcomes of adolescent AN. Clinical data at first admission and at discharge in 289 inpatients with AN (children: = 72; adolescents: = 217) from a German multicenter, web-based registry for consecutively enrolled patients with childhood and adolescent AN were analyzed. Inclusion criteria were a maximum age of 18 years, first inpatient treatment due to AN, and a BMI <10th BMI percentile at admission. Compared to adolescents, children with AN had a shorter duration of illness before admission (median: 6.0 months vs. 8.0 months, = 0.004) and higher BMI percentiles at admission (median: 0.7 vs. 0.2, = 0.004) as well as at discharge (median: 19.3 vs. 15.1, = 0.011). Thus, in our study, children with AN exhibited clinical characteristics that have been associated with better outcomes, including higher admission and discharge BMI percentile. Future studies should examine whether these factors are actually associated with positive long-term outcomes in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11112593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893829PMC
October 2019

No Association of Variants of the NPY-System With Obsessive-Compulsive Disorder in Children and Adolescents.

Front Mol Neurosci 2019 3;12:112. Epub 2019 May 3.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.

Obsessive-compulsive disorder (OCD) causes severe distress and is therefore counted by the World Health Organisation (WHO) as one of the 10 most impairing illnesses. There is evidence for a strong genetic underpinning especially in early onset OCD (eoOCD). Though several genes involved in neurotransmission have been reported as candidates, there is still a need to identify new pathways. In this study, we focussed on genetic variants of the Neuropeptide Y (NPY) system. NPY is one of the most abundant neuropeptides in the human brain with emerging evidence of capacity to modulate stress response, which is of high relevance in OCD. We focussed on tag-SNPs of and its receptor gene in a family-based approach. The sample comprised 86 patients (children and adolescents) with eoOCD with both their biological parents. However, this first study on genetic variants of the NPY-system could not confirm the association between the investigated SNPs and eoOCD. Based on the small sample size results have to be interpreted as preliminary and should be replicated in larger samples. However, also in an additional GWAS analysis in a large sample, we could not observe an associations between NPY and OCD. Overall, these preliminary results point to a minor role of NPY on the stress response of OCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnmol.2019.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511743PMC
May 2019

Family-based association study on functional α-synuclein polymorphisms in attention-deficit/hyperactivity disorder.

Atten Defic Hyperact Disord 2019 Mar 29;11(1):107-111. Epub 2019 Mar 29.

Department for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Tübingen, Tübingen, Germany.

Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for α-synuclein (SNCA). α-Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the α-synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, p = 1 p = 1) and rs356219 (OR 1.28; p = 0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, p = 0.020), which survived Bonferroni correction (p = 0.039); again, no association for NACP-Rep1 (OR 0.8, p = 0.317, p = 0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect α-synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12402-019-00286-8DOI Listing
March 2019

Signs of enhanced formation of gist memory in children with autism spectrum disorder - a study of memory functions of sleep.

J Child Psychol Psychiatry 2019 08 25;60(8):907-916. Epub 2019 Mar 25.

Institute of Medical Psychology and Behavioural Neurobiology, University of Tübingen, Tübingen, Germany.

Background: Autism spectrum disorder (ASD) is characterized by impaired cognitive and social skills, including emotional dysregulation, and symptoms have been suspected to partly arise from impaired formation of memory representations regulating these behaviours. Sleep, which is subjectively impaired in ASD, is critical for forming long-term memories and abstracted gist-based representations. We expected a generally reduced memory benefit from sleep in children with ASD, and a diminished enhancement of gist representations, in particular.

Methods: We compared effects of sleep on memory consolidation between boys (9-12 years) with ASD (n = 21) and typically developing (TD, n = 20) boys, matched for age and IQ, in a within-subjects crossover design. We employed an emotional picture recognition task and the Deese-Roediger-McDermott (DRM) word list task for assessing gist memory formation in the emotional and nonemotional domain, respectively. Learning took place before retention intervals of nocturnal sleep and daytime wakefulness, and retrieval was tested afterwards.

Results: Surprisingly, on the DRM task, children with ASD showed an enhanced sleep-dependent formation of gist-based memory (i.e. more recall of 'critical lure words' after sleep compared to wakefulness) than TD children, with this effect occurring on top of a diminished veridical word memory. On the picture recognition task, children with ASD also showed a stronger emotional enhancement in memory (i.e. relatively better memory for negative than neutral pictures) than TD children, with this enhancement occurring independent of sleep. Sleep polysomnography was remarkably comparable between groups.

Conclusions: Children with ASD show well-preserved sleep-dependent memory consolidation. Enhanced gist memory formation in these children might reflect a compensatory response for impairments at earlier stages of memory processing, that is during encoding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcpp.13048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850042PMC
August 2019

Long-term cardiovascular safety of psychostimulants in children with attention deficit hyperactivity disorder.

Int J Psychiatry Clin Pract 2019 Jun 21;23(2):157-159. Epub 2019 Jan 21.

a Department of Psychiatry, Psychosomatics and Psychotherapy , University Hospital of Tübingen , Tübingen , Germany.

Side effects are a concern during psychostimulant treatment. Unfortunately, many previous studies only investigated short-term effects of psychostimulants in laboratory settings which lack clinical daily routines. We examined 1042 patient records of patients with attention deficit hyperactivity disorder (ADHD) who were referred to a pediatric-psychiatry practice over 12 years. Data analysis was based on 466 children with ADHD who were newly treated with psychostimulants and who were not in treatment for elevated blood pressure. We analysed blood pressure percentiles, heart rate and BMI percentiles. There was a decrease in systolic and diastolic blood pressure percentiles. Heart rate was not affected. BMI slightly declined in girls. In general psychostimulants were safe. To further elucidate negative effects of psychostimulants, long-term controlled and randomized studies in naturalistic settings are of interest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13651501.2018.1519078DOI Listing
June 2019

Seasonal variation of BMI at admission in German adolescents with anorexia nervosa.

PLoS One 2018 11;13(9):e0203844. Epub 2018 Sep 11.

Department of Child and Adolescent Psychiatry, University Medicine of the Johannes Gutenberg-University, Mainz, Germany.

Objective: Recent preliminary studies indicated a seasonal association of BMI at admission to inpatient treatment for anorexia nervosa (AN), indicating lower BMI in the cold season for restrictive AN. An impaired thermoregulation was proposed as the causal factor, based on findings in animal models of AN. However, findings regarding seasonality of BMI and physical activity levels in the general population indicate lower BMI and higher physical activity in summer than in winter. Therefore, we aimed to thoroughly replicate the findings regarding seasonality of BMI at admission in patients with AN in this study.

Method: AN subtype, age- and gender-standardized BMI scores (BMI-SDS) at admission, mean daily sunshine duration and ambient temperature at the residency of 304 adolescent inpatients with AN of the multi-center German AN registry were analyzed.

Results: A main effect of DSM-5 AN subtype was found (F(2,298) = 6.630, p = .002), indicating differences in BMI-SDS at admission between restrictive, binge/purge and subclinical AN. No main effect of season on BMI-SDS at admission was found (F(1,298) = 4.723, p = .025), but an interaction effect of DSM-5 subtype and season was obtained (F(2,298) = 6.625, p = .001). Post-hoc group analyses revealed a lower BMI-SDS in the warm season for restrictive AN with a non-significant small effect size (t(203.16) = 2.140, p = .033; Hedges'g = 0.28). Small correlations of mean ambient temperature (r = -.16) and daily sunshine duration (r = -.22) with BMI-SDS in restrictive AN were found. However, the data were widely scattered.

Conclusions: Our findings are contrary to previous studies and question the thermoregulatory hypothesis, indicating that seasonality in AN is more complex and might be subject to other biological or psychological factors, for example physical activity or body dissatisfaction. Our results indicate only a small clinical relevance of seasonal associations of BMI-SDS merely at admission. Longitudinal studies investigating within-subject seasonal changes might be more promising to assess seasonality in AN and of higher clinical relevance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203844PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133390PMC
March 2019

Near-Infrared Spectroscopy-Based Frontal Lobe Neurofeedback Integrated in Virtual Reality Modulates Brain and Behavior in Highly Impulsive Adults.

Front Hum Neurosci 2017 4;11:425. Epub 2017 Sep 4.

LEAD Graduate School & Research Network, University of TübingenTübingen, Germany.

Based on neurofeedback (NF) training as a neurocognitive treatment in attention-deficit/hyperactivity disorder (ADHD), we designed a randomized, controlled functional near-infrared spectroscopy (fNIRS) NF intervention embedded in an immersive virtual reality classroom in which participants learned to control overhead lighting with their dorsolateral prefrontal brain activation. We tested the efficacy of the intervention on healthy adults displaying high impulsivity as a sub-clinical population sharing common features with ADHD. Twenty participants, 10 in an experimental and 10 in a shoulder muscle-based electromyography control group, underwent eight training sessions across 2 weeks. Training was bookended by a pre- and post-test including go/no-go, n-back, and stop-signal tasks (SST). Results indicated a significant reduction in commission errors on the no-go task with a simultaneous increase in prefrontal oxygenated hemoglobin concentration for the experimental group, but not for the control group. Furthermore, the ability of the subjects to gain control over the feedback parameter correlated strongly with the reduction in commission errors for the experimental, but not for the control group, indicating the potential importance of learning feedback control in moderating behavioral outcomes. In addition, participants of the fNIRS group showed a reduction in reaction time variability on the SST. Results indicate a clear effect of our NF intervention in reducing impulsive behavior possibly via a strengthening of frontal lobe functioning. Virtual reality additions to conventional NF may be one way to improve the ecological validity and symptom-relevance of the training situation, hence positively affecting transfer of acquired skills to real life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnhum.2017.00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591376PMC
September 2017

First Sociodemographic, Pretreatment and Clinical Data from a German Web-Based Registry for Child and Adolescent Anorexia Nervosa.

Z Kinder Jugendpsychiatr Psychother 2017 Sep 21;45(5):393-400. Epub 2017 Aug 21.

18 Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Germany.

Objective: The first web-based registry for childhood and adolescent anorexia nervosa (AN) in Germany was established to systematically collect demographic and clinical data. These data as well as information on how young individuals with AN can find access to healthcare services are presented.

Method: Patients´ data from child and adolescent psychiatry departments of 12 university hospitals and two major nonuniversity hospitals in Germany were collected between January 2015 and December 2016. All patients met the ICD-10 diagnostic criteria for (atypical) AN. Sociodemographic data, type and amount of healthcare utilization before admission, and clinical data at admission and discharge were compiled.

Results: 258 patients with a mean age of 14.7 years and a mean BMI at admission of 15.3 kg/m were included. The parents and patients had a higher educational level than the general German population. More than 80 % of the patients reported having utilized healthcare before hospitalization. The mean duration of outpatient treatment before hospitalization was 7 months.

Conclusions: There seem to be major barriers to specialist treatment for young patients with AN in Germany, which should be analyzed in future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1024/1422-4917/a000544DOI Listing
September 2017

NIRS-based neurofeedback training in a virtual reality classroom for children with attention-deficit/hyperactivity disorder: study protocol for a randomized controlled trial.

Trials 2017 01 24;18(1):41. Epub 2017 Jan 24.

LEAD Graduate School & Research Network, University of Tübingen, Gartenstrasse 29, 72074, Tübingen, Germany.

Background: Children with attention-deficit/hyperactivity disorder (ADHD) suffer from attention deficits, motor hyperactivity, and impulsive behaviour. These impairments are experienced at home, at school, and with friends. Functional imaging studies show that ADHD behaviour and impairments in executive functions (EFs) are mirrored by aberrant neurophysiological functioning. Moreover, several studies show that ADHD behaviour, impairments in EFs, and a lack of self-control contribute to poor school performance. Non-pharmacological interventions such as neurofeedback training (NFT), for instance, aim at improving neurophysiological and neuropsychological functioning as well as behaviour. Consequently, NFT is expected to improve school performance, EFs, and self-control in children with ADHD. Generalization of acquired self-regulation skills from laboratory to real life is crucial for a transfer to everyday situations and is hypothesized to be facilitated via training using virtual reality (VR) environments. Consequently, experiencing NFT in VR is expected to yield greater effects than training in two dimensions (2D).

Methods/design: Ninety children with a clinical diagnosis of ADHD will be included in the study. Participants may be medicated or unmedicated. After random assignation to one of three conditions, all participants receive 15 training sessions of either near-infrared spectroscopy (NIRS)-based NFT in VR, NIRS-based NFT in 2D, or electromyogram-based biofeedback training in VR. ADHD symptoms, self-control, EF, health-related quality of life, school performance, and motor activity measured via parent, teacher, and child reports or objectively will be assessed before and after the intervention and at a 6 months follow-up. Furthermore, we are interested in parents' expectations about the training's effects.

Discussion: This is, to our knowledge, the first study investigating the efficacy of NFT for children with ADHD in a VR compared to a 2D environment. Furthermore, this study will contribute to the discussion about the efficacy and specific and unspecific effects of NFTs in children with ADHD. In addition to commonly assessed variables such as ADHD symptoms, NIRS and behavioural data obtained in EF measures, health-related quality of life, and parents' expectations about the intervention's effects, this study will investigate the effects on self-control, school performance, and motor activity.

Trial Registration: ClinicalTrials.gov, NCT02572180 . Registered on 19 November 2015.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-016-1769-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259870PMC
January 2017

The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits.

J Neural Transm (Vienna) 2016 08 30;123(8):849-58. Epub 2016 Apr 30.

Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.

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 traits in the adult ADHD sample and overlapped with risk alleles for comorbid disorders in childhood. None of the findings survived correction for multiple testing, thus, results do not support a major role of common variants in ASTN2 in the pathogenesis of ADHD, its comorbid disorders or ADHD associated personality traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-016-1553-2DOI Listing
August 2016

Autonomic hypoactivity in boys with attention-deficit/hyperactivity disorder and the influence of methylphenidate.

World J Biol Psychiatry 2014 Jan 9;15(1):56-65. Epub 2013 Sep 9.

Department of Psychology (Biological Psychology, Clinical Psychology, and Psychotherapy), University of Würzburg , Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/15622975.2013.829584DOI Listing
January 2014

Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.

PLoS Genet 2013 Oct 24;9(10):e1003864. Epub 2013 Oct 24.

Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1003864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812053PMC
October 2013

Haplotype co-segregation with attention deficit-hyperactivity disorder in unrelated German multi-generation families.

Am J Med Genet B Neuropsychiatr Genet 2013 Dec 3;162B(8):855-63. Epub 2013 Sep 3.

Department of Neurobehavioral Genetics, University of Trier, Institute of Psychobiology, Trier, Germany.

Complex disorders have proved to be elusive in the search for underlying genetic causes. In the presence of large multi-generation pedigrees with multiple affected individuals, heritable familial forms of the disorders can be postulated. Observations of particular chromosomal haplotypes shared among all affected individuals within pedigrees may reveal chromosomal regions, in which the disease-related genes may be located. Hence, the biochemical pathways involved in pathogenesis can be exposed. We have recruited eight large Attention Deficit-Hyperactivity Disorder (ADHD, OMIM: #143465) families of German descent. Densely spaced informative microsatellite markers with high heterozygosity rates were used to fine-map and haplotype chromosomal regions of interest in these families. In three subsets and one full family of the eight ADHD families, haplotypes co-segregating with ADHD-affected individuals were identified at chromosomes 1q25, 5q11-5q13, 9q31-9q32, and 18q11-18q21. Positive LOD scores supported these co-segregations. The existence of haplotypes co-segregating among affected individuals in large ADHD pedigrees suggests the existence of Mendelian forms of the disorder and that ADHD-related genes are located within these haplotypes. In depth sequencing of these haplotype regions can identify causative genetic mechanisms and will allow further insights into the clinico-genetics of this complex disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.32192DOI Listing
December 2013

High loading of polygenic risk for ADHD in children with comorbid aggression.

Am J Psychiatry 2013 Aug;170(8):909-16

MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1176/appi.ajp.2013.12081129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935265PMC
August 2013

Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder.

Am J Med Genet B Neuropsychiatr Genet 2013 Jun 26;162B(4):295-305. Epub 2013 Mar 26.

Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatics, LVR Klinikum Essen, University of Duisburg-Essen, D-45147 Essen, Germany.

Children with attention-deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) for ADHD based on 495 patients and 1,300 population-based controls and performed in silico analyses of the SNPs in an ADHD meta-analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X-type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10(-4) ; Pcorr  = 0.01). In the meta-analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein-coupled receptor, family C, group 5, member B; P = 7.2 × 10(-4) ; Pcorr  = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine-6-phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen-activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta-analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.32144DOI Listing
June 2013

KCNIP4 as a candidate gene for personality disorders and adult ADHD.

Eur Neuropsychopharmacol 2013 Jun 14;23(6):436-47. Epub 2012 Sep 14.

Department of Psychiatry, ADHD Clinical Research Network, Molecular Psychiatry Laboratory of Translational Neuroscience; Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children with striking persistence into adulthood and a high co-morbidity with other psychiatric disorders, including personality disorders (PD). The 4p15.31 region was shown to be associated with ADHD in several genome wide association studies (GWAS). In the present study we also report association of the 4p15.31 locus with Cluster B and Cluster C PD as identified by a pooled genome-wide association study in 400 individuals suffering from PD. The gene coding for the Kv channel-interacting protein 4 (KCNIP4) is located in this region. KCNIP4 is an interaction partner of presenilin and plays a role in a negative feedback loop in the Wnt/β-catenin pathway. Thus, we reasoned it to be a promising candidate gene for ADHD as well as for PD. To clarify the role of KCNIP4 in those disorders, we conducted candidate gene based association studies in 594 patients suffering from adult ADHD and 630 PD patients as compared to 974 healthy control individuals. In the adult ADHD sample, six single markers and one haplotype block revealed to be associated with disease (p values from 0.0079 to 0.049). Seven markers within the KCNIP4 gene showed an association with PD (p values from 0.0043 to 0.0437). The results of these studies suggest a role of KCNIP4 in the etiology of ADHD, PD and other co-morbid disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euroneuro.2012.07.017DOI Listing
June 2013

COMT x DRD4 epistasis impacts prefrontal cortex function underlying response control.

Cereb Cortex 2013 Jun 22;23(6):1453-62. Epub 2012 May 22.

Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Würzburg, 97080 Würzburg, Germany.

The prefrontal cortex plays a major role in cognitive control, but it is unclear how single genes and gene-gene interactions (genetic epistasis) impact neural and behavioral phenotypes. Both dopamine (DA) availability ("inverted U-model") and excitatory versus inhibitory DA receptor stimulation ("dual-state theory") have been linked to important principles of prefrontal processing. Catechol-O-methyltransferase (COMT; Val158Met) and DA D4-receptor (DRD4; 48 bp VNTR) genotypes were analyzed for effects on behavioral and neural correlates of prefrontal response control (NoGo-anteriorization, NGA) using a Go-NoGo task and electroencephalography (114 controls and 181 patients with attention-deficit/hyperactivity disorder).  DRD4 and COMT epistatically interacted on the NGA, whereas single genes and diagnosis showed no significant impact. Subjects with presumably relatively increased D4-receptor function (DRD4: no 7R-alleles) displayed an inverted U-relationship between the NGA and increasing COMT-dependent DA levels, whereas subjects with decreased D4-sensitivity (7R) showed a U-relationship. This interaction was supported by 7R-allele dose effects and mirrored by reaction time variability (non-significant after multiple testing correction). Combining previous theories of prefrontal DA functioning, neural stability at intermediate DA levels may be accompanied by the risk of overly decreased neural flexibility if inhibitory DA receptor function is additionally decreased. Our findings might help to disentangle the genetic basis of dopaminergic mechanisms underlying prefrontal (dys)function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cercor/bhs132DOI Listing
June 2013

Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3.

Am J Psychiatry 2012 Feb;169(2):195-204

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, and School of Medicine, Cardiff University, Cardiff, UK.

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology.

Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium.

Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder.

Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601405PMC
http://dx.doi.org/10.1176/appi.ajp.2011.11060822DOI Listing
February 2012

Candidate system analysis in ADHD: evaluation of nine genes involved in dopaminergic neurotransmission identifies association with DRD1.

World J Biol Psychiatry 2012 Apr 9;13(4):281-92. Epub 2012 Mar 9.

Department of Psychiatry, Hospital Universitari Vall d'Hebron, and Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.

Objectives: Several pharmacological and genetic studies support the involvement of the dopamine neurotransmitter system in the aetiology of attention-deficit hyperactivity disorder (ADHD). Based on this information we evaluated the contribution to ADHD of nine genes involved in dopaminergic neurotransmission (DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, TH, DBH and COMT).

Methods: We genotyped a total of 61 tagging single nucleotide polymorphisms (SNPs) in a sample of 533 ADHD patients (322 children and 211 adults), 533 sex-matched unrelated controls and additional 196 nuclear ADHD families from Spain.

Results: The single- and multiple-marker analysis in both population and family-based approaches provided preliminary evidence for the contribution of DRD1 to combined-type ADHD in children (P=8.8e-04; OR=1.50 (1.18-1.90) and P=0.0061; OR=1.73 (1.23-2.45)) but not in adults. Subsequently, we tested positive results for replication in an independent sample of 353 German families with combined-type ADHD children and replicated the initial association between DRD1 and childhood ADHD (P=8.4e-05; OR=3.67 (2.04-6.63)).

Conclusions: The replication of the association between DRD1 and ADHD in two European cohorts highlights the validity of our finding and supports the involvement of DRD1 in childhood ADHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/15622975.2011.584905DOI Listing
April 2012

Heart rate variability and methylphenidate in children with ADHD.

Atten Defic Hyperact Disord 2012 Jun 11;4(2):85-91. Epub 2012 Feb 11.

Department of Paediatrics, Caritas Krankenhaus, Bad Mergentheim, Germany.

Although an extensive number of studies support the efficacy and tolerability of stimulants in the treatment of attention deficit/hyperactivity disorder (ADHD), in recent years, increasing concerns have been raised about their cardiovascular safety. We investigated whether a time domain analysis of heart rate variability (HRV) recordings in 24-h ECG under medication with stimulants yielded new information about therapy control in ADHD. We analysed the HRV parameter standard deviation of all normal sinus RR intervals over 24 h (SDNN), percentage of successive normal sinus RR intervals > 50 ms (pNN50) and root-mean-square of the successive normal sinus RR interval difference (rMSSD) from 23 children diagnosed by ADHD (19 boys and 4 girls), aged 10.5 ± 2.2 years, who were consecutively referred to our outpatient clinic for paediatric cardiology. Eleven children received medication with methylphenidate (MPH), while twelve children were initially examined without medication. Of these, eight probands were re-examined after therapy with MPH was established. Controls comprised 19 children (10 boys, 9 girls) from our Holter ECG data base without any cardiac or circulatory disease. Compared to healthy controls, the ADHD children with and without MPH treatment showed significantly higher mean heart rates (ADHD without MPH: 94.3 ± 2.2; ADHD with MPH: 90.5 ± 1.8, controls: 84.7 ± 1.8). pNN50 (ADHD without MPH: 6.5 ± 2.7; ADHD with MPH: 14.2 ± 6.9, controls: 21.5 ± 9.0) and rMSSD (ADHD without MPH: 26.1 ± 4.1; ADHD with MPH: 36.7 ± 8.3, controls: 44.5 ± 10.1) were lowest in ADHD children without MPH, middle in ADHD children with MPH and highest in controls. SDNN values were not significantly different. The hourly analysis shows highly significant reduced pNN50 and rMSSD values in untreated ADHD children between 5:00 pm and 6:00 am while the pattern approaches to levels of controls during MPH treatment. Data of this pilot study indicate a decreased vagal tone with significantly diminished HRV and higher heart rates in unmedicated ADHD children. These parameters of autonomic activation are ameliorated by MPH treatment. No evidence for negative impact of MPH on HRV was detected. Further studies will clarify a potential cardio-protective effect of MPH in ADHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12402-012-0072-8DOI Listing
June 2012

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

Nat Genet 2011 Dec 4;44(1):78-84. Epub 2011 Dec 4.

Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.1013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310555PMC
December 2011

Genome-wide association study in German patients with attention deficit/hyperactivity disorder.

Am J Med Genet B Neuropsychiatr Genet 2011 Dec 19;156B(8):888-97. Epub 2011 Oct 19.

Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.31246DOI Listing
December 2011

Pervasive refusal syndrome. Three German cases provide further illustration.

Z Kinder Jugendpsychiatr Psychother 2011 Sep;39(5):351-8; quiz 359

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Würzburg University Hospital.

Pervasive refusal syndrome (PRS) has been proposed as a new diagnostic entity among child and adolescent psychiatric disorders. It is characterized by a cluster of life-threatening symptoms including refusal of hood intake, decreased or complete lack of mobilization, and lack of communication as well as retreat from normal life activities. Active refusal to accept help as well as neglect of personal care have been core features of PRS in the limited number of cases reported in the last decade. There have, however; been cases with predominantly passive resistance, indicating the possibility that there may be a continuum from active refusal to passive resistance within PRS. Postulating this continuum allows for the integration of "depressive devitalization" -- a refusal syndrome mainly characterized by passive resistance -- into the concept of PRS. Here, three case vignettes of adolescent patients with PRS are presented. The patients' symptomatology can be allocated on this continuum of PRS. PRS and dissociative disorders are compared in greater detail and contrasted within this discussion of differential diagnoses at the poles of such a continuum. PRS is a useful diagnosis for cases involving symptoms of predominating refusal and retreat which cannot satisfactorily be classified by existing diagnostic categories, and which can mostly clearly be separated from dissociative disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1024/1422-4917/a000128DOI Listing
September 2011

DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders.

Neuropsychopharmacology 2011 Oct 13;36(11):2318-27. Epub 2011 Jul 13.

Department of Psychiatry, University of Würzburg, Würzburg, Germany.

Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008-0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/npp.2011.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176568PMC
October 2011

Influence of a genetic variant of the neuronal growth associated protein Stathmin 1 on cognitive and affective control processes: an event-related potential study.

Am J Med Genet B Neuropsychiatr Genet 2011 Apr 13;156B(3):291-302. Epub 2011 Jan 13.

Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Germany.

Stathmin 1 (STMN1) is a neuronal growth associated protein (NGAP) that is involved in microtubule dynamics and plays an important role in neurite outgrowth and synaptic plasticity. It is highly expressed in the amygdala, but also in different areas of the neocortex including the frontal lobe. Based on previous findings regarding an impact of STMN1 on fear processing, the present study aimed at extending the evidence concerning its functional role to include the domain of executive (frontal lobe) functions. To this end, a group of 59 healthy volunteers stratified for the single-nucleotide polymorphism rs182455 of the STMN1 gene was examined by means of three experimental paradigms probing different aspects of cognitive-affective functioning. Event-related potential measures of cognitive response control, emotional interference processing, and action monitoring were analyzed. STMN1 genotype significantly affected the NoGo-anteriorization (NGA)-a neurophysiological marker of cognitive response control associated with medial prefrontal cortex activation-as well as the modulation of the P300 by the valence of emotional Stroop stimuli. In both cases, carriers of the rs182455 C-allele showed altered cognitive-affective processing; effects appeared to be more pronounced in females. Our findings indicate a functional impact of STMN1 on cognitive and affective control processes, thereby complementing previous evidence on its role in fear processing. Based on these results, an influence of STMN1 should be considered in studies aiming at the etiopathogenesis of a broad range of neuropsychiatric disorders with dysfunctional networking, including neurodegenerative disorders as well as schizophrenia, autism spectrum disorders, anxiety disorders, depression, and ADHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.31161DOI Listing
April 2011

Association between reward-related activation in the ventral striatum and trait reward sensitivity is moderated by dopamine transporter genotype.

Hum Brain Mapp 2011 Oct 15;32(10):1557-65. Epub 2010 Sep 15.

Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, 97080 Würzburg, Germany.

The impact of individual differences on human reward processing has been a focus of research in recent years, particularly, as they are associated with a variety of neuropsychiatric diseases including addiction and attention-deficit/hyperactivity disorder. Studies exploring the neural basis of individual differences in reward sensitivity have consistently implicated the ventral striatum (VS) as a core component of the human reward system. However, the mechanisms of dopaminergic neurotransmission underlying ventral striatal activation as well as trait reward sensitivity remain speculative. We addressed this issue by investigating the triadic interplay between VS reactivity during reward anticipation using functional magnetic resonance imaging, trait reward sensitivity, and dopamine (DA) transporter genotype (40-bp 3'VNTR of DAT, SLC6A3) affecting synaptic DA neurotransmission. Our results show that DAT variation moderates the association between VS-reactivity and trait reward sensitivity. Specifically, homozygote carriers of the DAT 10-repeat allele exhibit a strong positive correlation between reward sensitivity and reward-related VS activity whereas this relationship is absent in the DAT 9-repeat allele carriers. We discuss the possibility that this moderation of VS-trait relation might arise from DAT-dependent differences in DA availability affecting synaptic plasticity within the VS. Generally, studying the impact of dopaminergic gene variations on the relation between reward-related brain activity and trait reward sensitivity might facilitate the investigation of complex mechanisms underlying disorders linked to dysregulation of DA neurotransmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hbm.21127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870133PMC
October 2011