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Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

The excitatory/inhibitory (E/I) imbalance hypothesis posits that an imbalance between glutamatergic and GABAergic neurotransmission contributes to autism symptomatology. Whether this is due to altered GABAergic or glutamatergic functioning, or both, remains largely unknown. We integrated genetic, brain structure and brain chemistry data to investigate the relationship between E/I genetic variation and expression, glutamate concentrations and cortical thickness (CT). Participants (60 autism and 104 neurotypical controls, aged 8-13 years) underwent magnetic resonance imaging and spectroscopy for glutamate quantification in the anterior cingulate cortex (ACC) and left dorsal striatum. Genetic involvement in these regional glutamate concentration levels was investigated using competitive gene-set association and polygenic scores (PGS). Further, glutamate as well as GABA gene-set expression profiles were investigated in relation to CT. Aggregated genetic variation in the glutamate gene-set was associated with ACC but not striatal glutamate concentrations. PGS analysis, however, showed a genome-wide PGS for autism to be predictive of striatal but not ACC glutamate levels. Expression profiles of GABAergic-but not glutamatergic genes were associated with differences in cortical thickness between groups. This study showed differential involvement of aggregated glutamatergic and GABAergic genetic variation in brain structure and chemistry in autism, which suggests regional variability in E/I imbalance.

Contains fulltext : 208629.pdf (Publisher’s version ) (Open Access) Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children and adults. It is characterized by inappropriate levels of inattention (IA) and/or hyperactivity and impulsivity (HI). The ADHD diagnosis is hypothesized to represent the extreme of a continuous distribution of ADHD symptoms in the general population. In this study, we investigated whether factors linked to adult ADHD as a disorder are associated with adult ADHD symptoms in the general population. Our population-based sample included 4987 adults (mean age 56.1 years; 53.8% female) recruited by the Nijmegen Biomedical Study (NBS). Participants completed the Dutch ADHD DSM-IV Rating Scale for current and childhood ADHD symptoms, the Symptom Check List-90-R (SCL-90-R) anxiety subscale, and the Eysenk Personality Questionnaire (EPQR-S). Partial Spearman correlation and Hurdle negative binomial regression analysis were used to assess how age, sex, childhood ADHD symptoms, anxiety symptoms, and personality traits (neuroticism, extraversion, and psychoticism) are associated with current IA and HI symptoms. Increasing age was associated with a lower proportion of participants reporting HI symptoms and with reduced levels of HI; IA levels remained fairly stable over the age-range, but the probability of reporting IA symptoms increased throughout middle/late adulthood. Females were more likely to report IA symptoms than males. Childhood ADHD symptoms, neuroticism, and psychoticism were positively associated with current IA and HI symptoms, while extraversion had an opposite association with these symptom domains. Anxiety symptoms affected HI symptoms in females. Our results indicate that factors associated with categorical ADHD are also correlated with ADHD symptoms in the adult population.

Contains fulltext : 204848.pdf (Publisher’s version ) (Open Access) BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder, putatively induced by dissociable dysfunctional biobehavioral pathways. Here, we present a proof-of-concept study to parse ADHD-related heterogeneity in its underlying neurobiology by investigating functional connectivity across multiple brain networks to 1) disentangle categorical diagnosis-related effects from dimensional behavior-related effects and 2) functionally map these neural correlates to neurocognitive measures. METHODS: We identified functional connectivity abnormalities related to ADHD across 14 networks within a large resting-state functional magnetic resonance imaging dataset (n = 409; age = 17.5 +/- 3.3 years). We tested these abnormalities for their association with the categorical ADHD diagnosis and with dimensional inattention and hyperactivity/impulsivity scores using a novel modeling framework, creating orthogonalized models. Next, we evaluated the relationship of these findings with neurocognitive measures (working memory, response inhibition, reaction time variability, reward sensitivity). RESULTS: Within the default mode network, we mainly observed categorical ADHD-related functional connectivity abnormalities, unrelated to neurocognitive measures. Clusters within the visual networks primarily related to dimensional scores of inattention and reaction time variability, while findings within the sensorimotor networks were mainly linked to hyperactivity/impulsivity and both reward sensitivity and working memory. Findings within the cerebellum network and salience network related to both categorical and dimensional ADHD measures and were linked to response inhibition and reaction time variability. CONCLUSIONS: This proof-of-concept study identified ADHD-related neural correlates across multiple functional networks, showing distinct categorical and dimensional mechanisms and their links to neurocognitive functioning.

Dysregulation of executive function (EF) involves alterations in cognitive flexibility / control and is underscored by learning impairments in neurodevelopmental disorders. Here, we examine cognitive inflexibility in BALB/cJ mice (a mouse model showing diminished sociability, increased anxiety and inattentive behaviour) and closely related "reference" BALB/cByJ mice. We used an appetitive extinction paradigm to investigate if cognitive flexibility measures are different between learning acquisition and extinction. The two BALB/c sub-strains learned to respond to a stimulus in a touchscreen operant chamber, after which the reward was removed and responses should be inhibited. Both mice sub-strains showed a different rate of learning while acquiring the task, in which the BALB/cJ mice were faster learners compared to the BALB/cByJ mice. This was not observed during the extinction phase, in which the BALB/cJ mice were able to extinguish responding to unrewarded stimuli equally. Within the BALB/cJ sub-strain, variation in the ability to inhibit a learnt response was observed when comparing them to similar grouped BALB/cByJ mice: BALB/cJ animals that reached the criterion were more reward driven, while BALB/cJ mice failing to reach the set criterion during extinction processing make more mistakes. Additionally, the changes observed during acquisition, were driven by animals not reaching the extinction criterion. Our results suggest that the BALB/c mice sub-strains may use different strategies to learn during appetitive extinction. This may be useful in the phenotypic dissection of cognitive flexibility in BALB/c sub-strains and their mapping on genetic variance revealed by next-generation sequencing in future studies.

Background: Pregnancy factors have been implicated in offspring oppositional-defiant disorder (ODD) and conduct disorder (CD) symptoms. Literature still holds notable limitations, such as studying only a restricted set of pregnancy factors, use of screening questionnaires which assess broadly defined outcome measures, and lack of control for disruptive behavior comorbidity and genetic confounds. We aimed to address these gaps by prospectively studying a broad range of pregnancy factors in relation to both offspring ODD and CD symptomatology in the Avon Longitudinal Study of Parent and Children.& para;& para;Methods: Outcomes were ODD and CD symptom scores at age 7;9 years using the Development and Well-Being Assessment interview. We analyzed maternal (N = 6300) and teacher ratings (N 4400) of ODD and CD scores separately using negative binomial regression in multivariable models. Control variables included comorbid attention-deficit/hyperactivity disorder symptoms, ODD or CD symptoms as appropriate, and genetic risk scores based on an independent CD genome-wide association study.& para;& para;Results: Higher ODD symptom scores were linked to paracetamol use (IRR = 1.24 [98.3% confidence interval 1.05-1.47], P = 0.002, teacher ratings) and life events stress (IRR = 1.22 [1.07-1.39], P = 0.002, maternal ratings) during pregnancy. Higher CD symptom scores were linked to maternal smoking (IRR = 1.33 [1.18-1.51], P

Serotonin (5-HT) is an important factor for prenatal neurodevelopment whereby its neurotrophic actions can be regulated through maternal-fetal interactions. We explored if maternal 5-HTTLPR genotype is associated with clinical and cognitive measures of attention-deficit/hyperactivity disorder (ADHD) and comorbid autism spectrum disorder (ASD) in typically-developing and ADHD-diagnosed offspring, beyond classical inheritance and environmental- and comorbidity-mediators/confounders. Family-based variance decomposition analyses were performed incorporating 6–31 year-old offsprings' as well as parental genotypes of 462 ADHD and control families from the NeuroIMAGE cohort. Dependent measures were offsprings' ADHD symptom- and ASD trait-scores and cognitive measures including executive functioning (including response inhibition and cognitive flexibility), sustained attention, reward processing, motor control, and emotion recognition. Offsprings' stereotyped behavior was predicted by an interaction between maternal 5-HTTLPR genotype and offsprings' sex. Furthermore, offspring of mothers with low-expressing genotypes demonstrated larger reward-related reductions in reaction time. While specifically adult male offspring of these mothers reported a faster reversal learning with less errors, specifically young female offspring of these mothers were more accurate in identifying happy faces. Adult offspring from the mothers with low-expressing 5-HTTLPR genotypes were also slower in identifying happy faces. However, this association seemed to be mediated by offsprings' high anxiety levels. In sum, we found some support for a role of the maternal 5-HT system in modulating fetal brain development and behavior. Offsprings' cognitive measures might be more sensitive to small alterations within the maternal 5-HT system than their ADHD and ASD clinical phenotypes. Further studies are needed to specify the association between maternal genotype and risk for neurodevelopmental disorders.

Objective The objectives of this study were to model more homogeneous subgroups within autism spectrum disorder (ASD) based on early trajectories of core symptoms; and to further characterize these subgroups in terms of trajectories of language, cognition, co-occurring (attention-deficit/hyperactivity disorder [ADHD]–related) traits and clinical outcome diagnosis. Method Children (N = 203) referred for possible ASD at ages 1 to 4 years were assessed at three time points at intervals ranging from 9 months to 3 years. Assessments included standardized measures for ASD (Autism Diagnostic Observation Schedule [ADOS]), language (ADOS-language item), nonverbal IQ (NV-IQ; different tests adequate to chronological/mental age), and parent-reported behavioral problems (Infant-Toddler Social and Emotional Assessment, Child Behavior Checklist). Results Latent-class growth curve analysis with ADOS total scores led to the identification of three main stable and two small improving groups: a severe–stable group (19.5% of sample)—the only group without considerable language improvement—showed persistent low NV-IQ and marked increase in attention problems over time; a moderate–stable group (21.7%) with below-average increasing NV-IQ; and a mild–stable group (48%) with stable–average NV-IQ and the highest scores on ADHD-related traits, whose ASD outcome diagnoses increased despite stable–low ASD scores. Two groups (each 5.4%) improved: one moved from severe to moderate ASD scores, and the other moved from moderate to mild/nonspectrum scores. Both of these groups improved on language, NV-IQ, and ADHD-related traits. Conclusion Results support the high stability of ASD symptoms into various severity levels, but also highlight the significant contribution of non-ASD domains in defining and explaining the different ASD trajectories.

Contains fulltext : 232366.pdf (Publisher’s version ) (Open Access) Most theoretical accounts of autism posit difficulties in predicting others' actions, and this difficulty has been proposed to be at the root of autistic individuals’ social communication differences. Empirical results are mixed, however, with autistic individuals showing reduced action prediction in some studies but not in others. It has recently been proposed that this effect might be observed primarily when observed actions are less predictable, but this idea has yet to be tested. To assess the influence of predictability on neural and behavioural action prediction, the current study employed an action observation paradigm with multi-step actions that become gradually more predictable. Autistic and non-autistic adolescents showed similar patterns of motor system activation during observation, as seen in attenuated mu and beta power compared to baseline, with beta power further modulated by predictability in both groups. Bayesian statistics confirmed that action predictability influenced beta power similarly in both groups. The groups also made similar behavioural predictions, as seen in three eye-movement measures. We found no evidence that autistic adolescents responded differently than non-autistic adolescents to the predictability of an observed action. These findings show that autistic adolescents do spontaneously predict others’ actions, both neurally and behaviourally, which calls into question the role of action prediction as a key mechanism underlying autism. 10 p.

Repetitive behavior is a core symptom of Autism Spectrum Disorder (ASD) and Obsessive-Compulsive Disorder (OCD), and has been associated with impairments in cognitive control. However, it is unclear how cognitive control and associated neural circuitry relate to the development of repetitive behavior in children with these disorders. In a multicenter, longitudinal study (TACTICS; Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes), the development of cognitive control was assessed during late childhood using a longitudinal fMRI design with a modified stop-signal task in children with ASD or OCD, and typically developing (TD) children (baseline: N = 95 (8-12 y), follow-up: N = 53 (10-14 y), average interval: 1.48 y (sd: 0.36, range: 0.98–2.52 y). Stop-signal reaction time (SSRT) decreased over development, regardless of diagnosis. Repetitive behavior in children with ASD and OCD was not associated with performance on the stop-signal task. There were no whole-brain between-group differences in brain activity, but ROI-analyses showed increases in activity in right precentral gyrus over development for children with OCD. In sum, even though subtle differences were observed in the development of brain activity in children with OCD, overall the findings suggest that the development of cognitive control, as assessed by the stop signal task, is similar to typical in children with ASD and OCD.

Contains fulltext : 158855.pdf (Publisher’s version ) (Closed access) OBJECTIVE: This study aimed to characterize alpha modulations in children with ADHD in relation to their attentional performance. METHODS: The posterior alpha activity (8-12Hz) was measured in 30 typically developing children and 30 children with ADHD aged 7-10years, using EEG while they performed a visuospatial covert attention task. We focused the analyses on typically developing boys (N=9) and boys with ADHD (N=17). RESULTS: Alpha activity in typically developing boys was similar to previous results of healthy adults: it decreased in the hemisphere contralateral to the attended hemifield, whereas it relatively increased in the other hemisphere. However, in boys with ADHD this hemispheric lateralization in the alpha band was not obvious (group contrast, p=.018). A robust relation with behavioral performance was lacking in both groups. CONCLUSIONS: The ability to modulate alpha oscillations in visual regions with the allocation of spatial attention was clearly present in typically developing boys, but not in boys with ADHD. SIGNIFICANCE: These results open up the possibility to further study the underlying mechanisms of ADHD by examining how differences in the fronto-striatal network might explain different abilities in modulating the alpha band activity. 10 p.

Background Magnetic resonance imaging (MRI) is able to provide detailed insights into the structural organization of the brain, e.g., by means of mapping brain anatomy and white matter microstructure. Understanding interrelations between MRI modalities, rather than mapping modalities in isolation, will contribute to unraveling the complex neural mechanisms associated with neuropsychiatric disorders as deficits detected across modalities suggest common underlying mechanisms. Here, we conduct a multimodal analysis of structural MRI modalities in the context of attention-deficit/hyperactivity disorder (ADHD). Methods Gray matter volume, cortical thickness, surface areal expansion estimates, and white matter diffusion indices of 129 participants with ADHD and 204 participants without ADHD were entered into a linked independent component analysis. This data-driven analysis decomposes the data into multimodal independent components reflecting common inter-subject variation across imaging modalities. Results ADHD severity was related to two multimodal components. The first component revealed smaller prefrontal volumes in participants with more symptoms, co-occurring with abnormal white matter indices in prefrontal cortex. The second component demonstrated decreased orbitofrontal volume as well as abnormalities in insula, occipital, and somato-sensory areas in participants with more ADHD symptoms. Conclusions Our results replicate and extend previous unimodal structural MRI findings by demonstrating that prefrontal, parietal, and occipital areas, as well as fronto-striatal and fronto-limbic systems are implicated in ADHD. By including multiple modalities, sensitivity for between-participant effects is increased, as shared variance across modalities is modeled. The convergence of modality-specific findings in our results suggests that different aspects of brain structure share underlying pathophysiology and brings us closer to a biological characterization of ADHD., Highlights • We use a multimodal approach (Linked ICA) to investigate changes in brain structure related to ADHD. • Linked ICA decomposes multimodal data into networks and links the modalities by assigning a shared-subject course. • Both white and gray matter show spatially consistent abnormalities. • Same subjects are driving the patterns present in different modalities. • We replicate previous unimodal findings.

Background Tourette Syndrome (TS) and Obsessive-Compulsive Disorder (OCD) are heritable neuropsychiatric disorders with a childhood onset. TS is characterized by multiple and involuntary motor tics and at least one vocal tic that persists for more than one year. TS has a prevalence of 0,3-0,8%. OCD is characterized by recurring obsessions and/or compulsions and affects up to 2% of the population. The disorders often co-occur, with their comorbidity ranging between 20–60%. Moreover, there are striking similarities in the phenotypic representation of TS/tics and OCD. Previous studies indicate that TS and OCD may share some common genetic susceptibility factors - with an estimated genetic correlation of 0.41 - but also suggest that there are distinct components to the genetic architectures of the two disorders. Two recent population-based twin sample studies also reported genetic correlations between tics and OCD-related traits (0.37 and 0.45). In this study we further investigated the shared genetic etiology between TS, OCD, and OCD traits as well as tic traits in the general population. Methods We conducted a number of Polygenic Risk Score (PRS)-based analyses. For these analyses, we used the summary statistics data from the Genome-Wide Association Study (GWAS) of TS and the summary statistics from the meta-analysis of the two GWASs of OCD conducted by the Psychiatric Genomics Consortium (PGC) (unpublished, provided by PGC OCD Working Group) as the 'base' sample. As 'target' samples, we used summary statistics of GWASs of OCD traits and tic traits in the general population. For these GWASs, we used phenotypic and genotyping data from the Children's Hospital of Philadelphia (CHOP) cohort obtained from dbGaP (phs000607.v1.p1). To conduct the OCD trait GWASs, we first developed a questionnaire consisting of 22 OCD trait questions and conducted a factor analysis of the questionnaire, to reveal the subsets of OCD traits that group together and may better capture the underlying genetic architecture. We then conducted GWASs of the total score on the 22 OCD trait questions and of six OCD trait factors in 650 children and adolescents from the CHOP cohort. For tic traits, we conducted a GWAS on the total score on 4 tic trait questions in 207 individuals from the CHOP cohort. Results The factor analysis of the 22 OCD trait questions revealed 8 factors that constitute the best fit and explain 58,6% of the variance in the total score on the 22 questions, i.e. 'impairment', 'symmetry/counting/ordering', 'contamination/cleaning', 'aggressive taboo thoughts (tt)', 'repetition', 'guilty tt', 'distress' and 'religious tt'. The PRS-based analyses yielded a significant evidence for shared genetic etiology between OCD and the three OCD traits 'impairment' (1.06% variance explained (ve)), 'contamination/cleaning' (3.54% ve,) and 'guilty taboo thoughts' (5.64% ve). Furthermore, we found significant shared genetic etiology between TS and four OCD traits: 'symmetry/counting/ordering' (3.03% ve), 'contamination/cleaning' (1.28% ve), 'aggressive taboo thoughts' (4.96% ve) and 'distress' (1.83% ve), and between TS and the total score on tic traits (4.78% ve). OCD and TS did not show significant genetic overlap with the total score on the 22 OCD trait questions. Discussion Our findings provide additional and novel evidence that certain OCD traits show genetic overlap with OCD and TS, which adds to our understanding of the genetic risk factors that are shared by and unique to these comorbid disorders.

Current studies of aggression in heterogenous cohorts often display considerable genetic and phenotypic variance. The study of inbred mouse strains with reduced genetic variability between sub-strains and more amenable control of the environment enables a platform for the dissection of genetic and epigenetic moderators of aggression and it's cognitive and emotional underpinnings. Comparison of the BALB/cJ and BALB/cByJ sub-strains is one approach to utilise this method which has been deployed in the EU FP7 Aggressotype and MATRICS consortia. The BALB/cJ mouse model compared to its BALB/cByJ control shows increased aggression (reduced latency to attack; increased number of bites and atypical bite pattern) coupled to increased anxiety-like behaviour as demonstrated in the elevated plus maze. MRI studies of these mice using an 11.7T Bruker Biospec MRI scanner demonstrates reduced white matter integrity in the anterior cingulate cortex (ACC) and dorsomedial striatum (DMS) and increased brain gray matter volume coupled to lower body weight. In high resolution ex vivo MRI studies of these sub-strains, marked volumetric increases are seen in the striatum, hypothalamus, hippocampus. Decreases in the volume are apparent in the frontal, insular and sensory cortices. Furthermore, 1H-MRS of the aggressive BALB/cJ mouse model demonstrates no change in anterior cingulate cortex (ACC) excitatory glutamate but a reduction in ACC GABA levels compared to the BALB/cByJ control strain. Realtime quantitative polymerase chain reaction (qPCR) estimates of GABA related gene expression demonstrates no change in ACC expression of the GABA synthetic enzymes GAD1 or GAD2 (coding for glutamate decarboxylase (GAD)67 and GAD65 respectively) but a 20 fold increase in the mRNA expression of the GABA catabolic enzyme 4-Aminobutyrate aminotransferase (ABAT) in the ACC. Furthermore, 1H-MRS estimates of total ACC choline levels (which may reflect intrinsic choline tone at nicotinic alpha7 receptors as well as excitatory acetylcholine and phosphocholine concentrations) are decreased in the aggressive BALB/cJ strain. Taken together, this suggests a dysregulation in the BALB/cJ mice of excitatory / inhibitory balance within the ACC, a crucial prefrontal cortical control region involved in the regulation of both cognitive and emotional processing. Causal modelling in human childhood and adolescent ADHD cohorts has suggested a causative role for inattention in mediating aggressive responses. Interestingly, BALB/cJ mice also demonstrate decreased attention performance (increased omissions) compared to BALB/cByJ mice in the 5-choice serial reaction time task. Indications that this might result from altered (threat) sensitivity to their environment is underlined by behavioural data showing that BALB/cJ fail to learn to punishment and demonstrate altered fear conditioning. Reduced cortisol levels are seen in blood samples from aggressive BALB/cJ mice both before and following the resident intruder task compared to their BALB/cByJ controls; this is linked to reduced ACC expression of corticotrophin-releasing hormone (Crh) mRNA in BALB/cJ mice. Finally, the psycho-stimulant methylphenidate (which is effective in the clinic) normalises aggressive behaviour and aberrant fear conditioning in BALB/cJ mice suggesting that methylphenidate's blockade of dopamine and norepinephrine uptake may regulate stress sensitivity and inhibitory control in these mice.

Contains fulltext : 218295.pdf (Publisher’s version ) (Open Access) Learning from feedback is one of the key mechanisms within cognitive flexibility, which is needed to react swiftly to constantly changing environments. The motivation to change behavior is highly dependent on the expectancy of positive (reward) or negative (punishment) feedback. Individuals with conduct disorder (CD) with high callous unemotional traits show decreased sensitivity to negative feedback and increased reward seeking. Previous studies have modeled traits associated with CD (i.e. heightened aggression and anti-social behavior) in BALB/cJ mice (compared to the BALB/cByJ mouse as controls). Based on these findings, we hypothesized reduced negative feedback-related cognitive flexibility to be present in BALB/cJ mice. The effect of negative feedback and reward sensitivity on cognitive flexibility in BALB/cJ and BALB/cByJ mice was examined in a reversal learning paradigm. BALB/cJ mice were more flexible in the acquisition of new contingencies under rewarding conditions compared to BALB/cByJ mice, while the presence of an aversive punishing stimulus decreased their learning performance. Additionally, BALB/cJ mice needed more correction trials to reach the reversal learning criterion. This was accompanied by a higher rate of perseverance, which could represent impaired error detection. The addition of a second punishment enhanced punishment sensitivity in BALB/cJ mice. In contrast, the performance of the BALB/cByJ mice was not affected by additional negative feedback. Taken together, the BALB/cJ can be considered to be less sensitive to learn from negative feedback and therefore may be a useful model to further characterize molecular and neural underpinnings of callous unemotional traits in CD.

Contains fulltext : 127698.pdf (Publisher’s version ) (Open Access) Children with attention-deficit/hyperactivity disorder (ADHD) have smaller volumes of total brain matter and subcortical regions, but it is unclear whether these represent delayed maturation or persist into adulthood. We performed a structural MRI study in 119 adult ADHD patients and 107 controls and investigated total gray and white matter and volumes of accumbens, caudate, globus pallidus, putamen, thalamus, amygdala and hippocampus. Additionally, we investigated effects of gender, stimulant treatment and history of major depression (MDD). There was no main effect of ADHD on the volumetric measures, nor was any effect observed in a secondary voxel-based morphometry (VBM) analysis of the entire brain. However, in the volumetric analysis a significant gender by diagnosis interaction was found for caudate volume. Male patients showed reduced right caudate volume compared to male controls, and caudate volume correlated with hyperactive/impulsive symptoms. Furthermore, patients using stimulant treatment had a smaller right hippocampus volume compared to medication-naive patients and controls. ADHD patients with previous MDD showed smaller hippocampus volume compared to ADHD patients with no MDD. While these data were obtained in a cross-sectional sample and need to be replicated in a longitudinal study, the findings suggest that developmental brain differences in ADHD largely normalize in adulthood. Reduced caudate volume in male patients may point to distinct neurobiological deficits underlying ADHD in the two genders. Smaller hippocampus volume in ADHD patients with previous MDD is consistent with neurobiological alterations observed in MDD.

Contains fulltext : 116474.pdf (Publisher’s version ) (Closed access) Objectives: Previous research identified alexithymia as a potential risk factor for substance use disorders (SUD). More insight into the relation between alexithymia and SUD is needed in order to treat SUD effectively. Therefore, we investigated whether a familial vulnerability to alcoholism relates to the presence and severity of alexithymia in SUD patients. Method: Hospitalized, abstinent SUD-patients (n = 187), were assessed with the Toronto Alexithymia Scale (TAS-20) and Addiction Severity Index (EuropASI). A maternal, paternal, and total continuous measure of the Family History of Alcohol (FHA) was developed. Kruskal-Wallis tests and Spearman correlations were used to relate the composite scores of FHA to alexithymia as a categorical and continuous measure. Multivariate regression models were performed to control for the effects of confounders on the relation between FHA and alexithymia. Results: Compared to moderate (33%) and low (17%) alexithymic SUD-patients, high alexithymic (50%) patients were more likely to have fathers with alcohol problems (P = 0.004). Such a difference was not found for mothers with alcohol problems. The composite FHA-score was significantly associated with alexithymia (Rs = .19, P = 0.01). However, only a paternal FHA, independent from disturbed family functioning, related to the degree of alexithymia (beta = .13, P = 0.06), especially to the Difficulty Identifying Feelings as measured by the TAS-20 (beta = .16, P = 0.02). Conclusions: The relation between a paternal FHA and a higher degree of alexithymia in SUD-patients suggests that alexithymia could mediate the familiality of alcoholism or SUD in the paternal line. 7 p.

Although externalizing behavior problems show in general a high stability over time, the course of externalizing behavior problems may vary from individual to individual. Our main goal was to investigate the predictive role of parenting on externalizing behavior problems. In addition, we investigated the potential moderating role of gender and genetic risk (operationalized as familial loading of externalizing behavior problems (FLE), and presence or absence of the dopamine receptor D4 (DRD4) 7-repeat and 4-repeat allele, respectively). Perceived parenting (rejection, emotional warmth, and overprotection) and FLE were assessed in a population-based sample of 1768 10- to 12-year-old adolescents. Externalizing behavior problems were assessed at the same age and 2 1/2 years later by parent report (CBCL) and self-report (YSR). DNA was extracted from blood samples. Parental emotional warmth predicted lower, and parental overprotection and rejection predicted higher levels of externalizing behavior problems. Whereas none of the parenting factors interacted with gender and the DRD4 7-repeat allele, we did find interaction effects with FLE and the DRD4 4-repeat allele. That is, the predictive effect of parental rejection was only observed in adolescents from low FLE families and the predictive effect of parental overprotection was stronger in adolescents not carrying the DRD4 4-repeat allele. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Resumen El trastorno por deficit de atencion/hiperactividad (TDAH) es un trastorno neuropsiquiatrico frecuente, con una intensa persistencia a lo largo del tiempo. Con frecuencia se utiliza medicacion para su manejo clinico. Tras la obtencion de una respuesta, la medicacion suele prescribirse durante meses o anos. No esta claro si un tratamiento farmacologico prolongado aporta un efecto beneficioso a largo plazo ni durante cuanto tiempo debe mantenerse. Por otra parte, existe cierta preocupacion respecto a la seguridad a largo plazo de la medicacion para el TDAH. El objetivo de esta revision sistematica es abordar estas cuestiones y presentar recomendaciones respecto a la decision de suspender o no el tratamiento farmacologico para el TDAH. Realizamos una busqueda en PubMed y nos centramos en los estudios de uso de medicacion con un tratamiento durante mas de 12 semanas en pacientes de 6-18 anos de edad. No hay estudios de grupos paralelos, controlados con placebo y doble ciego de larga duracion. Los estudios de retirada del tratamiento controlados con placebo y los estudios prospectivos observacionales de tratamiento a largo plazo aportan evidencias indicativas de que el tratamiento farmacologico proporciona una reduccion sustancial de los sintomas de TDAH y un menor deterioro de la funcion a lo largo de un periodo de unos 2 anos. Hay una evidencia limitada y poco consistente respecto a la ventaja de un tratamiento farmacologico a largo plazo, mas alla del control de los sintomas, por ejemplo en cuanto a mejora de la funcion social, los logros academicos, la situacion laboral y la evolucion psiquiatrica menos adversa. Por lo que respecta a la seguridad, los efectos a largo plazo de la medicacion sobre el crecimiento, la presion arterial y la frecuencia cardiaca son limitados, y la aparicion de sintomas suicidas, psicoticos y maniacos es muy poco frecuente. Los datos obtenidos en animales sobre efectos neurotoxicos de los psicoestimulantes no pueden extrapolarse directamente al ser humano. En consecuencia, las decisiones clinicas acerca de la instauracion, continuacion y suspension de la medicacion para el TDAH deben tomarse de forma individualizada. Deben utilizarse periodos sin medicacion a intervalos regulares para investigar la necesidad de mantener la medicacion. Deben abandonarse las asunciones no fundamentadas acerca de un efecto beneficioso continuado con el empleo de medicacion. Es necesaria una vigilancia cuidadosa de los efectos secundarios, que debe permitir detectar de forma temprana las senales de alarma.

Background The gene-gene associations in functional genomics are typically operationalized through correlational or information-theoretical measures: as an undirected graph of pairwise interactions between genes, where nodes represent genes and edges represent associations between pairs of genes. Such a functional connectivity can be uninformative as expression of genes tend to be very densely correlated. Moreover, functional connectivity does not contain information about the causal, or directed, interactions between genes. Causal inference would allow to answer the question whether phenotypes are a product of multiple gene-gene interactions or rather, if there are epicentres in the genome, leading to the phenotypes by influencing a number of genes in the network. Methods We use open-access data from study by Jaffe et al. (2014), reporting the expression of genes within the Dorsolateral Pre-Frontal Cortex (DLPFC) in post-mortem humans. We selected the data from 239 genes that were found to be associated with Obsessive Compulsive Disorder (OCD) in this study, as well as a random selection of 239 genes that were not found to be associated with OCD. In order to avoid confounders, we only consider the control cohort of N=102 participants. The data were normalized using log-transform, first gene-wise and then subject-wise. The method is based on definition of causality (Pearl, 2000): if a high expression level in gene 1 is associated with high functional link between gene 1 and gene 2, we can infer that gene 1 has certain causal effect on gene 2. This influence can be established by windowing the data. The confidence intervals are then computed through permutation testing. Results The results demonstrate that, as opposed to functional connectivity, the directed connectivity clearly differentiates gene co-expression network associated with OCD from an exemplary co-expression network unrelated with OCD. Although inhibition in the network is potentially possible (as influence of a value lower than zero), it was not found. The highest significance was found for the following: MED9 -> SLC25A3, MED9 -> RALB, CTSZ -> GAD1, RGS7 -> DOK1, DCLK1 -> C6ORF57. These results are interesting since MED9 takes part in creating new mRNA, therefore its increase can indeed influence the transcription of new mRNA. Also, most connections appear relatively symmetrical, although symmetry is now imposed by the method. However, one particular gene, Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B), has substantially higher influence on the most of the other genes in the network than the feedback influence of these genes on CAMK2B. This suggests that CAMK2B might be a key component of the gene-expression network underlying OCD. Discussion Classic interventional studies can be problematic in causal research in the gene co-expression networks as often dozens to thousands of genes underlie one phenotype. In this work, we propose a framework which addresses this issue and quantifies causal interactions without the need to employ any experimental manipulation. This can help in understanding hierarchy in gene co-expression networks, and possibly, in localizing the genes lying at the beginning of a causal chain leading to a particular phenotype. The method proposed in this study is novel, model-free and nonparametric, and the preliminary results when applied to the gene co-expression network of OCD in DLPFC are very promising. Therefore, we believe that it should be further tested, and validated in larger cohorts.

Background Autism Spectrum Disorders (ASDs) are highly heritable and recent findings indicate that at the group level, individuals with ASDs have a larger intracranial volume (ICV, a measure of total brain volume) compared to people without ASDs (results from the ENIGMA-ASD consortium comparing 1027 participants with ASDs and 1047 controls; van Rooij et al., submitted). There is now substantial evidence that ASDs represent the extreme end of a continuum of autistic traits within the general population. We previously showed shared genetic etiology and biology between autistic traits in the general population (n=1981) and ASDs (Bralten et al., Mol Psych, in press), which implies that general population studies of autistic traits could yield additional, novel ASD genes and loci. Methods We used a customized self-report questionnaire of autistic traits containing six items from the DSM-5 section about ASDs and twelve items from the Autism-Spectrum Quotient (AQ), administered to participants from the Nijmegen Biomedical Study (NBS), an adult population sample. We extended our previous genome-wide association study (GWAS) in NBS (new n=3098) investigating five factors/subscores - i.e., ‘childhood behaviour’, ‘rigidity’, ‘social skills’, ‘attention to detail’, and ‘imagination’ - constituting the best-fitting model to explain the observed variance in the total score of autistic traits. We are currently increasing the sample size of the autistic traits GWAS by meta-analyzing the NBS data with data from two other cohorts:(1) the Brain Imaging Genetics (Guadalupe et al. 2014) cohort (n=436), which has the same questionnaire available, and (2) the Raine study (n=965; Jones et al. 2014), which has AQ data available. We integrated the data of the ASD GWAS data from the large Psychiatric Genomics Consortium Autism Working Group (PGC-ASD; GWAS of 5305 ASD cases and 5305 pseudocontrols), with GWAS summary statistics from a recent, large-scale meta-analysis of ICV across 50 cohorts worldwide by the ENIGMA consortium (n=13171) testing potential mediating brain measures (Hibar et al. 2015). We performed LD score regression to investigate genetic correlation and SNP Effect Concordance Analysis (SECA) to investigate pleiotropy and concordance. Results In total, 174 single nucleotide polymorphisms (SNPs) were found to be associated with the total autistic traits score or any of its five factors/subscores at P Using summary statistic data of PGC-ASD and ENIGMA-ICV we were able to show significant genetic correlation between clinical ASD and population-based ICV measures (0.27, p=0.0025) and significant pleiotropy (p=0.0015) and concordance (p=0.0033) in the expected direction (larger ICV was associated with higher ASD risk). Discussion Our findings strengthen our hypothesis that novel ASD genes and loci can be identified by performing GWASs of autistic traits assessed through self-report questionnaires in the general population. We also showed a genetic correlation between ASDs and ICV indicating that the mechanism underlying ASD susceptibility may work through brain volume. We are excited to test how the genetic association results of our meta-analysis will stand compared to the genetics of ASDs and the genetics of an ASD-relevant brain measure (ICV), which will be presented at the conference.

Contains fulltext : 88056.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed. METHOD: We used case-control analyses of 896 cases with DSM-IV ADHD genotyped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affymetrix 6.0 arrays. A consensus SNP set was imputed using BEAGLE 3.0, resulting in an analysis dataset of 1,033,244 SNPs. Data were analyzed using a generalized linear model. RESULTS: No genome-wide significant associations were found. The most significant results implicated the following genes: PRKG1, FLNC, TCERG1L, PPM1H, NXPH1, PPM1H, CDH13, HK1, and HKDC1. CONCLUSIONS: The current analyses are a useful addition to the present literature and will make a valuable contribution to future meta-analyses. The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles. 01 september 2010

Contains fulltext : 88967.pdf (Publisher’s version ) (Closed access) BACKGROUND: Research examining the course of depressive symptoms during electroconvulsive therapy (ECT) is relatively scarce. OBJECTIVE: To classify patients according to the course of their depressive symptoms while receiving ECT. METHODS: The sample consisted of 156 consecutive patients receiving ECT for unipolar depressive disorder. Depressive symptoms were measured weekly with the Montgomery-Asberg Depression Rating Scale. Latent class analysis was applied to identify distinct trajectories of symptom improvement. RESULTS: We identified five classes of different trajectories (improvement rates) of depressive symptoms, i.e. fast improvement (39 patients), intermediate improvement (47 patients), slow improvement (30 patients), slow improvement with delayed onset (18 patients), and finally a trajectory with no improvement (20 patients). The course of depressive symptoms at the end of the treatment within the trajectories of intermediate improvement, slow improvement and slow improvement with delayed onset, was still improving and did not achieve a plateau. CONCLUSION: The different courses of depressive symptoms during ECT probably contribute to mixed results of prediction studies of ECT outcome. Data suggest that for a large group of patients no optimal clinical endpoint can be identified, other than full remission or no improvement at all, to discontinue ECT. 01 juli 2010