David L. Pauls

The present study examined attention and memory load-dependent differences in the brain activation and deactivation patterns between adolescents with autism spectrum disorders (ASDs) and typically developing (TD) controls using functional magnetic resonance imaging. Attentional (0-back) and working memory (WM; 2-back) processing and load differences (0 vs. 2-back) were analysed. WM-related areas activated and default mode network deactivated normally in ASDs as a function of task load. ASDs performed the attentional 0-back task similarly to TD controls but showed increased deactivation in cerebellum and right temporal cortical areas and weaker activation in other cerebellar areas. Increasing task load resulted in multiple responses in ASDs compared to TD and in inadequate modulation of brain activity in right insula, primary somatosensory, motor and auditory cortices. The changes during attentional task may reflect compensatory mechanisms enabling normal behavioral performance. The inadequate memory load-dependent modulation of activity suggests diminished compensatory potential in ASD.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as ‘response’ (n=514) or ‘non-response’ (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10⁻⁸), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P−5) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10⁻⁶ and 8.41 × 10⁻⁶, respectively. The other 35 variations with signals of potential significance (P−4) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

In resting state functional magnetic resonance imaging (fMRI) studies of autism spectrum disorders (ASDs) decreased frontal-posterior functional connectivity is a persistent finding. However, the picture of the default mode network (DMN) hypoconnectivity remains incomplete. In addition, the functional connectivity analyses have been shown to be susceptible even to subtle motion. DMN hypoconnectivity in ASD has been specifically called for re-evaluation with stringent motion correction, which we aimed to conduct by so-called scrubbing. A rich set of default mode subnetworks can be obtained with high dimensional group independent component analysis (ICA) which can potentially provide more detailed view of the connectivity alterations. We compared the DMN connectivity in high-functioning adolescents with ASDs to typically developing controls using ICA dual-regression with decompositions from typical to high dimensionality. Dual-regression analysis within DMN subnetworks did not reveal alterations but connectivity between anterior and posterior DMN subnetworks was decreased in ASD. The results were very similar with and without motion scrubbing thus indicating the efficacy of the conventional motion correction methods combined with ICA dual-regression. Specific dissociation between DMN subnetworks was revealed on high ICA dimensionality, where networks centered at the medial prefrontal cortex and retrosplenial cortex showed weakened coupling in adolescents with ASDs compared to typically developing control participants. Generally the results speak for disruption in the anterior-posterior DMN interplay on the network level whereas local functional connectivity in DMN seems relatively unaltered.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469 410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case–control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case–control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10⁻⁶ and P=3.44 × 10⁻⁶), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10⁻⁸. However, when trios were meta-analyzed with the case–control samples, the P-value for this variant was 3.62 × 10⁻⁵, losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio–case–control sample, a significant enrichment of methylation QTLs (PP=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio–case–control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10⁻⁶). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10⁻⁷ for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

FMRI was performed with the dynamic facial expressions fear and happiness. This was done to detect differences in valence processing between 25 subjects with autism spectrum disorders (ASDs) and 27 typically developing controls. Valence scaling was abnormal in ASDs. Positive valence induces lower deactivation and abnormally strong activity in ASD in multiple regions. Negative valence increased deactivation in visual areas in subjects with ASDs. The most marked differences between valences focus on fronto-insular and temporal regions. This supports the idea that subjects with ASDs may have difficulty in passive processing of the salience and mirroring of expressions. When the valence scaling of brain activity fails, in contrast to controls, these areas activate and/or deactivate inappropriately during facial stimuli presented dynamically.

Tourette's disorder (TD) frequently co‐occurs with attention‐deficit/hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). While the relationship between TD and OCD suggests that they share etiological factors, the exact relationship between TD and ADHD is less clear. The goal of the current analyses was to understand better the familial relationship between DSM‐IV ADHD and TD. Direct interview diagnostic data from a case–control study of 692 relatives of 75 comorbid TD and ADHD (TD + ADHD), 74 TD without ADHD (TD Only), 41 ADHD without TD (ADHD Only), and 49 control probands were analyzed. Hierarchical loglinear modeling was used to explore association patterns between TD, ADHD, and OCD or sub‐clinical OCD (OCD/OCDsub) diagnoses among the 190 affected probands and their 538 relatives. The presence of OCD or OCDsub diagnosis in a proband was associated with a significantly increased risk of comorbid TD + ADHD in his/her relatives. The finding of an association between TD, ADHD and a proband OCD/OCDsub diagnosis was unexpected. The current results suggest that TD, ADHD, and OCD symptoms have overlapping neurobiology when occurring in families of TD and/or ADHD probands.

Obsessive-compulsive disorder (OCD) is a serious psychiatric disorder that affects approximately 2% of the populations of children and adults. Family aggregation studies have demonstrated that OCD is familial, and results from twin studies demonstrate that the familiality is due in part to genetic f …