Failure to deactivate the default mode network indicates a possible endophenotype of autism.

BACKGROUND: Reduced activity during cognitively demanding tasks has been reported in the default mode network in typically developing controls and individuals with autism. However, no study has investigated the default mode network (DMN) in first-degree relatives of those with autism (such as siblings) and it is not known whether atypical activation of the DMN is specific to autism or whether it is also present in unaffected relatives. Here we use functional magnetic resonance imaging to investigate the pattern of task-related deactivation during completion of a visual search task, the Embedded Figures Task, in teenagers with autism, their unaffected siblings and typically developing controls. FINDINGS: We identified striking reductions in deactivation during the Embedded Figures Task in unaffected siblings compared to controls in brain regions corresponding to the default mode network. Adolescents with autism and their unaffected siblings similarly failed to deactivate regions, including posterior cingulate and bilateral inferior parietal cortex. CONCLUSIONS: This suggests that a failure to deactivate these regions is a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Default Mode Hypoconnectivity Underlies a Sex-Related Autism Spectrum.

BACKGROUND: Females and males differ significantly in the prevalence and presentation of autism spectrum conditions. One theory of this effect postulates that autistic traits lie on a sex-related continuum in the general population, and autism represents the extreme male end of this spectrum. This theory predicts that any feature of autism in males should 1) be present in autistic females, 2) differentiate between the sexes in the typical population, and 3) correlate with autistic traits. We tested these three predictions for default mode network (DMN) hypoconnectivity during the resting state, one of the most robustly found neurobiological differences in autism. METHODS: We analyzed a primary dataset of adolescents (N = 121, 12-18 years of age) containing a relatively large number of females and a replication multisite dataset including children, adolescents, and adults (N = 980, 6-58 years of age). We quantified the average connectivity between DMN regions and tested for group differences and correlation with behavioral performance using robust regression. RESULTS: We found significant differences in DMN intraconnectivity between female controls and females with autism (p = .001 in the primary dataset; p = .009 in the replication dataset), and between female controls and male controls (p = .036 in the primary dataset; p = .002 in the replication dataset). We also found a significant correlation between DMN intraconnectivity and performance on a mentalizing task (p = .001) in the primary dataset. CONCLUSIONS: Collectively, these findings provide the first evidence for DMN hypoconnectivity as a behaviorally relevant neuroimaging phenotype of the sex-related spectrum of autistic traits, of which autism represents the extreme case.The authors thank the participants and their families for their participation and the autism support organizations who assisted with recruitment. We thank colleagues at the Brain Mapping Unit for methodological discussions. The present analysis was funded by a Rubicon Fellowship from the Netherlands Organization for Scientific Research (RJFY), a NARSAD Young Investigator award (MR) and by the Isaac Newton Trust (MR). Data collection was funded by a Clinical Scientist Fellowship from the UK Medical Research Council (MRC) (G0701919) to MDS, imaging data acquired from the depressed adolescents was from the MR-IMPACT study funded by the Medical Research Council. NR was supported by the Cambridge Trust; LRC was supported by the Gates Cambridge Scholarship Trust; RH was supported by the MRC and the Innovative Medicines Initiative (IMI) during the period of this work. The study was conducted in association with the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for Cambridgeshire, and Peterborough National Health Service (NHS) Foundation Trust. The Brain Mapping Unit (RJFY, RLM, NR, JS, ETB and MR) is part of the Behavioral & Clinical Neuroscience Institute, which is funded by the MRC and the Wellcome Trust. High performance computing facilities were supported by the NIHR Cambridge Biomedical Research Centre.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Elsevier

Organizational effects of fetal testosterone on human corpus callosum size and asymmetry

Previous theory and research in animals has identified the critical role that fetal testosterone (FT) plays in organizing sexually dimorphic brain development. However, to date there are no studies in humans directly testing the organizational effects of FT on structural brain development. In the current study we investigated the effects of FT on corpus callosum size and asymmetry. High-resolution structural magnetic resonance images (MRI) of the brain were obtained on 28 8-11-year-old boys whose exposure to FT had been previously measured in utero via amniocentesis conducted during the second trimester. Although there was no relationship between FT and midsaggital corpus callosum size, increasing FT was significantly related to increasing rightward asymmetry (e.g., Right>Left) of a posterior subsection of the callosum, the isthmus, that projects mainly to parietal and superior temporal areas. This potential organizational effect of FT on rightward callosal asymmetry may be working through enhancing the neuroprotective effects of FT and result in an asymmetric distribution of callosal axons. We suggest that this possible organizational effect of FT on callosal asymmetry may also play a role in shaping sexual dimorphism in functional and structural brain development, cognition, and behavior

Failure to deactivate the default mode network indicates a possible endophenotype of autism

Abstract Background Reduced activity during cognitively demanding tasks has been reported in the default mode network in typically developing controls and individuals with autism. However, no study has investigated the default mode network (DMN) in first-degree relatives of those with autism (such as siblings) and it is not known whether atypical activation of the DMN is specific to autism or whether it is also present in unaffected relatives. Here we use functional magnetic resonance imaging to investigate the pattern of task-related deactivation during completion of a visual search task, the Embedded Figures Task, in teenagers with autism, their unaffected siblings and typically developing controls. Findings We identified striking reductions in deactivation during the Embedded Figures Task in unaffected siblings compared to controls in brain regions corresponding to the default mode network. Adolescents with autism and their unaffected siblings similarly failed to deactivate regions, including posterior cingulate and bilateral inferior parietal cortex. Conclusions This suggests that a failure to deactivate these regions is a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings.</p

Impact of lifestyle factors on ovarian function and reproductive health in women

Copyright © 2007 Future Medicine LtdLindsay R Chura & Robert J Norma

Obese Women Exhibit Differences in Ovarian Metabolites, Hormones, and Gene Expression Compared with Moderate-Weight Women

Context: Obese women experience longer times to conception, even if they are young and cycling regularly, which is suggestive of alterations in ovarian function during the periconceptual period. Objective: This study sought to determine whether there are alterations in the preovulatory follicular environment that are likely to influence oocyte developmental competence. Design, Setting, and Participants: Women attending a private infertility clinic were categorized into body mass index (BMI) groups of moderate (n = 33; BMI 20–24.9 kg/m2), overweight (n = 31; BMI 25–29.9 kg/m2), and obese (n =32; BMI 30 kg/m2). Intervention: For each patient, follicular fluid was recovered from single follicles at oocyte retrieval, granulosa cells were pooled from multiple follicular aspirates and cumulus cells were pooled after separation from the oocytes. Main Outcome Measures: Follicle fluid was assayed for hormones and metabolites. Granulosa and cumulus cells were analyzed for mRNA expression of insulin signaling components (IRS-2 and Glut4), glucose-regulated genes (ChREBP, ACC, and FAS) and insulin-regulated genes (SREBP-1, CD36, and SR-BI) associated with obesity/insulin resistance. Results: Increasing BMI was associated with increased follicular fluid insulin (P &lt; 0.001), lactate (P = 0.01), triglycerides (P = 0.0003), and C-reactive protein (P &lt; 0.0001) as well as decreased SHBG (P = 0.001). IRS-2, Glut4, ChREBP, and SREBP exhibited cell-type-specific expression but were not affected by BMI. CD36 and SRBI mRNA were modestly altered in granulosa cells of obese compared with moderate-weight women. Conclusions: Obese women exhibit an altered ovarian follicular environment, particularly increased metabolite, C-reactive protein, and androgen activity levels, which may be associated with poorer reproductive outcomes typically observed in these patients.Rebecca L. Robker, Lisa K. Akison, Brenton D. Bennett, Penny N. Thrupp, Lindsay R. Chura, Darryl L. Russell, Michelle Lane and Robert J. Norma