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1.  Specific neural correlates of successful learning and adaptation during social exchanges 
Cooperation and betrayal are universal features of social interactions, and knowing who to trust is vital in human society. Previous studies have identified brain regions engaged by decision making during social encounters, but the mechanisms supporting modification of future behaviour by utilizing social experience are not well characterized. Using functional magnetic resonance imaging (fMRI), we show that cooperation and betrayal during social exchanges elicit specific patterns of neural activity associated with future behaviour. Unanticipated cooperation leads to greater behavioural adaptation than unexpected betrayal, and is signalled by specific neural responses in the striatum and midbrain. Neural responses to betrayal and willingness to trust novel partners both decrease as the number of individuals encountered during repeated social encounters increases. We propose that, as social groups increase in size, uncooperative or untrustworthy behaviour becomes progressively less surprising, with cooperation becoming increasingly important as a stimulus for social learning. Effects on reputation of non-trusting decisions may also act to drive pro-social behaviour. Our findings characterize the dynamic neural processes underlying social adaptation, and suggest that the brain is optimized to cooperate with trustworthy partners, rather than avoiding those who might betray us.
PMCID: PMC3831550  PMID: 22956669
cooperation; trust; learning; neuroeconomics; fMRI
2.  Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence 
Molecular Autism  2014;5:18.
Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence.
Social-communication difficulties were ascertained at ages 8, 11, 14 and 17 years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N ≤ 5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P ≤ 10−5) were also followed up in Autism Genetic Resource Exchange pedigrees (N = 793) and the Autism Case Control cohort (Ncases/Ncontrols = 1,204/6,491).
GCTA heritability was strongest in childhood (h2(8 years) = 0.24) and especially in later adolescence (h2(17 years) = 0.45), with a marked drop during early to middle adolescence (h2(11 years) = 0.16 and h2(14 years) = 0.08). Genome-wide screens at ages 8 and 17 years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P = 9.3 × 10−9; genome-wide empirical P = 0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P = 7.9 × 10−8; genome-wide empirical P = 0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location = 0.007).
Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum.
PMCID: PMC3940728  PMID: 24564958
ALSPAC; ASD; Autism; GCTA heritability; GWAS; Social communication
3.  Behavioral epigenetics 
Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the University of Massachusetts Boston, “Behavioral Epigenetics” was held on October 29–30, 2010 at the University of Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epigenetic modulation of normative development, developmental disorders, and psychopathology. This report provides an overview of the research presented by leading scientists and lively discussion about the future of investigation at the behavioral epigenetic level.
PMCID: PMC3783959  PMID: 21615751
behavior; epigenetics; chromosome; gene regulation; transcription; methylation
4.  White matter microstructure correlates with autism trait severity in a combined clinical–control sample of high-functioning adults☆ 
NeuroImage : Clinical  2013;3:106-114.
Diffusion tensor imaging (DTI) studies have demonstrated white matter (WM) abnormalities in tracts involved in emotion processing in autism spectrum disorder (ASD), but little is known regarding the nature and distribution of WM anomalies in relation to ASD trait severity in adults. Increasing evidence suggests that ASD occurs at the extreme of a distribution of social abilities. We aimed to examine WM microstructure as a potential marker for ASD symptom severity in a combined clinical–neurotypical population. SIENAX was used to estimate whole brain volume. Tract-based spatial statistics (TBSS) was used to provide a voxel-wise comparison of WM microstructure in 50 high-functioning young adults: 25 ASD and 25 neurotypical. The severity of ASD traits was measured by autism quotient (AQ); we examined regressions between DTI markers of WM microstructure and ASD trait severity. Cognitive abilities, measured by intelligence quotient, were well-matched between the groups and were controlled in all analyses. There were no significant group differences in whole brain volume. TBSS showed widespread regions of significantly reduced fractional anisotropy (FA) and increased mean diffusivity (MD) and radial diffusivity (RD) in ASD compared with controls. Linear regression analyses in the combined sample showed that average whole WM skeleton FA was negatively influenced by AQ (p = 0.004), whilst MD and RD were positively related to AQ (p = 0.002; p = 0.001). Regression slopes were similar within both groups and strongest for AQ social, communication and attention switching scores. In conclusion, similar regression characteristics were found between WM microstructure and ASD trait severity in a combined sample of ASD and neurotypical adults. WM anomalies were relatively more severe in the clinically diagnosed sample. Both findings suggest that there is a dimensional relationship between WM microstructure and severity of ASD traits from neurotypical subjects through to clinical ASD, with reduced coherence of WM associated with greater ASD symptoms. General cognitive abilities were independent of the relationship between WM indices and ASD traits.
•Novel comparison of white matter microstructure in neurotypical and autistic adults•White matter coherence related to autistic trait severity in combined sample•The relationship between social intelligence and white matter is independent of IQ.•White matter anomalies are significantly more pronounced in the autistic subjects.
PMCID: PMC3791280  PMID: 24179854
Autism spectrum disorder; Autism quotient; Diffusion tensor imaging; Tract-based spatial statistics; White matter
5.  Autism-lessons from the X chromosome 
Recognized cases of autism spectrum disorders are on the rise. It is unclear whether this increase is attributable to secular trends in biological susceptibility, or to a change in diagnostic practices and recognition. One hint concerning etiological influences is the universally reported male excess (in the range of 4:1 to 10:1). Evidence suggests that genetic influences from the X chromosome play a crucial role in engendering this male vulnerability. In this review, we discuss three categories of genetic disease that highlight the importance of X-linked genes in the manifestation of an autistic phenotype: aneuploides (Turner syndrome and Klinefelter syndrome), trinucleotide expansions (Fragile X syndrome) and nucleotide mutations (Rett Syndrome, Neuroligins 3 & 4, and SLC6A8). The lessons from these diseases include an understanding of autistic features as a broad phenotype rather than as a single clinical entity, the role of multiple genes either alone or in concert with the manifestation of autistic features, and the role of epigenetic factors such as imprinting and X-inactivation in the expression of disease severity. Better understanding of the clinical phenotypes of social cognition and the molecular neurogenetics of X-linked gene disorders will certainly provide additional tools for understanding autism in the years to come.
PMCID: PMC2555419  PMID: 18985105
autism; X chromosome; social cognition; genetics
6.  Cortical Anatomy in Human X Monosomy 
NeuroImage  2009;49(4):2915-2923.
Turner syndrome (TS) is a model for X-chromosome influences on neurodevelopment because it is most commonly caused by absence of one X-chromosome, and associated with altered brain structure and function. However, all prior in vivo magnetic resonance imaging studies of the brain in TS have either used manual approaches or voxel-based-morphometry (VBM) to measure cortical volume (CV). These methods, unlike surface-based-morphometry (SBM), cannot measure the two neurobiologically distinct determinants of CV– cortical thickness (CT) and surface area (SA) – which have differing genetic determinants, and may be independently altered. Therefore, in 24 adults with X-monosomy and 19 healthy female controls, we used SBM to compare (i) lobar CV, CT and SA, (ii) an index of hemispheric gyrification (iii) CT throughout the cortical sheet, and (iv) CT correlation between cortical regions. Compared to controls, females with TS had (i) significantly increased CT and decreased SA in parietal and occipital lobes (resulting in no significant difference in lobar CV), (ii) reduced hemispheric gyrification bilaterally, (iii) foci of significantly increased CT involving inferior-temporal, lateral-occipital, intraparietal sulcus (IPS), cingulate, and orbito-frontal cortices, (iv) significantly reduced CT correlation between the left IPS and cortical regions including supramarginal and lateral-occipital gyri. Our findings suggest that females with TS have complex, sometimes ‘opposing’, abnormalities in SA/gyrification (decreased) and CT (increased); which can result in no overall detectable differences in CV. Thus haploinsufficiency of X-chromosome genes, may differentially impact the distinct mechanisms shaping SA (e.g. cortical folding) and CT (e.g. dendritic arborization/pruning). CT disruptions are maximal within and between cortical regions previously implicated in the TS cognitive phenotype.
PMCID: PMC3229914  PMID: 19948228
Turner syndrome; MRI; cortical thickness; structural covariance
7.  Links Between Co-occurring Social-Communication and Hyperactive-Inattentive Trait Trajectories 
There is overlap between an autistic and hyperactive-inattentive symptomatology when studied cross-sectionally. This study is the first to examine the longitudinal pattern of association between social-communication deficits and hyperactive-inattentive symptoms in the general population, from childhood through adolescence. We explored the interrelationship between trajectories of co-occurring symptoms, and sought evidence for shared prenatal/perinatal risk factors.
Study participants were 5,383 singletons of white ethnicity from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multiple measurements of hyperactive-inattentive traits (Strengths and Difficulties Questionnaire) and autistic social-communication impairment (Social Communication Disorder Checklist) were obtained between 4 and 17 years. Both traits and their trajectories were modeled in parallel using latent class growth analysis (LCGA). Trajectory membership was subsequently investigated with respect to prenatal/perinatal risk factors.
LCGA analysis revealed two distinct social-communication trajectories (persistently impaired versus low-risk) and four hyperactive-inattentive trait trajectories (persistently impaired, intermediate, childhood-limited and low-risk). Autistic symptoms were more stable than those of attention-deficit/hyperactivity disorder (ADHD) behaviors, which showed greater variability. Trajectories for both traits were strongly but not reciprocally interlinked, such that the majority of children with a persistent hyperactive-inattentive symptomatology also showed persistent social-communication deficits but not vice versa. Shared predictors, especially for trajectories of persistent impairment, were maternal smoking during the first trimester, which included familial effects, and a teenage pregnancy.
Our longitudinal study reveals that a complex relationship exists between social-communication and hyperactive-inattentive traits. Patterns of association change over time, with corresponding implications for removing exclusivity criteria for ASD and ADHD, as proposed for DSM-5.
PMCID: PMC3163265  PMID: 21871371
social-communication trait; hyperactive-inattentive trait; maternal smoking; teenage pregnancy; ALSPAC
8.  Association Between a High-Risk Autism Locus on 5p14 and Social Communication Spectrum Phenotypes in the General Population 
The American journal of psychiatry  2010;167(11):1364-1372.
Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum.
Study participants were 7,313 children from the Avon Longitudinal Study of Parents and Children. Single-trait and joint-trait genotype associations were investigated for 29 measures related to language and communication, verbal intelligence, social interaction, and behavioral adjustment, assessed between ages 3 and 12 years. Analyses were performed in one-sided or directed mode and adjusted for multiple testing, trait interrelatedness, and random genotype dropout.
Single phenotype analyses showed that an increased load of rs4307059 risk allele is associated with stereotyped conversation and lower pragmatic communication skills, as measured by the Children's Communication Checklist (at a mean age of 9.7 years). In addition a trend toward a higher frequency of identification of special educational needs (at a mean age of 11.8 years) was observed. Variation at rs4307059 was also associated with the phenotypic profile of studied traits. This joint signal was fully explained neither by single-trait associations nor by overall behavioral adjustment problems but suggested a combined effect, which manifested through multiple subthreshold social, communicative, and cognitive impairments.
Our results suggest that common variation at 5p14.1 is associated with social communication spectrum phenotypes in the general population and support the role of rs4307059 as a quantitative trait locus for autism spectrum disorder.
PMCID: PMC3008767  PMID: 20634369

Results 1-8 (8)