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Objective. Autism Spectrum Disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. However, the link between biological pathways and differences in brain anatomy, which may pave the way towards targeted therapeutic interventions, remains poorly understood.Methods. Our study examined neurodevelopmental differences in cortical thickness (CT) and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 270 typically developing controls (aged 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). We also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups, which differed in the severity and pattern of sensory features.Results. In addition to significant between-group differences in 'core' ASD brain regions (i.e. fronto-temporal and cingulate regions), we found that ASD individuals manifested as neuroanatomical outliers within the neurotypical CT range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e. accumulated) degree of neuroanatomical atypicality was significantly correlated with the higher polygenic scores for ASD, and other psychiatric conditions, and scaled with measures of symptom severity. Differences in CT deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission.Conclusions. Our findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping. shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. Sven Bölte discloses that he has in the last 5 years acted as an author, consultant or lecturer for Shire, Medice, Roche,

BackgroundHistological evidence suggests that autism spectrum disorder (ASD) is accompanied by a reduced integrity of the grey-white matter boundary. This has also recently been confirmed by a structural neuroimaging study in vivo reporting significantly reduced grey-white matter tissue contrast (GWC) in adult individuals (18–42 years of age) with ASD relative to typically developing (TD) controls. However, it remains unknown whether the neuroanatomical differences in ASD at the grey-white matter boundary are stable across development or are age-dependent.MethodsHere, we examined differences in the neurodevelopmental trajectories of GWC in a cross-sectional sample of 77 male ASD individuals and 76 typically developing (TD) controls across childhood and early adulthood (from 7 to 25 years).ResultsUsing nested model comparisons, we first established that the developmental trajectory of GWC is complex in many regions across the cortex and includes linear and non-linear effects of age. Second, while ASD individuals have significantly reduced GWC overall, these differences are age-dependent and are most prominent during childhood (< 15 years).ConclusionsTaken together, our findings suggest that differences in GWC in ASD are unlikely to reflect atypical grey matter cytoarchitecture alone, but may also represent other aspects of the cortical architecture such as age-dependent variability in myelin integrity.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0232-6) contains supplementary material, which is available to authorized users.

Dopamine dysfunction is associated with a wide range of neuropsychiatric disorders commonly treated pharmacologically or invasively. Recent studies provide evidence for a nonpharmacological and noninvasive alternative that allows similar manipulation of the dopaminergic system: transcranial direct current stimulation (tDCS). In rodents, tDCS has been shown to increase neural activity in subcortical parts of the dopaminergic system, and recent studies in humans provide evidence that tDCS over prefrontal regions induces striatal dopamine release and affects reward-related behavior. Based on these findings, we used fMRI in healthy human participants and measured the fractional amplitude of low-frequency fluctuations to assess spontaneous neural activity strength in regions of the mesostriatal dopamine system before and after tDCS over prefrontal regions (n ϭ 40, 22 females). In a second study, we examined the effect of a single dose of the dopamine precursor levodopa (L-DOPA) on mesostriatal fractional amplitude of low-frequency fluctuation values in male humans (n ϭ 22) and compared the results between both studies. We found that prefrontal tDCS and L-DOPA both enhance neural activity in core regions of the dopaminergic system and show similar subcortical activation patterns. We furthermore assessed the spatial similarity of whole-brain statistical parametric maps, indicating tDCS-andL-DOPA-inducedactivation,andϾ100neuronalreceptorgeneexpressionmapsbasedontranscriptionaldatafromtheAllenInstitute forBrainScience.Inlinewithaspecificactivationofthedopaminergicsystem,wefoundthatbothinterventionspredominantlyactivatedregions with high expression levels of the dopamine receptors D2 and D3.

The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual differences in the developmental trajectory of cortical thickness (CT) in childhood and adolescence, and their genomic underpinnings, in 33 individuals with ASD and 37 typically developing controls (aged 11–18 years). Moreover, we aimed to link regional atypical CT development to intra-individual variations in restricted and repetitive behavior (RRB) over a two-year time period. Individuals with ASD showed significantly reduced cortical thinning in several of the brain regions functionally related to wider autism symptoms and traits (e.g., fronto-temporal and cingulate cortices). The spatial patterns of the neuroanatomical differences in CT were enriched for genes known to be associated with ASD at a genetic and transcriptomic level. Further, intra-individual differences in CT correlated with within-subject variability in the severity of RRBs. Our findings represent an important step towards characterizing the neuroanatomical underpinnings of ASD across development based upon measures of CT. Moreover, our findings provide important novel insights into the link between microscopic and macroscopic pathology in ASD, as well as their relationship with different clinical ASD phenotypes.

Increased cortical thickness (CT) has been reported in Down syndrome (DS) during childhood and adolescence, but it remains unclear, which components of the neural architecture underpin these increases and if CT remains altered in adults. Among other factors, differences in CT measures could be driven by reduced tissue contrast between grey and white matter (GWC), which has been reported in neurodegenerative disorders, such as Alzheimer's disease. Using structural magnetic resonance imaging, we therefore examined differences in CT and GWC in 26 adults with DS, and 23 controls, to (1) examine between-group differences in CT in adulthood, (2) establish whether DS is associated with significant reductions in GWC, and (3) determine the influence of GWC variability on between-group differences in CT. As hypothesized, we observed that DS was accompanied by wide-spread increases in CT, and significantly reduced GWC in several large clusters distributed across the cortex. Out of all vertices with a significant between-group difference in CT, 38.50% also displayed a significant reduction in GWC. This percentage of overlap was also statistically significant and extremely unlikely to be obtained by chance (p = .0002). Differences in GWC thus seem to explain some, although not all, of the differences in CT observed in DS. In addition, our study is the first to extend previous in vivo reports of altered CT in DS during childhood and adolescence to older adults, implying that the regional pattern of neuroanatomical differences associated with DS remains stable across the lifespan.

22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans, with a heterogenous clinical presentation including medical, behavioural and psychiatric conditions. Previous neuroimaging studies examining the neuroanatomical underpinnings of 22q11.2DS show alterations in cortical volume (CV), cortical thickness (CT) and surface area (SA). The aim of this study was to identify (1) the spatially distributed networks of differences in CT and SA in 22q11.2DS compared to controls, (2) their unique and spatial overlap, as well as (3) their relative contribution to observed differences in CV. Structural MRI scans were obtained from 62 individuals with 22q11.2DS and 57 age-and-gender-matched controls (aged 6–31). Using FreeSurfer, we examined differences in vertex-wise estimates of CV, CT and SA at each vertex, and compared the frequencies of vertices with a unique or overlapping difference for each morphometric feature. Our findings indicate that CT and SA make both common and unique contributions to volumetric differences in 22q11.2DS, and in some areas, their strong opposite effects mask differences in CV. By identifying the neuroanatomic variability in 22q11.2DS, and the separate contributions of CT and SA, we can start exploring the shared and distinct mechanisms that mediate neuropsychiatric symptoms across disorders, e.g. 22q11.2DS-related ASD and/or psychosis/schizophrenia.

The excitatory/inhibitory (E/I) imbalance hypothesis posits that imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) mechanisms underlies the behavioral characteristics of autism. However, how E/I imbalance arises and how it may differ across autism symptomatology and brain regions is not well understood. We used innovative analysis methods—combining competitive gene-set analysis and gene-expression profiles in relation to cortical thickness (CT) to investigate relationships between genetic variance, brain structure and autism symptomatology of participants from the AIMS-2-TRIALS LEAP cohort (autism = 359, male/female = 258/101; neurotypical control participants = 279, male/female = 178/101) aged 6–30 years. Using competitive gene-set analyses, we investigated whether aggregated genetic variation in glutamate and GABA gene-sets could be associated with behavioral measures of autism symptoms and brain structural variation. Further, using the same gene-sets, we corelated expression profiles throughout the cortex with differences in CT between autistic and neurotypical control participants, as well as in separate sensory subgroups. The glutamate gene-set was associated with all autism symptom severity scores on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) within the autistic group. In adolescents and adults, brain regions with greater gene-expression of glutamate and GABA genes showed greater differences in CT between autistic and neurotypical control participants although in opposing directions. Additionally, the gene expression profiles were associated with CT profiles in separate sensory subgroups. Our results suggest complex relationships between E/I related genetics and autism symptom profiles as well as brain structure alterations, where there may be differential roles for glutamate and GABA.