White matter development and language abilities during infancy in autism spectrum disorder.

White matter (WM) fiber tract differences are present in autism spectrum disorder (ASD) and could be important markers of behavior. One of the earliest phenotypic differences in ASD are language atypicalities. Although language has been linked to WM in typical development, no work has evaluated this association in early ASD. Participants came from the Infant Brain Imaging Study and included 321 infant siblings of children with ASD at high likelihood (HL) for developing ASD; 70 HL infants were later diagnosed with ASD (HL-ASD), and 251 HL infants were not diagnosed with ASD (HL-Neg). A control sample of 140 low likelihood infants not diagnosed with ASD (LL-Neg) were also included. Infants contributed expressive language, receptive language, and diffusion tensor imaging data at 6-, 12-, and 24 months. Mixed effects regression models were conducted to evaluate associations between WM and language trajectories. Trajectories of microstructural changes in the right arcuate fasciculus were associated with expressive language development. HL-ASD infants demonstrated a different developmental pattern compared to the HL-Neg and LL-Neg groups, wherein the HL-ASD group exhibited a positive association between WM fractional anisotropy and language whereas HL-Neg and LL-Neg groups showed weak or no association. No other fiber tracts demonstrated significant associations with language. In conclusion, results indicated arcuate fasciculus WM is linked to language in early toddlerhood for autistic toddlers, with the strongest associations emerging around 24 months. To our knowledge, this is the first study to evaluate associations between language and WM development during the pre-symptomatic period in ASD.

Mate selection and current trends in the prevalence of autism.

BACKGROUND: According to the most recent U.S. CDC surveillance data, the rise in prevalence of childhood autism spectrum disorder among minority children has begun to outpace that of non-Hispanic white children. Since prior research has identified possible differences in the extent of mate selection for autistic traits across families of different ethnicity, this study examined variation in autism related traits in contemporaneous, epidemiologically ascertained samples of spousal pairs representing Hispanic and non-Hispanic white populations. The purpose was to determine whether discrepancies by ethnicity could contribute to differential increases in prevalence in the current generation of young children. METHODS: Birth records were used to identify all twin pairs born between 2011 and 2013 in California and Missouri. Families were selected at random from pools of English-speaking Hispanic families in California and Non-Hispanic White families in Missouri. Autistic trait data of parents was obtained using the Adult Report Form of the Social Responsiveness Scale (SRS-2). RESULTS: We did not identify a statistically significant difference in the degree of mate selection for autism related traits between Hispanic and non-Hispanic white spousal pairs. However, the degree of spousal correlation observed in this recent cohort was pronounced (on the order of ICC 0.45) and exceeded that typically reported in prior research (on the order of 0.30), surpassing also widely reported estimates for sibling correlation (also on the order of 0.30). LIMITATIONS: The sample did not allow for a direct appraisal of change in the magnitude of spousal correlation over time and the ascertainments of trait burden were derived from spouse report. CONCLUSION: Across two epidemiologically ascertained samples of spousal pairs representing Hispanic and non-Hispanic white families across two U.S. states (respectively, California and Missouri), the extent of autism-related trait co-variation for parents of the current generation of young children is substantial and exceeds correlations typically observed for siblings. Given the heritability of these traits and their relation to autism risk, societal trends in the degree of mate selection for these traits should be considered as possible contributors to subtle increases in the incidence of autism over time and across generations.

Mapping neural correlates of biological motion perception in autistic children using high-density diffuse optical tomography.

BACKGROUND: Autism spectrum disorder (ASD), a neurodevelopmental disorder defined by social communication deficits plus repetitive behaviors and restricted interests, currently affects 1/36 children in the general population. Recent advances in functional brain imaging show promise to provide useful biomarkers of ASD diagnostic likelihood, behavioral trait severity, and even response to therapeutic intervention. However, current gold-standard neuroimaging methods (e.g., functional magnetic resonance imaging, fMRI) are limited in naturalistic studies of brain function underlying ASD-associated behaviors due to the constrained imaging environment. Compared to fMRI, high-density diffuse optical tomography (HD-DOT), a non-invasive and minimally constraining optical neuroimaging modality, can overcome these limitations. Herein, we aimed to establish HD-DOT to evaluate brain function in autistic and non-autistic school-age children as they performed a biological motion perception task previously shown to yield results related to both ASD diagnosis and behavioral traits. METHODS: We used HD-DOT to image brain function in 46 ASD school-age participants and 49 non-autistic individuals (NAI) as they viewed dynamic point-light displays of coherent biological and scrambled motion. We assessed group-level cortical brain function with statistical parametric mapping. Additionally, we tested for brain-behavior associations with dimensional metrics of autism traits, as measured with the Social Responsiveness Scale-2, with hierarchical regression models. RESULTS: We found that NAI participants presented stronger brain activity contrast (coherent > scrambled) than ASD children in cortical regions related to visual, motor, and social processing. Additionally, regression models revealed multiple cortical regions in autistic participants where brain function is significantly associated with dimensional measures of ASD traits. LIMITATIONS: Optical imaging methods are limited in depth sensitivity and so cannot measure brain activity within deep subcortical regions. However, the field of view of this HD-DOT system includes multiple brain regions previously implicated in both task-based and task-free studies on autism. CONCLUSIONS: This study demonstrates that HD-DOT is sensitive to brain function that both differentiates between NAI and ASD groups and correlates with dimensional measures of ASD traits. These findings establish HD-DOT as an effective tool for investigating brain function in autistic and non-autistic children. Moreover, this study established neural correlates related to biological motion perception and its association with dimensional measures of ASD traits.

Infant Visual Brain Development and Inherited Genetic Liability in Autism.

OBJECTIVE: Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings. METHODS: In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months. RESULTS: Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy. CONCLUSIONS: The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.

Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk.

BACKGROUND: Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3-5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling. METHODS: We assembled what is to our knowledge the largest collection of data on the ability of four measurable characteristics of unaffected prospective parents to specify risk for autism among their offspring: (1) sub clinical autistic trait burden, (2) parental history of a sibling with ASD, (3) transmitted autosomal molecular genetic abnormalities, and (4) parental age. Leveraging phenotypic and genetic data in curated family cohorts, we evaluate the respective associations between these factors and child outcome when autism is present in the family in the parental generation. RESULTS: All four characteristics were associated with elevation in offspring risk; however, the magnitude of their predictive power-with the exception of isolated rare inherited pathogenic variants -does not yet reach a threshold that would typically be considered actionable for reproductive decision-making. CONCLUSIONS: Individual specification of risk to offspring of adults in ASD-affected families is not straightforwardly improved by ascertainment of parental phenotype, and it is not yet clear whether genomic screening of prospective parents in families affected by idiopathic ASD is warranted as a clinical standard. Systematic screening of affected family members for heritable pathogenic variants, including rare sex-linked mutations, will identify a subset of families with substantially elevated transmission risk. Polygenic risk scores are only weakly predictive at this time but steadily improving and ultimately may enable more robust prediction either singly or when combined with the risk variables examined in this study.