Sarah Paterson

Differences in White Matter Fiber Tract Development Present From 6 to 24 Months in Infants With Autism

OBJECTIVE Evidence from prospective studies of high-risk infants suggests that early symptoms of autism usually emerge late in the first or early in the second year of life after a period of relatively typical development. The authors prospectively examined white matter fiber tract organization from 6 to 24 months in high-risk infants who developed autism spectrum disorders (ASDs) by 24 months. METHOD The participants were 92 high-risk infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months; a majority contributed additional imaging data at 12 and/or 24 months. At 24 months, 28 infants met criteria for ASDs and 64 infants did not. Microstructural properties of white matter fiber tracts reported to be associated with ASDs or related behaviors were characterized by fractional anisotropy and radial and axial diffusivity. RESULTS The fractional anisotropy trajectories for 12 of 15 fiber tracts differed significantly between the infants who developed ASDs and those who did not. Development for most fiber tracts in the infants with ASDs was characterized by higher fractional anisotropy values at 6 months followed by slower change over time relative to infants without ASDs. Thus, by 24 months of age, those with ASDs had lower values. CONCLUSIONS These results suggest that aberrant development of white matter pathways may precede the manifestation of autistic symptoms in the first year of life. Longitudinal data are critical to characterizing the dynamic age-related brain and behavior changes underlying this neurodevelopmental disorder.

Atypical development of language and social communication in toddlers with Williams syndrome

Williams syndrome (WS) is a genetic disorder which results in an uneven cognitive profile. Despite superior language compared to other syndromes in the phenotypic outcome, toddlers with WS are as delayed in their language onset and early linguistic development as are toddlers with other syndromes. The cause of this delay in WS is as yet unknown. In a series of experiments, we examined whether atypical socio-interactive precursors to language could contribute to the explanation of the late language onset and atypical developmental pathways observed in WS. Experiment 1 showed that despite superficially good social skills, toddlers with WS were only proficient at dyadic interaction. They were impaired in triadic interaction, essential for the referential uses of language, and showed none of the correlations between socio-interactive markers and language seen in the typical controls. Experiment 2 focused on the comprehension and production of referential pointing. Again, the WS group was impaired, despite vocabulary levels higher than those of typically developing controls. Finally, Experiment 3 examined fine motor skills. The WS lack of pointing could not be explained in terms of motor impairments, since the WS toddlers were proficient at fine motor control, such as the pincer grip. Overall, our data indicate that the early stages of WS language follow an atypical pathway. The findings challenge the frequent claims in the literature that individuals with Williams syndrome have preserved linguistic and social skills.

Early brain development in infants at high risk for autism spectrum disorder

Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6–12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.

Dethroning the myth: cognitive dissociations and innate modularity in Williams syndrome.

Despite increasing empirical data to the contrary, it continues to be claimed that morphosyntax and face processing skills of people with Williams syndrome are intact. This purported intactness, which coexists with mental retardation, is used to bolster claims about innately specified, independently functioning modules, as if the atypically developing brain were simply a normal brain with parts intact and parts impaired. Yet this is highly unlikely, given the dynamics of brain development and the fact that in a genetic microdeletion syndrome the brain is developing differently from the moment of conception, throughout embryogenesis, and during postnatal brain growth. In this article, we challenge the intactness assumptions, using evidence from a wide variety of studies of toddlers, children, and adults with Williams syndrome.

White Matter Microstructure and Atypical Visual Orienting in 7-Month-Olds at Risk for Autism

OBJECTIVE The authors sought to determine whether specific patterns of oculomotor functioning and visual orienting characterize 7-month-old infants who later meet criteria for an autism spectrum disorder (ASD) and to identify the neural correlates of these behaviors. METHOD Data were collected from 97 infants, of whom 16 were high-familial-risk infants later classified as having an ASD, 40 were high-familial-risk infants who did not later meet ASD criteria (high-risk negative), and 41 were low-risk infants. All infants underwent an eye-tracking task at a mean age of 7 months and a clinical assessment at a mean age of 25 months. Diffusion-weighted imaging data were acquired for 84 of the infants at 7 months. Primary outcome measures included average saccadic reaction time in a visually guided saccade procedure and radial diffusivity (an index of white matter organization) in fiber tracts that included corticospinal pathways and the splenium and genu of the corpus callosum. RESULTS Visual orienting latencies were longer in 7-month-old infants who expressed ASD symptoms at 25 months compared with both high-risk negative infants and low-risk infants. Visual orienting latencies were uniquely associated with the microstructural organization of the splenium of the corpus callosum in low-risk infants, but this association was not apparent in infants later classified as having an ASD. CONCLUSIONS Flexibly and efficiently orienting to salient information in the environment is critical for subsequent cognitive and social-cognitive development. Atypical visual orienting may represent an early prodromal feature of an ASD, and abnormal functional specialization of posterior cortical circuits directly informs a novel model of ASD pathogenesis.

Early Word Segmentation by Infants and Toddlers With Williams Syndrome

This study tested the ability of English infants and toddlers with Williams syndrome to segment, that is, to extract from fluent speech, bisyllabic nouns that had either a strong–-weak stress pattern (predominant in English), or a weak–-strong stress pattern. The testing procedure was the same for both types of words: Children were familiarized with instances of isolated nouns, and then tested on their recognition of these nouns embedded in passages. In English, typically developing infants start segmenting strong–-weak nouns by 7.5 months of age, and weak–-strong nouns by 10.5 months. Our clinical population was able to segment strong–-weak nouns, but failed, despite chronological ages above 15 months, to segment weak–-strong words. These results suggest that the development of word segmentation is seriously delayed in Williams syndrome. This deficit in early phonological processing may contribute to a fuller understanding of the late lexical onset in this population, a phenomenon that had hitherto only been explained in terms of cognitive and semantic deficits.

Network inefficiencies in autism spectrum disorder at 24 months.

Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral symptoms that emerge during the first years of life. Associated with these symptoms are differences in the structure of a wide array of brain regions, and in the connectivity between these regions. However, the use of cohorts with large age variability and participants past the generally recognized age of onset of the defining behaviors means that many of the reported abnormalities may be a result of cascade effects of developmentally earlier deviations. This study assessed differences in connectivity in ASD at the age at which the defining behaviors first become clear. There were 113 24-month-old participants at high risk for ASD, 31 of whom were classified as ASD, and 23 typically developing 24-month-old participants at low risk for ASD. Utilizing diffusion data to obtain measures of the length and strength of connections between anatomical regions, we performed an analysis of network efficiency. Our results showed significantly decreased local and global efficiency over temporal, parietal and occipital lobes in high-risk infants classified as ASD, relative to both low- and high-risk infants not classified as ASD. The frontal lobes showed only a reduction in global efficiency in Broca’s area. In addition, these same regions showed an inverse relation between efficiency and symptom severity across the high-risk infants. The results suggest delay or deficits in infants with ASD in the optimization of both local and global aspects of network structure in regions involved in processing auditory and visual stimuli, language and nonlinguistic social stimuli.

Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age

Functional brain imaging of 6-month-old infants with a high familial risk for autism predicts a diagnosis of autism at 24 months of age. Predicting the future with brain imaging In a new study, Emerson et al. show that brain function in infancy can be used to accurately predict which high-risk infants will later receive an autism diagnosis. Using machine learning techniques that identify patterns in the brain’s functional connections, Emerson and colleagues were able to predict with greater than 96% accuracy whether a 6-month-old infant would develop autism at 24 months of age. These findings must be replicated, but they represent an important step toward the early identification of individuals with autism before its characteristic symptoms develop. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% [95% confidence interval (CI), 62.9 to 100], correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified [specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3)]. These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD.

Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism

BACKGROUND We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. METHODS A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. RESULTS Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohens d = 0.54). Extra-axial CSF volume remained elevated through 24 months (d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. CONCLUSIONS This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

Accurate age classification of 6 and 12 month-old infants based on resting-state functional connectivity magnetic resonance imaging data

Highlights • SVMs classified 6 versus 12 month-old infants above chance based on fcMRI data alone.• We carefully accounted for the effects of fcMRI motion artifact.• These results coincide with a period of dramatic change in infant development.• Two interpretations about connections supporting this age categorization are given.