This study investigated the extent to which sensory responsivity in infancy contributes to adaptive behavior development among toddlers at high-familial likelihood for autism. Prospective, ...longitudinal data were analyzed for 218 children, 58 of whom received an autism diagnosis. Results indicated that sensory profiles at age one year (hyperresponsivity, sensory seeking) were negatively associated with later adaptive behavior, particularly for socialization, at age 3 years regardless of diagnostic status. These results suggest that early differences in sensory responsivity may have downstream developmental consequences related to social development among young children with high-familial likelihood for autism.
Specific differences in visual orienting, critical in social-cognitive development, are associated with differences in white matter microstructure of the splenium.
ObjectiveThe 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.MethodData 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.ResultsVisual 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.ConclusionsFlexibly 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.
Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, ...impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.
Objective: To examine patterns of early brain growth in young children with fragile X syndrome (FXS) compared with a comparison group (controls) and a group with idiopathic autism. Method: The study ...included 53 boys 18 to 42 months of age with FXS, 68 boys with idiopathic autism (autism spectrum disorder), and a comparison group of 50 typically developing and developmentally delayed controls. Structural brain volumes were examined using magnetic resonance imaging across two time points, at 2 to 3 and again at 4 to 5 years of age, and total brain volumes and regional (lobar) tissue volumes were examined. In addition, a selected group of subcortical structures implicated in the behavioral features of FXS (e.g., basal ganglia, hippocampus, amygdala) was studied. Results: Children with FXS had larger global brain volumes compared with controls but were not different than children with idiopathic autism, and the rate of brain growth from 2 to 5 years of age paralleled that seen in controls. In contrast to children with idiopathic autism who had generalized cortical lobe enlargement, children with FXS showed specific enlargement in the temporal lobe white matter, cerebellar gray matter, and caudate nucleus, but a significantly smaller amygdala. Conclusions: This structural longitudinal magnetic resonance imaging study of preschoolers with FXS observed generalized brain overgrowth in children with FXS compared with controls, evident at age 2 and maintained across ages 4 to 5. In addition, different patterns of brain growth that distinguished boys with FXS from boys with idiopathic autism were found. (Contains 3 figures and 7 tables.)
Genetic polymorphisms leading to variations in human milk oligosaccharide (HMO) composition have been reported. Alpha-Tetrasaccharide (A-tetra), an HMO, has been shown to only be present (>limit of ...detection; A-tetra+) in the human milk (HM) of women with blood type A, suggesting genetic origins determining the presence or absence (A-tetra-) of A-tetra in HM.
This study aimed to determine whether associations exist between HMO concentrations and cognitive development, and whether the associations vary between A-tetra+ and A-tetra- groups in children (<25 months old).
We enrolled typically developing children (2–25 months old; mean, 10 months old) who were at least partially breastfed at the study visit. The Mullen Scales of Early Learning (MSEL) were used as the primary outcome measure to assess early cognitive development. Linear mixed effects models were employed by stratifying children based on A-tetra levels (A-tetra+ or A-tetra-) to assess associations between age-removed HMO concentrations and both MSEL composite scores and the 5 subdomain scores.
A total of 99 mother-child dyads and 183 HM samples were included (A-tetra+: 57 samples, 33 dyads; A-tetra-: 126 samples, 66 dyads). No significant association was observed between HMOs and MSEL when all samples were analyzed together. The composite score and 3’-sialyllactose (3’-SL) levels were positively associated P = 0.002; effect size (EF), 13.12; 95% CI, 5.36–20.80 in the A-tetra + group. This association was driven by the receptive (adjusted P = 0.015; EF, 9.95; 95% CI, 3.91–15.99) and expressive (adjusted P = 0.048; EF, 7.53; 95% CI, 2.51–13.79) language subdomain scores. Furthermore, there was an interaction between 3’-SL and age for receptive language (adjusted P = 0.03; EF, -14.93; 95% CI, -25.29 to -4.24).
Our study reports the association of 3’-SL and cognition, particularly language functions, in typically developing children who received HM containing detectable A-tetra during infancy.
Background
Atypical sensory responsivity and sensory interests are now included in the DSM 5 diagnostic criteria for autism spectrum disorder (ASD) under the broad domain of restricted and repetitive ...behavior (RRB). However, relatively little is known about the emergence of sensory‐related features and their relation to conventionally defined RRB in the first years of life.
Methods
Prospective, longitudinal parent‐report data using the Sensory Experiences Questionnaire (SEQ) were collected for 331 high‐risk toddlers (74 of whom met diagnostic criteria for ASD at age 2) and 135 low‐risk controls. Longitudinal profiles for SEQ scores were compared between groups across ages 12–24 months. Associations between SEQ measures and measures of RRB subtypes (based on the Repetitive Behavior Scale, Revised) were also examined.
Results
Longitudinal profiles for all SEQ scores significantly differed between groups. SEQ scores were elevated for the ASD group from age 12 months, with differences becoming more pronounced across the 12–24 month interval. At both 12 and 24 months, most measures derived from the SEQ were significantly associated with all subtypes of RRB.
Conclusions
These findings suggest that differences in sensory responsivity may be evident in high‐risk infants later diagnosed with ASD in early toddlerhood, and that the magnitude of these differences increases over the second year of life. The high degree of association between SEQ scores and RRB supports the conceptual alignment of these features but also raises questions as to explanatory mechanisms.
Numerous brain imaging studies indicate that the corpus callosum is smaller in older children and adults with autism spectrum disorder. However, there are no published studies examining the ...morphological development of this connective pathway in infants at-risk for the disorder. Magnetic resonance imaging data were collected from 270 infants at high familial risk for autism spectrum disorder and 108 low-risk controls at 6, 12 and 24 months of age, with 83% of infants contributing two or more data points. Fifty-seven children met criteria for ASD based on clinical-best estimate diagnosis at age 2 years. Corpora callosa were measured for area, length and thickness by automated segmentation. We found significantly increased corpus callosum area and thickness in children with autism spectrum disorder starting at 6 months of age. These differences were particularly robust in the anterior corpus callosum at the 6 and 12 month time points. Regression analysis indicated that radial diffusivity in this region, measured by diffusion tensor imaging, inversely predicted thickness. Measures of area and thickness in the first year of life were correlated with repetitive behaviours at age 2 years. In contrast to work from older children and adults, our findings suggest that the corpus callosum may be larger in infants who go on to develop autism spectrum disorder. This result was apparent with or without adjustment for total brain volume. Although we did not see a significant interaction between group and age, cross-sectional data indicated that area and thickness differences diminish by age 2 years. Regression data incorporating diffusion tensor imaging suggest that microstructural properties of callosal white matter, which includes myelination and axon composition, may explain group differences in morphology.
Children who developed autism spectrum disorders (ASDs) by age 2 had greater development of cerebral white matter fiber tracts by 6 months than unaffected children. After the initial accelerated ...white matter development, the children who developed ASDs had slower development, so that by age 2 their white matter development was less than that in the unaffected children.
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.
As compared to the utility of early emerging social communicative risk markers for predicting a later diagnosis of autism spectrum disorder (ASD), less is known about the relevance of early patterns ...of restricted and repetitive behaviors. We examined patterns of stereotyped motor mannerisms and repetitive manipulation of objects in 12-month-olds at high and low risk for developing ASD, all of whom were assessed for ASD at 24 months.
Observational coding of repetitive object manipulation and stereotyped motor behaviors in digital recordings of the Communication and Symbolic Behavior Scales was conducted using the Repetitive and Stereotyped Movement Scales for 3 groups of 12-month-olds: low-risk infants (LR, n = 53); high-familial-risk infants who did not meet diagnostic criteria for ASD at 24 months (HR-negative, n = 75); and high-familial-risk infants who met diagnostic criteria for ASD at 24 months (HR-ASD, n = 30).
The HR-ASD group showed significantly more stereotyped motor mannerisms than both the HR-negative group (p = .025) and the LR group (p = .001). The HR-ASD and HR-negative groups demonstrated statistically equivalent repetitive object manipulation scores (p = .431), and both groups showed significantly more repetitive object manipulation than the LR group (p < .040). Combining the motor and object stereotypy scores into a Repetitive and Stereotyped Movement Scales (RSMS) composite yielded a disorder-continuum effect such that each group was significantly different from one another (LR < HR-negative < HR-ASD).
These results suggest that targeted assessment of repetitive behavior during infancy may augment early ASD identification efforts.
Early intervention is a valuable tool to support the development of toddlers with neurodevelopmental disorders. With recent research advances in early identification that allow for pre-symptomatic ...detection of autism in infancy, scientists are looking forward to intervention during infancy. These advances may be supported by the identification of biologically based treatment and outcome measures that are sensitive and dimensional. The purpose of this review is to evaluate white matter neurodevelopment as a monitoring biomarker for early treatment of neurodevelopmental disorders. Fragile X syndrome (FXS) and autism spectrum disorder (ASD) as used as exemplars. White matter has unique neurobiology, including a prolonged period of dynamic development. This developmental pattern may make white matter especially responsive to treatment. White matter develops aberrantly in children with ASD and FXS. Histologic studies in rodents have provided targets for FXS pharmacological intervention. However, pharmaceutical clinical trials in humans failed to garner positive clinical results. In this article, we argue that the use of neurobiological monitoring biomarkers may overcome some of these limitations, as they are objective, not susceptible to placebo effects, and are dimensional in nature.
As the field moves towards earlier detection and early intervention for neurodevelopmental disorders, we encourage scientists to consider the advantages of using neurobiological features as monitoring biomarkers.
PDF
