Blunted Trajectories of White Matter Development Associated with Autism in High-Risk Infants

Background: Findings from prospective studies of infant siblings of individuals with autism suggest that defining symptoms of the disorder typically emerge late in the first- or early in the second-year of life. Neuroimaging research and studies of head size likewise point to infancy as a time of divergence from typical development. Converging evidence from functional and structural connectivity studies of older children and adults with autism suggest that altered neurocircuitry may underlay the neurobehavioral phenotype of autism. 

Objectives: To compare trajectories of white matter fiber tract development over the 6 to 24 month interval between high-risk infants with and without evidence of an ASD at 24 months.

Methods: As part of the IBIS protocol, infants were scanned using a 25 direction DTI sequence on identical 3T scanners. Participants in the present study included 92 high-risk infant siblings with diffusion tensor imaging (DTI) at 6 months and behavioral assessments at 24 months. The majority of these participants contributed additional imaging data at either or both 12 and 24 month time points. At 24 months, 28 infants met ADOS criteria for an ASD, while 64 infants were classified as non-spectrum. Microstructural properties of 6 bilateral fiber pathways and 3 divisions of the corpus callosum were characterized by fractional anisotropy (FA) and radial and axial diffusivity. Longitudinal trajectories of diffusion measures were compared between high-risk ASD+ and ASD- groups using random coefficient linear growth curve models.

Results: FA trajectories differed significantly between infants who did versus did not develop ASDs for 12 of 15 fiber tracts. Development for most fiber tracts in ASD+ infants was characterized by elevated FA at 6 months followed by slower change over-time relative to infants without ASDs. Thus, by 24 months of age, lower FA values were evident for those with ASDs. At the six month time point, FA values for 5 fiber tracts were significantly higher for infants who went on to develop autism. With the exception of the internal capsule, trajectories of axial and radial diffusivity did not differ between groups.

Conclusions: These preliminary data suggest that the onset of core autistic symptoms may be preceded by the aberrant development of structural connectivity very early in life. During a time typically characterized by robust, experience-dependent change in neurocircuitry, infants with autism show evidence of blunted axonal organization. These results are consistent with DTI findings from older children and adults with autism as well as recent histological findings, and add to a body of evidence suggesting that autism is a disorder of atypical neural connectivity.