Altered Structural Connectivity of Language Tracts in 6-Week-Old Infants at High Risk for ASD

Background: Altered structural connectivity has been identified as a possible biomarker of autism spectrum disorder (ASD) risk in the developing brain. Several studies using diffusion tensor imaging (DTI) have shown reduced integrity of major white matter tracts in infants and toddlers who later developed ASD (Conti et al., 2015). Moreover, infants eventually diagnosed with ASD showed slower development of white matter tracts from 6 to 24 months (as indexed by fractional anisotropy (FA) values; Wolff et al. 2012), suggesting that altered or delayed structural connectivity in the early infant brain may be a useful biomarker of ASD. Examining white matter tracts specifically associated with social communicative functions (i.e., language) may lend further insight into early signs of ASD risk. For instance, the arcuate fasciculus (AF), connecting posterior temporal to premotor cortex, and the superior longitudinal fasciculus (SLF), connecting posterior temporal cortex to the inferior frontal gyrus, are two dorsal fiber tracts that connect key language regions of the brain. The AF is myelinated before the SLF, suggesting that the integration of sensory and motor representations must precede more advanced aspects of language processing (Perani et al., 2011). As such, structural connectivity in these tracts could also be used as a predictor of language outcome and ASD diagnosis.

Objectives: Here we investigated key white matter pathways of the dorsal language network in 6-week-old infants at high (HR) and low risk (LR) for ASD to identify atypicalities in structural connectivity that may predict altered developmental trajectories prior to overt language delays and the onset of ASD symptomatology.

Methods: DTI data were collected while infants underwent MRI during natural sleep. Preprocessing was conducted in FSL. Probabilistic tractography was used to examine the AF and SLF in both hemispheres. Indices of white matter integrity (including average fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)) were extracted from probabilistic tractography and subsequently related to behavioral indices of language development and ASD symptomatology.

Results: Average FA in the AF was significantly higher in the LR group compared to the HR group, but only in the left hemisphere. In contrast, no significant between-group differences were observed for the SLF. Interestingly, however, indices of white matter integrity significantly correlated with later behavioral outcome as indexed by the Autism Observation Scale for Infants (AOSI) at 12 months of age.

Conclusions: These data suggest that early patterns of structural connectivity in the developing brain are measurably different in infants at high risk for developing ASD as early as 6 weeks of age. In line with prior evidence indicating that the SLF matures at a slower rate than the AF, significant differences were observed in the AF but not in the SLF. Specifically, LR infants show higher FA in the left AF, indicating a more mature pattern relative to HR infants. Furthermore, measures of white matter integrity relate to ASD symptomatology. These findings indicate that early differences in language-relevant white matter pathways may predict future language development and provide an early biomarker of ASD risk.