This study represents the first prospective, longitudinal imaging study of infants at-risk for ASD. The findings reveal a distinct and pervasive course of aberrant white matter fiber tract development in HR infants who go on to develop autistic symptoms. Trajectories of fractional anisotropy (FA) values for 12 of the 15 tracts examined in the present study differed significantly between groups. Most fiber tracts for HR(+) infants were characterized by higher FA at 6 months followed by blunted developmental trajectories such that FA was lower by 24 months. Around 12 months of age, HR groups appear similar across all tracts excepting the ATR, potentially indicating differential timing of development for this specific fiber bundle. Understanding why FA values for multiple fiber tracts are elevated at 6 months but show less change over time may be critical to understanding the development of ASD and shed light on the neural mechanisms underlying its onset.
In agreement with findings from typically developing infants, FA values for HR(−) infants were characterized by rapid change during the 6 to 24 month interval (35
). The blunted trajectories seen in the HR(+) group are consistent with the reduced FA and comparative absence of age-related associations observed in older children and adolescents with ASD (24
), although these patterns may vary by fiber pathway throughout development (25
). The differences in white matter development between HR groups observed in this study are particularly striking considering evidence that individuals with ASD and nonaffected family members of individuals with ASD share a neural phenotype consisting of specific structural and functional brain abnormalities (48
). In follow-up analysis, we examined axial and radial diffusivities to elucidate FA results. With a few exceptions, trajectories for these diffusivity measures were not significantly different between groups, suggesting that FA results stem in part from the proportional relationship of AD and RD and not from one measure alone.
The altered trajectories of development seen here ostensibly begin in advance of both the onset of clinical symptoms (3
) and volumetric changes (6
), suggesting that core behavioral features of ASD arise from an altered neurobiological foundation. Instantiated by the present results, the organization of neural networks underlying ASD is characterized by atypical patterns of connectivity that differ across systems and time (14
) and are not specific to any one brain region or behavioral domain. The relevance of developmental trajectories to understanding these dynamic processes is undeniable (30
). Had the present study included only cross-sectional data centered at 12 months, for instance, it might have followed that the ATRs are uniquely relevant to the early development of ASD. The wider view afforded by longitudinal data indicate that the ATRs are but one of many fiber tracts implicated in the disorder, with associations at 12 months the product of differential development.
Both highly experience-dependent and less environmentally mediated processes contribute to functional and structural organization of the brain, and the dynamic interplay of these processes over time yield specialized cortical circuits designed to optimally process complex information (50
). For example, differences in structural organization prior to a period of experience-dependent developmental processes related to social-cognition (51
) may decrease neural plasticity through limitations on environmental input, preventing typical neural specialization (50
). These alterations could have a ripple effect through decreasing environmental responsiveness and escalating invariance, thus canalizing a specific neural trajectory resulting in the behavioral phenotype that defines ASD. In typical development, the selective refinement of neural connections via axonal pruning (54
), along with constructive processes such as myelination (55
), combine to yield efficient signal transmission among brain regions. One or both of these mechanisms may underlie the widespread differences in white matter fiber pathways observed in the current study. Intriguingly, our data is consistent with recent evidence from postmortem stereological research (56
) and mouse models of autism (57
) suggesting that axonal plasticity may be implicated in the development of ASD.
It is clear that the neurodevelopmental story of ASD neither begins at 6 months of age nor ends at 24. Downward extending neuroimaging to infants prior to 6 months would help clarify the temporal origin of diverging trajectories, while extending to later ages would capture increasingly stable neurobehavioral outcomes. Additional data points would likewise refine the calibration of trajectories beyond linear models. A multimodal approach to neuroimaging could potentially sharpen our understanding of early brain changes in ASD, allowing for the investigation of functional and structural covariance. To better understand the mechanisms which engender and maintain the trajectories evidenced here, subsequent research might also consider the role of genetic and epigenetic variables in the development of structural neural circuitry.
Finally, the presence of significant differences in FA at 6 months raises the exciting possibility of developing imaging biomarkers for risk of ASD in advance of symptom onset. Future work might investigate the potential of predictive models for ASD in early infancy, a process which could include refined imaging techniques or combined bio-behavioral markers. Identifying infants at highest risk for ASD before the full syndrome is manifest offers the possibility of implementing behavioral and other interventions during infancy that could reduce or even prevent the manifestation of the full syndrome (58
There are several limitations to the present study. The absence of a low-risk contrast group limits interpretation of results outside of a familial background for ASD. Although changes in FA correspond to organizational properties indicative of development (19
) as well as histological findings (59
), it is an imperfect index of white matter microstructure, and may reflect the effects of axonal packing, crossing fibers, or partial volumes related to noise in DTI data (20
). In this study, ASD status was based on ADOS scores at 24 months of age. Follow-up diagnostic assessment at 36–48 months will provide greater assurance of diagnostic outcomes.
This study is the first to identify brain changes related to later ASD as early as 6 months of age. The aberrant development of multiple white matter pathways seen here, along with previously reported brain and behavioral change during infancy (3
), suggest a period of critical importance to the pathogenesis of ASD. A developmental approach to understanding neural and behavioral changes during this time, sensitive to characterizing longitudinal trajectories, is crucial to understanding the complexities inherent to the neurodevelopmental processes implicated in the emergence of ASD.