White Matter Microstructure in Youth with a History of Autism Spectrum Disorder Who Have Achieved an Optimal Outcome

Background: A minority of persons with an autism spectrum disorder (ASD) lose the symptoms, a phenomenon referred to as an “optimal outcome” (OO). Ongoing research is revealing clinical differences between OO and ASD youth, but the neural basis of the phenomenon is currently unknown. One functional MRI investigation of language comprehension in a sample that overlaps with the current study found evidence of compensatory functional activation and residual ASD-like activation patterns, but no evidence of normalization toward the activation patterns of typically developing (TD) comparison participants. This suggests an equifinality model, in which multiple neurodevelopmental pathways yield similar behavioral outcomes. There has not yet been an attempt to uncover neurostructural differences that facilitate or characterize OO. Given the prominence of white matter atypicalities in ASD and the emergence of a disconnection model of ASD (e.g. Belmonte et al., 2004, J. Neuroscience), the current study investigated white matter microstructure in OO. 

Objectives: This study evaluated white matter tract microstructure in OO youth to determine whether it differed from those with ASD and TD.

Methods: Three age- and IQ-matched groups comprised 14 typically developing, 22 high functioning ASD (HFA), and 11 youths with a well-established early childhood history of an ASD who no longer met diagnostic criteria (OO). Participants underwent magnetic resonance diffusion tensor imaging (DTI). Data were subjected to strict screening for head motion, leading to exclusion if more than 10% of motion estimates for any image was greater than one voxel length. One OO and two HFA participants were excluded on this basis. A tract-based spatial statistics analysis was implemented using Functional MRI of the Brain Software Library (FSL) tools. Whole-brain three-group ANOVAs were conducted to compare fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). Post-hoc pairwise comparisons were evaluated on tracts with positive findings. 

Results: FA differences did not survive correction for multiple comparisons. Uncorrected findings showed differences in multiple cortical association tracts. The TD group had the highest FA, followed by the HFA group. The OO group had the lowest FA of the three groups in multiple tracts. These FA differences were driven by RD differences, which appropriately showed the opposite pattern. The OO group had the greatest RD, followed by HFA and TD. There were no group differences in AD. 

Conclusions: The presence of white matter microstructural differences in OO raises the possibility that these characteristics contribute to achievement of OO. Lower FA and greater RD in OO youth may represent plasticity mechanisms that facilitated movement off the spectrum. Provided they can be replicated, these findings can guide future research seeking to understand the relationship of white matter structure to OO. The findings converge with prior functional MRI work to support a model in which movement off the spectrum involves compensation rather than normalization.