Developmental Differences in the Uncinate Fasciculus Vary by Sex in Autism Spectrum Disorders

Background:  Although autism spectrum disorders (ASD) are typically life-long, the symptoms observed in early childhood may improve for some children over the course of development. Our previous study demonstrated that white matter integrity appears to change from adolescence to adulthood. The major biological change in adolescence is the onset of puberty, which results from an elevation of sex steroid hormones. Since the sex steroid hormones also influence brain structural development, we theorize that the observed brain changes may stem, in part from an interaction between sexual and developmental processes that occur over time both in the brain and in the behavioral expression of ASD.  

Objectives:  We employed Diffusion Tensor Imaging (DTI) with a probabilistic tracking algorithm to identify white matter tracts in a sample that varied in terms of age, diagnosis, and sex. We hypothesized that (1) there was an interaction between sex and age in white matter integrity in ASD, and (2) the integrity of white matter tracts were related to clinical measures of autism symptoms.

Methods:  Forty-seven participants with ASD and 49 with typical development (TD) participated in the study. The ASD group included 27 adolescents (females=5; mean age=14.79±0.75; range=13.58–16.47) and 20 adults (females=6; mean age=24.82±4.63; range=19.43–35.72). The TD and ASD groups were age- and gender-matched. All ASD participants met DSM-IV, Autism Diagnostic Interview-Revised (ADI-R), and Autism Diagnostic Observation Schedule (ADOS) criteria for an ASD. DTI scans were collected on a 3T Philips Achieva MR system (version 1.5, Philips Medical Systems, Best, Netherlands). DTI parameters: single-shot echo-planar sequence (TR/TE/flip angle: 10.5s/63ms/90°, matrix size of 128×128, FoV of 240×240, 2mm slice thickness, 72 slices) with 32 gradient directions and a b-factor of 1000s/mm². Probabilistic tractography maps of the uncinate fasciculus (UF), cingulum (CIN), genu (GEN) and splenium (SPL) of corpus callosum were reconstructed with FSL. The mean values of diffusion parameters (FA, MD, AxD, RaD) of each tract were computed. Three-way (agexgroupxsex) ANOVA was performed on all the diffusion parameters of each tract to test the interaction. Partial correlations were performed between diffusion parameters and clinical measures (ADI-R, ADOS) with full scale IQ as a covariate. 

Results: Three-way interactions of sex, age, and diagnosis were found in FA, MD, RaD in the UF (p=0.023, 0.015, 0.009) and AxD in SPL (p=0.007). Numerous correlations between white matter integrity and ADI-R and ADOS measures were also found. Notably, different correlation patterns were found between males and females with ASD.

Conclusions: This study demonstrated that differences in white matter integrity between the ASD and TD groups varied from adolescence to adulthood and between males and females. The results implied atypical developmental trajectories of white matter tracts in ASD. Further, our correlational analyses indicated that the integrity of different white matter tracts correlated to functional differences and, in some cases, were sex- specific. Our results implied that the pathological developmental trajectory of the UF, a white matter tract associated with socioemotional processing, differs according to sex in ASD. Additional studies with larger numbers of females are needed to confirm these preliminary findings.