Abnormal Functional Connectivity Is Associated with Disrupted Organisation of White Matter in Autism

Background:  Autism spectrum disorders (ASDs) are devastating neurodevelopmental disorders of childhood of unknown aetiology. The theory of abnormal cortical connectivity holds that core features of ASD are underpinned by abnormal interregional brain connectivity. There is accumulating neuroimaging and genetic evidence supporting this theory; aberrant structural and functional connectivity has been widely reported, and genes involved in neural connectivity have been implicated as susceptibility genes for ASD. Previous work from our group has identified marked abnormalities of functional connectivity during visuospatial processing in ASD (McGrath et al, 2012, In Press, doi:10.1002/aur.1245). There is however a striking lack of research investigating the relationship between abnormal functional connectivity and white matter structure. In addition, the impact of aberrant neural connectivity on behaviour in ASD is poorly understood. 

Objectives:  The aims of this study were 1. to determine whether functional connectivity abnormalities were associated with structural abnormalities of white matter in ASD and 2. to examine the relationships between aberrant neural connectivity and behaviour in ASD. 

Methods:  Twenty-two non-medicated individuals with ASD and twenty-two age and IQ-matched controls completed a high-angular-resolution (61 directions) diffusion MRI scan. Structural connectivity was analysed using constrained spherical deconvolution (CSD)-based tractography, an advanced tractography method that avoids a number of critical confounds associated with traditional tensor based tractography. Seed regions for tractography were generated from functional connectivity maps during a visuo-spatial processing task that the same study group had completed (McGrath et al, 2012, In Press, doi:10.1002/aur.1245) and consisted of ten pairs of brain regions that showed abnormal functional connectivity in ASD. This tractography protocol allowed isolation of white matter tracts that directly connected brain regions showing abnormal functional connectivity. Fractional anisotropy (FA), a measure of micro-structural organisation of white matter, was extracted from isolated white matter tracts. Correlation analyses were used to investigate the relationships between functional connectivity, structural connectivity and behaviour in ASD.

Results:  CSD-based tractography revealed that there were white matter tracts directly connecting five of the ten seed-pair regions in most participants; between a seed region in the left occipital lobe (left BA19) and left caudate head, left caudate body, left uncus, left thalamus and left cuneus. FA in all five white matter tracts was reduced in the ASD group relative to controls, and this reduction was significant for white matter connecting the left BA19 and left caudate head, and left BA19 and left thalamus. In addition, there were significant correlations between structural and functional connectivity in the occipito-thalamic and occipito-striatal (caudate body) tracts, and between visuospatial processing speed and structural and functional connectivity measures. 

Conclusions:  This is the first study in ASD research to directly investigate how structural and functional connectivity are interrelated. Using an original approach integrating functional connectivity MRI and diffusion tractography, this work has revealed that abnormal functional connectivity in ASD is associated with disrupted organisation of white matter. This is particularly interesting as it provides novel evidence to suggest that structural brain pathology may contribute to the abnormal functional connectivity that has been widely reported in the autism literature.