Increased Ratio of Short to Long Range Structural Connections in the BRAIN in ASD – the Relationship Between Grey- and White-Matter Wiring

Background:   Evidence suggests that Autism Spectrum Disorder (ASD) is accompanied by atypical structural brain connectivity.  More specifically, it is thought that the brain in ASD is over-connected locally and under-connected globally.  However, while evidence for global under-connectivity is growing (e.g. (Koshino et al., 2008; Pugliese et al., 2009)), there is currently a lack of imaging markers that could be used to assess local grey-matter wiring in the brain in vivo.  Such local grey-matter connections are predominantly located in the outer layers of the cortex (layer 1-3), while the inner layers (layer 4-6) mainly contain myelinated axons extending into white matter (Lewis, Melchitzky, & Burgos, 2002).

Objectives:   Here, we therefore examined (1) the ratio between the outer (i.e. pial) and inner (i.e. white-matter) cortical surface as a surrogate marker of the proportion of short-range (i.e. local) to long-range (i.e. global) connections in the brain of individuals with ASD; and (2) established the relationship between atypical grey-matter wiring and white-matter connectivity within the frontal lobes.

Methods:   Structural MRI and DTI data was collected on 51 well-characterized male adults with an ADI-R confirmed diagnosis of ASD (mean age = 26 years, mean FSIQ = 112), and 51 age/FSIQ matched neurotypicals.  Surface reconstructions for all participants were performed using FreeSurfer software on the basis of high-resolution structural T₁-weighted inversion recovery images.  The ratio between outer (i.e. pial) and inner (i.e. white-matter) surface was computed at each cerebral vertex, and subsequently compared between groups using a general linear model.  In addition, we performed DTI tractography of association tracts within the frontal lobe, and determined their mean diffusivity, fractional anisotrophy and number of streamlines.

Results:   We found that the ratio of outer to inner surface area was significantly increased in individuals with ASD in the bilateral frontal and temporal lobes (p<0.05, corrected).  The increase in ratio was further correlated with the severity of autistic symptoms in the social domain.  Overall, the ratio of outer to inner frontal surface area was significantly correlated with the mean diffusivity and the number of streamlines of frontal association tracts, which were significantly increased/reduced (respectively) in ASD.

Conclusions:   Our results suggest that individuals with ASD may have a larger proportion of short- to long-range connections in frontal and temporal regions, and hence confirm the hypothesis that the brain may be over-connected locally and under-connected globally in ASD.  Furthermore, the significant association of grey- and white-matter connectivity implies that global white-matter under-connectivity in ASD should not be examined in isolation (i.e. without consideration of grey-matter wiring), and may be secondary to the abnormal development of grey-matter.