The anatomy of the callosal and visual-association pathways in high-functioning autism: A DTI tractography study

Abstract

There is increasing recognition that many of the core behavioral impairments that characterize autism potentially emerge from poor neural synchronization across nodes comprising dispersed cortical networks. A likely candidate for the source of this atypical functional connectivity in autism is an alteration in the structural integrity of intra- and inter-hemispheric white matter (WM) tracts that form large-scale cortical networks. To test this hypothesis, in a group of adults with high-functioning autism (HFA) and matched control participants, we used diffusion tensor tractography to compare the structural integrity of three intra-hemispheric visual-association WM tracts, the inferior longitudinal fasciculus (ILF), the inferior fronto-occipito fasciculus (IFOF) and the uncinate fasciculus (UF), with the integrity of three sub-portions of the major inter-hemispheric fiber tract, the corpus callosum. Compared with the control group, the HFA group evinced an increase in the volume of the intra-hemispheric fibers, particularly in the left hemisphere, and a reduction in the volume of the forceps minor (F-Mi) and body of the corpus callosum. The reduction in the volume of the F-Mi also correlated with an increase in repetitive and stereotypical behavior as measured by the Autism Diagnostic Interview. These findings suggest that the abnormalities in the integrity of key inter- and intra-hemispheric WM tracts may underlie the atypical information processing observed in these individuals.

Introduction

There is a growing body of literature suggesting that many of the cognitive and social deficits associated with autism might arise from abnormal functional connectivity between and within the distributed cortical networks that mediate complex behavior (Castelli et al., 2002, Just et al., 2004, Kennedy et al., 2006, Villalobos et al., 2005). These alterations in functional connectivity might arise, in turn, from a perturbation in the integrity of white matter (WM) tracts that link the spatially distant regions of the network. Indeed, several diffusion tensor imaging (DTI) studies have revealed significant reductions in fractional anisotropy (FA), a measure of micro-structural integrity of WM, and/or other measures of diffusivity, in individuals with autism (Barnea-Goraly et al., 2004, Keller et al., 2007, Lee et al., 2007a). Moreover, there appear to be functional consequences of this WM perturbation, as reduced micro-structural integrity is correlated with lower IQ scores (Alexander et al., 2007), with higher ratings of repetitive behavior (Thakkar et al., 2008) and with reduced functional connectivity in the Tower of London task (Just et al., 2007). Although these findings suggest an association between alterations in structural and functional connectivity and information processing, they do not pinpoint specific WM tracts that are compromised in individuals with autism.

The neurobiological properties of large-scale WM tracts can now be studied in vivo using diffusion tensor tractography (DTT), which essentially uses information about the magnitude of diffusion of water molecules and the direction of maximal diffusion in each voxel to trace the likely trajectory of a WM tract. Studies that have employed DTT to examine the integrity of specific WM tracts in individuals with autism relative to typically developing individuals have focused primarily on intra-hemispheric tracts. For example, one study reported alterations in the structural integrity of long-range fibers in the frontal cortex in children within the autism spectrum (Sundaram et al., 2008), while another reported significant reductions in the micro-structural integrity of the right superior cerebellar peduncle and short intra-cerebellar fibers in adults with Asperger syndrome (Catani et al., 2008). A more recent study revealed a significant increase in the number of streamlines (i.e., the lines that depict the fibers in a tract) in bilateral inferior longitudinal fasciculus (ILF) and the cingulum bundle, as well as a reduction in streamlines in the right uncinate fasciculus (UF) (Pugliese et al., 2009). Importantly, these tracts are associated with behavioral functions that are known to be impaired in autism. For example, the ILF and the inferior fronto-occipito fasciculus (IFOF) are critical for higher-level visual and emotion processing (Rudrauf et al., 2008, Thomas et al., 2009), domains shown to be atypical in individuals with autism (Behrmann et al., 2006b, Bertone et al., 2005, Humphreys et al., 2008, Lee et al., 2007b). In summary, these tractography studies reveal perturbations in intra-hemispheric WM tracts in individuals on the autism spectrum, which may account for some of their difficulties in information processing.

Such perturbations do not appear to be specific to intra-hemispheric tracts per se as individuals with autism also show structural abnormalities in the corpus callosum, the largest inter-hemispheric tract, which bridges the two cerebral hemispheres. For example, morphometric studies have found significant reductions in volume along the subdivisions of the callosum in individuals with autism (Frazier and Hardan, 2009). Non-tractography studies that used DTI showed reductions in FA in the corpus callosum in children, adolescents and adults with autism (Alexander et al., 2007, Barnea-Goraly et al., 2004, Keller et al., 2007). Additionally, a reduction in WM integrity of the corpus callosum has been found to account for the poor performance IQ (P-IQ) scores of a subgroup of individuals with autism (Alexander et al., 2007). It should be noted that information processing that requires integrated hemispheric function, such as fine coordination, is affected in individuals with autism (Nyden et al., 2004), suggesting that the perturbation of callosal connectivity may contribute to such impairments.

Taken together, although there is evidence for alterations in intra- and inter-hemispheric WM tracts in autism, a parallel examination of both fiber systems has not been undertaken. Moreover, whether alterations in these two WM systems are related or whether they account for the core behavioral profile of individuals with autism also remains unknown. Finally, commissural tracts such as the corpus callosum, and intra-hemispheric association tracts such as the ILF, IFOF and UF have distinctly different developmental and maturational trajectories (Keshavan et al., 2002, Rakic and Yakovlev, 1968) and a parallel investigation of inter- and intra-hemispheric connectivity in autism can potentially help elucidate the neuro-developmental mechanisms underlying autism.

The goal of the present study, therefore, is to compare the structural integrity of key inter-hemispheric and intra-hemispheric WM tracts in a group of high-functioning adults with autism (HFA) and matched typically developing controls, and to explore the functional relevance of these tracts. To this end, we use DTT to quantify the structural integrity of the largest inter-hemispheric tract, the corpus callosum and its subcomponent tracts, the forceps major (F-Ma) (Dougherty et al., 2005), body and forceps minor (F-Mi), as well as three intra-hemispheric WM tracts: the ILF, IFOF, and the UF (Catani and Thiebaut de Schotten, 2008). Our hypothesis is that the high-functioning autism (HFA) group will show significant alterations in the structural connectivity profile in both intra- and inter-hemispheric WM tracts.