Tract-specific analyses of diffusion tensor imaging show widespread white matter compromise in autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by sociocommunicative, cognitive, and sensorimotor impairments whose underlying neuropathology is not fully understood. Structural magnetic resonance imaging (MRI) findings have shown abnormal patterns of white matter growth in ASD. Courchesne et al. (2001) reported atypically increased cerebral white matter volume in boys with autism below the age of 5 years, whereas in adolescent boys cerebral white matter volume was reduced. Abnormal early growth patterns in ASD likely relate to atypical interregional connectivity later in life (Belmonte et al., 2004; Kana et al., 2008; Kleinhans et al., 2008; Koshino et al., 2005; Muller, 2007; Rippon et al., 2007; Villalobos et al., 2005). Deficiency in interhemispheric information transfer (Nyden et al., 2004) and interhemispheric functional underconnectivity have also been reported (Just et al., 2007). Impaired connectivity may be related to social and cognitive symptoms seen in ASD (Dawson et al., 1998; Hill, 2004). Compared with conventional anatomical MRI, DTI provides additional information about aberrant white matter microstructure. DTI indices (fractional anisotropy [FA], mean diffusion [MD], and axial and radial diffusion) are markers of pathological and developmental changes in axonal density and size, myelination, and organizational coherence of fibers within a voxel (Basser, 1995; Basser and Pierpaoli, 1996; Song et al., 2005). In a first small-sample DTI study of ASD, reduced FA was reported in brain regions related to social cognition, such as the ventromedial prefrontal, anterior cingulate, and temporoparietal regions (Barnea-Goraly et al., 2004). Several DTI studies have subsequently reported reduced FA in children and adults with ASD in corpus callosum (Alexander et al., 2007; Keller et al., 2007), internal capsule (Brito et al., 2009; Cheung et al., 2009; Keller et al., 2007), frontal (Sundaram et al., 2008), and temporal (Lee et al., 2007) regions. Contrary to these studies, increased FA in frontal lobe, right cingulate gyrus, bilateral insula, right superior temporal gyrus and bilateral middle cerebellar peduncle was reported in one recent study of children and adolescents with ASD (Cheung et al., 2009). Several autism DTI studies (Alexander et al., 2007; Catani et al., 2008; Lee et al., 2007) have reported region-of-interest (ROI) analyses, which rely on a priori hypotheses regarding regional impairment and are limited to selection of a few among numerous white matter tracts. Other studies have implemented voxelwise whole brain approaches (Barnea-Goraly et al., 2004; Cheung et al., 2009; Ke et al., 2009; Keller et al., 2007). While these studies are not limited to a priori selection of ROIs, they suffer from topological variability of the brain, which can cause misregistration of white matter tracts across participants. Spatial smoothing applied to compensate for such misregistration can also affect DTI indices (Jones et al., 2005). In the present study, we utilized a comparatively novel tract-based spatial statistics (TBSS) approach (Smith et al., 2006) to investigate white matter fiber tract specific changes in children with ASD compared to typically developing (TD) children. TBSS provides the ability to spatially localize group differences in DTI data in an observer-independent and hypothesis-free fashion. TBSS uses nonlinear registration and takes advantage of the spatial determinants of major white matter tracts, thus minimizing registration error and bias and eliminating the need for arbitrary smoothing. The data-driven approach of TBSS is particularly useful in a disorder like ASD, for which regional patterns of brain abnormalities are not fully determined. Our study aimed to examine whether expected white matter compromise in children and adolescents with ASD would localize to a limited number of tracts or would be distributed across many cortico-cortical as well as subcortico-cortical tracts.