The loss of asymmetry and reduced interhemispheric connectivity in adolescents with autism: A study using diffusion spectrum imaging tractography

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Abstract

Evidence from neuroimaging and neurobiological studies suggests that abnormalities in cortical–cortical connectivity involving both local and long-distance scales may be related to autism. The present study analyzed the microstructural integrity of the long-range connectivity related to social cognition and language processing with diffusion tractography among adolescents with autism compared with neurotypical adolescents. Tract-specific analyses were used to study the long-range connectivity responsible for integrating social cognition and language processing. Specifically, three pairs of association fibers and three portions of callosal fiber tracts were analyzed. Generalized fractional anisotropy (GFA) values were measured along individual targeted fiber tracts to investigate alterations in microstructure integrity. The asymmetry patterns were also assessed in three pairs of association fibers. In neurotypical participants, we found a consistent leftward asymmetry in three pairs of association fibers. However, adolescents with autism did not demonstrate such asymmetry. Moreover, adolescents with autism had significantly lower mean GFA in three callosal fiber tracts than neurotypical participants. The loss of leftward asymmetry and reduction of interhemispheric connection in adolescents with autism suggest alterations of the long-range connectivity involved in social cognition and language processing. Our results warrant further investigation by combining developmental and neurocognitive data.

Introduction

Autism is a common, multi-factorial, highly heritable, clinically heterogeneous neuro-developmental disorder that is diagnosed along severities related to the core impairments in social reciprocity and communication, as well as stereotyped and repetitive behaviors (Caronna et al., 2008). In the past few decades, several psychological theories have been proposed to explain the psychopathology of autism (Boucher, 2009). Evidence from neuroimaging and neurobiological studies suggests that the autistic disorder might be related to abnormalities in the cortical–cortical connectivity involving both local and long-distance scales (Courchesne & Pierce, 2005, Minshew & Williams, 2007). Aberrant connectivity theories based on information processing perspectives such as diffuse underconnectivity (Just et al., 2004) and a “globally underconnected and locally overconnected” brain (Belmonte et al., 2004, Baron-Cohen & Belmonte, 2005) have also been proposed.

Recently, researchers have applied diffusion tensor imaging (DTI) to obtain information about the white matter connectivity in individuals with autism (Barnea-Goraly et al., 2004, Alexander et al., 2007, Lee et al., 2007, Catani et al., 2008, Sundaram et al., 2008, Thakkar et al., 2008, Pugliese et al., 2009). DTI permits an examination of the microstructure integrity of white matter in terms of scalars derived from the diffusion tensor. One of the widely used scalars is fractional anisotropy (FA), a measure that reflects the directional anisotropy of water molecular diffusion (Basser, 1995). A higher FA value reflects a higher fiber density, larger axonal diameter, and more consistent myelination in the white matter (Johansen-Berg and Behrens, 2009). Many DTI studies, based either on regions of interest (ROI) approaches or voxel-based morphometry, have shown significantly reduced FA in the white matter adjacent to brain regions involved in the social cognition or language processing, such as the fusiform gyrus, the superior temporal sulcus, the ventromedial prefrontal cortex (Barnea-Goraly et al., 2004), the anterior cingulate cortex (Thakkar et al., 2008), the superior temporal gyrus, and the temporal stem (Lee et al., 2007). Taken together, these findings revealed abnormal white matter microstructure in various regions relevant to the core impairments of autism (Lee et al., 2007, Muller, 2007, Sundaram et al., 2008), suggesting that alterations of local connectivity might contribute to the pathology of autism.

With the advance of diffusion tractography, some studies have examined the microstructure integrity of long-range connectivity in autism. Conturo et al. (2008) found a normal size and shape but reduced FA of the hippocampo-fusiform and amygdalo-fusiform pathways in individuals with autism. In individuals with Asperger's disorder, Catani et al. (2008) found significantly lower FA in the intracerebellar fibers, while Pugliese et al. (2009) reported no significant differences in FA for limbic white matter tracts, i.e., the cingulum bundles and fornix, compared with healthy participants. Given the above reports, it is still unclear how the long-range connectivity specifically involved in the core impairments is altered in autism.

Given that deficits in social cognition and language processing are central to autism, that the fronto-temporal regions are responsible for most social and language processing, and that altered local connectivity in autistic brains is mostly found in the frontal and temporal lobes, it is plausible that the three major long-range fiber tracts connecting the frontal and temporal lobes, namely the cingulum (CG), arcuate fasciculus (AF), and uncinate fasciculus (UF), might be related to the neurostructural characteristics of autism. Results from neurocognitive studies have demonstrated that these three fiber tracts are involved in social or language functions. For example, CG is associated with empathic cognition and social behaviors (Wang et al., 2004), AF is responsible for the functions of language comprehension and expression (Vernooij et al., 2007), and UF is related to episodic memory and autonoetic awareness (Kubicki et al., 2002).

Therefore, the present study aimed to use diffusion tractography to analyze the microstructural integrity of the three pairs of association fibers, namely the bilateral CG, AF, and UF. In addition, the asymmetry patterns of these three pairs of association fibers were also analyzed. Moreover, we analyzed the long-range interhemispheric connections between the bilateral UF, i.e., the callosal fiber tracts connecting the bilateral orbitofrontal lobes, and between the bilateral AF, i.e., the callosal fiber tracts connecting the bilateral inferior frontal gyri and bilateral superior temporal gyri. We hypothesized that the long-range connectivity of the networks involved in social cognition and language processing is altered in autism, which could be revealed by diffusion tractography analyses.

Section snippets

Participants

We assessed 15 Taiwanese male adolescents with autism, aged 14 to 17, as well as 15 neurotypical control participants who were matched to the patients on age and full-scale intelligence quotient (IQ) (see Table 1). All participants were right-handed, as assessed with the Edinburgh Inventory (Oldfield, 1971). Participants with autism were clinically diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) and International Classification of Diseases-10

Results

The clinical assessment and ADI-R clearly showed that patients' past symptoms fulfilled the criteria of the diagnosis of pervasive developmental disorders, as defined by the DSM-IV (autistic disorder, n = 15) and ICD-10 (childhood autism, n = 15). The ADI-R interviews of the past behaviors revealed that patients scored 18.24 ± 8.39 in the “qualitative abnormalities in reciprocal social interaction” (cut-off = 10), 12.33 ± 6.05 in the “qualitative abnormalities in communication” (cut-off = 8), and 6.16 ± 1.96

Discussion

In this study, we used diffusion tractography to investigate the long-range connectivity involved in social cognition and language processing in participants with autism. Specifically, we investigated three pairs of association fibers, namely the bilateral CG, bilateral AF and bilateral UF, and three callosal fiber tracts connecting the bilateral orbitofrontal lobes, bilateral inferior frontal gyri, and bilateral superior temporal gyri. The major findings of this study were that a consistent

Acknowledgements

This work was supported by the National Science Council, Taiwan (NSC93-2413-H-002-014 to Dr. W.T. Soong, NSC97-3112-B-002-009 to Dr. S.S. Gau, and NSC98-3112-B-002-041 and NSC99-3112-B-002-030 to Dr. W.Y.I. Tseng), and in part by the Department of Medical Imaging and the Advanced Biomedical MRI Laboratory, National Taiwan University Hospital, Taipei, Taiwan. We thank all of the participants for their involvement in this study.

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