Special issue: ReviewAltered white matter connectivity as a neural substrate for social impairment in Autism Spectrum Disorder
Introduction
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by core impairments in social interaction and social communication, and the presence of repetitive, restrictive and stereotyped patterns of interests, activities and behaviours (American Psychiatric Association, 2013). Although the presentation of ASD is highly heterogeneous, varying considerably with respect to clinical severity, comorbid language, intellectual, medical and psychiatric impairment, socio-emotional deficits are ubiquitous across the autism spectrum and represent a significant barrier to social integration and functional independence for those affected (Howlin, Goode, Hutton, & Rutter, 2004).
While the complex etiopathogenic mechanisms contributing to ASD remain elusive, the past decade has seen convergence across advanced genetic, post-mortem and neuroimaging research modalities pointing to the importance of altered brain connectivity in this disorder (Ameis & Szatmari, 2012). For example, functional analyses applied to genetic findings have indicated that diverse genetic factors associated with ASD may converge with respect to their influence on common biological pathways involved in synaptogenesis, axon guidance and neuronal motility (Geschwind, 2011), post-mortem studies point to alterations in axonal properties and neural circuit formation (Voineagu et al., 2011, Zikopoulos and Barbas, 2010), and neuroimaging studies have provided in vivo evidence of atypical neural network activity, connectivity, and white matter impairment in ASD (Ameis & Szatmari, 2012).
White matter tracts form the structural foundation for brain connectivity by linking discrete grey matter regions into integrated neural circuits. Optimal white matter tract connectivity regulates the speed and timing of activation across neural networks (Fields, 2008a, Fields, 2008b, Schmahmann et al., 2007). Complex socio-emotional task performance is highly reliant on integrated activity across an extended socio-emotional processing network (Catani, Dell'acqua, & Thiebaut de Schotten, 2013). Therefore, disruption of the long-range white matter tracts that mediate connectivity within this system may be an important pathogenic factor contributing to core social impairments in ASD.
In the present article, we review the evidence for impaired white matter connectivity as a neural substrate for socio-emotional dysfunction in ASD. We begin with a brief introduction to socio-emotional deficits in ASD and the neural correlates of complex socio-emotional functioning. We then go on to a focused review of pathology relevant to socio-emotional processing systems from post-mortem, structural and functional imaging research in ASD. Finally, a comprehensive review of ASD studies that have utilized diffusion tensor imaging (DTI), a neuroimaging tool used to infer the in vivo microstructural properties of white matter connections is presented. The aims of this review are to: (i) evaluate whether current evidence supports the hypothesis that impaired development of long-range white matter connectivity contributes to social deficits in ASD, (ii) summarize the limitations of the current research, and (iii) highlight future directions for progress in the field.
Section snippets
Typical socio-emotional development and differences in ASD
In typical development, a preferential interest for social stimuli is observed almost immediately following birth. By six months of age, infants develop the ability to discriminate affective expressions in others, and social referencing emerges as a tool to make sense of the environment (Molnar-Szakacs et al., 2009). Toward the end of the first year of life, joint attention develops (the ability to direct another's attention to an object/person of interest), which predicts later language
Neural correlates of complex socio-emotional processing
Expert reviews synthesizing human lesion, structural and functional imaging research provide a working model for understanding how socio-emotional signals are processed within the human brain (Adolphs, 2003, Catani et al., 2013, Frith and Frith, 2007, Mesulam, 1998). Recent reviews highlight a number of interconnected cortical and subcortical structures that process different aspects of the social environment and can be grouped into three complementary neural systems, including: (i) a broad
Post-mortem findings
Post-mortem studies of socio-emotional processing regions in ASD point to alterations in neuronal and axonal development, organization, and connectivity within frontal and temporal cortical regions. However, small sample sizes, examination of a limited number of selected regions, and inclusion of individuals spanning development from childhood to late adulthood, often with language impairment, intellectual disability, and comorbid seizure disorder, limit the interpretation and generalizability
Review of DTI findings in ASD
In recent years, DTI, an MRI-based neuroimaging method that can infer properties of white matter microstructure in vivo by quantifying the distinct movement of water molecules in white matter regions, has been applied to ASD. In DTI, information derived from a number of diffusion-weighted images is combined and represented in the diffusion tensor, a mathematical matrix describing the magnitude (eigenvalue) and orientation (eigenvector) of water molecule movement along three principal directions
Discussion and future directions
In our review of post-mortem, structural and functional neuroimaging studies examining brain regions involved in socio-emotional processing in ASD, we find evidence pointing to broad neurodevelopmental alterations in this complex disorder. Direct post-mortem data has implicated disruptions to white matter myelin and axon density in regions corresponding to fronto-limbic white matter pathways (i.e., uncinate fasciculus, cingulum bundle) in ASD (Zikopoulos & Barbas, 2010). Structural MRI results
Financial disclosures
The authors report no biomedical financial interests or potential conflicts of interest.
Acknowledgements
SA is supported by an Ontario Mental Health Foundation fellowship and the CAMH Foundation (through the O'Brien Scholars Program). MC is supported by Guy's and St Thomas' Charity, The Wellcome Trust, and partially supported by the Medical Research Council, UK Autism Multi-Centre Imaging Study network and the National Division of the South London and Maudsley NHS Foundation Trust.
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