Atypical development of white matter microstructure in adolescents with autism spectrum disorders
Introduction
Autism spectrum disorders (ASD) is a relative common brain developmental disorder that occurs in one in 150 children (Van Naarden Braun et al., 2007). It is characterized by early onset of impaired social reciprocity and communication difficulties, along with restricted interest and stereotyped behavior (WHO, 1994). Several lines of evidence suggest that cascade failure of neurodevelopment is most likely the core deficit of ASD (Amaral et al., 2008, Baron-Cohen and Belmonte, 2005, Courchesne and Pierce, 2005a, Courchesne et al., 2007, Geschwind and Levitt, 2007). Using tract-based spatial statistics (TBSS) on the quantitative indices from diffusion tensor imaging (DTI), the present study aimed to examine the developmental change of white matter (WM) skeleton during adolescence in ASD.
Currently, several lines of evidence suggest that the brain of ASD individuals, as indexed by head circumference and brain volume, undergoes a period of precocious growth during early postnatal life followed by a deceleration in age-related growth, as compared to typically developing children (Courchesne et al., 2003, Dawson et al., 2007, Dementieva et al., 2005, Sparks et al., 2002). Disproportional increases in WM were postulated to account for this abnormal brain enlargement, as indicated by studies of young children (Courchesne et al., 2003, Dementieva et al., 2005, Herbert et al., 2003, Herbert et al., 2004). In addition, abnormal structures of the gray matter may be related to malformations of the WM, which is especially intriguing in ASD considering the fact that the cognitive deficit is most likely to arise from impaired integrative processing through intrahemispheric and interhemispheric transfer of information (Just et al., 2004, Minshew et al., 1997). Thus, whether aberrant WM development persists into later childhood and adolescence is a crucial issue to probe (Hazlett et al., 2006, Lotspeich et al., 2004, Palmen et al., 2005).
With the advent of DTI, a technique based on the measurement of water molecular diffusion, the architecture of human WM tracts can be more thoroughly scrutinized in vivo (Engelbrecht et al., 2002, Mukherjee and McKinstry, 2006, Mukherjee et al., 2002, Neil et al., 2002, Neil et al., 1998). In comparison to other MRI measures (e.g., T1-and T2-weighted images), DTI is a much more sensitive measure of WM maturation (Baratti et al., 1999, Huppi et al., 1998, Neil et al., 1998). Fractional anisotropy (FA) is a quantitative parameter derived from DTI which measures the direction-dependent diffusivity of water molecules, and is an indicator of the diameter and density of fibers, myelination, and macrostructural features (such as fiber tract coherence) of WM fibers (Beaulieu, 2002).
To date, studies that have used DTI measures in ASD are limited (Alexander et al., 2007, Barnea-Goraly et al., 2004, Ben Bashat et al., 2007, Catani et al., 2008, Conturo et al., 2008, Keller et al., 2007, Lee et al., 2007, Sundaram et al., 2008, Thakkar et al., 2008). The manner through which ASD alters FA values remains controversial. For instance, one study reported that the adolescents, ages 11–18 years, with high functioning autism have reduced FA values in brain regions that are implicated in social cognitive processes, such as theory of mind (ventromedial prefrontal cortex, anterior cingulate cortex, temporoparietal junction, superior temporal sulcus, and amygdala) (Barnea-Goraly et al., 2004). Other studies of adults with ASD reported lower FA values in the corpus callosum (Alexander et al., 2007), the genu and splenium of corpus callosum, and the internal capsule (Keller et al., 2007), the superior temporal gyrus (Lee et al., 2007), the cerebellar feedback projections (Catani et al., 2008), and the anterior cingulate gyrus (Thakkar et al., 2008). In contrast, young children with autism had increased FA values in the frontal lobe or no change at all (Ben Bashat et al., 2007). Another study found that an interaction of age by group in the posterior limb of the right internal capsule as shown by an age-related increase in FA values in the ASD participants and an age-related decrease in the controls (Keller et al., 2007). However, superior temporal gyrus displayed minimal change in ASD but an increase in the controls (Lee et al., 2007). Similarly, children with ASD appeared to have an imbalance of FA in the frontal lobe as indicated by lower FA for short range fibers and higher FA for long range association fibers (Sundaram et al., 2008). Thus, we speculated that age is an important factor in determining the brain manifestations observed in ASD.
Furthermore, some issues with DTI analysis should be acknowledged. First, the interpretation of FA changes, particularly increases in FA values in individuals with pathological conditions (e.g., subjects with ASD) vs. controls, needs to be determined. The degree of diffusion anisotropy conventionally described in terms of the FA has been referred to as a measure of the microstructural integrity of WM tissue. Importantly, FA might only provide an indirect marker for the microstructural properties of WM (Tuch et al., 2005). Greater FA may reflect greater myelination of WM fibers, increased number of myelinated fibers, smaller axonal diameter, or reduced neural branches within MRI voxel (Beaulieu, 2002, Hoeft et al., 2007). Alternatively, FA changes may result from excessive partial volume averaging from differently oriented fibers (Beaulieu, 2002, Le Bihan, 1995, Schwartz and Hackney, 2003). Reduced FA has been associated with local edema, cerebrospinal fluid (Mukherjee and McKinstry, 2006, Mukherjee et al., 2002), compromised myelin structure, changes in axonal morphologic structure, and altered interaxonal spacing of fiber bundles (Arfanakis et al., 2002, Beaulieu, 2002, Concha et al., 2005, Thomalla et al., 2004). Therefore, eigenvalues representing measures of longitudinal and radial diffusivities have been derived and validated (Hasan and Narayana, 2006, Song et al., 2002) as more specific measures of diffusivity in the longitudinal diffusion direction and transverse direction, respectively. These measures can help interpret FA changes in WM tracts in pathologic groups by providing information regarding likely alternations in the proportions of longitudinal vs. radial diffusivity. Reduced longitudinal diffusivity may suggest the decline of axonal integrity, and decreased radial diffusivity may be a non-invasive surrogate marker of demyelination (Budde et al., 2008, Song et al., 2003).
A second issue is that DTI analysis is compromised by the use of standard registration algorithms, such that there was not yet a satisfactory convention for the alignment of FA images from multiple subjects in voxel-wise analyses (Smith et al., 2006). A recent advance is to develop TBSS, an automated observer-independent method of aligning FA images from multiple subjects to allow group-wise comparisons of DTI data (Smith et al., 2006, Smith et al., 2007). TBSS focuses on the WM skeleton (i.e., the most compact whole-brain WM). This technique has been used to study preterm infants and adolescent development (Anjari et al., 2007, Giorgio et al., 2008), patients with schizophrenia (Douaud et al., 2007, Karlsgodt et al., 2008), fetal alcohol syndrome (Li et al., 2009), epilepsy (Schoene-Bake et al., 2009), attention deficit hyperactivity disorder (Silk et al., 2008), multiple sclerosis (Bodini et al., 2009, Cader et al., 2007, Dineen et al., 2009, Roosendaal et al., 2009), bipolar disorder (Barnea-Goraly et al., 2009, Versace et al., 2008), amyotrophic lateral sclerosis (Sage et al., 2009), and Alzheimer's disease (Stricker et al., 2009), marijuana users (Arnone et al., 2008), and young adults exposed to parental verbal abuse (Choi et al., 2009), but not, to our knowledge, individuals with ASD.
During adolescence, the structural maturation of fiber tracts in the human brain, including increases in axon myelination and FA, plays a role in cognitive development (Ashtari et al., 2007, Barnea-Goraly et al., 2005, Paus et al., 1999, Schmithorst et al., 2005). Thus, we hypothesized that individuals with ASD might fail to undergo complete maturation of WM tracts, particularly in the frontal lobe, during adolescence. The goal of the present study was to utilize the TBSS method of DTI analysis to investigate differences in FA and longitudinal and radial diffusivities over age in adolescents with ASD and matched controls.
Section snippets
Participants
All participants were right-handed ethnic Chinese males with IQ > 80 as estimated by Wechsler Intelligence Scale for Children (Wechsler, 1991). Adolescents with a co-morbid psychiatric or medical condition (e.g., epilepsy), history of head injury, or genetic disorder associated with autism (e.g., fragile × syndrome) were excluded. The ASD group had twenty-five non-medicated adolescents with ASD aged 10–18 years, recruited from a community autism program. The diagnosis of ASD was confirmed using the
Demographics
The characteristics of the participants were listed in Table 1. The ASD group consisted of 25 participants with the diagnosis at the time of DTI: 11 autism, 12 Asperger's disorder, and 2 pervasive developmental disorders not otherwise specified. The subjects with ASD and the controls were group-matched on age, full-scale IQ, and handedness.
Direct group comparisons
Controlling for age and IQ as covariates, the exploratory groupwise comparison of the ASD group and the controls (SVC-FDR-corrected P < 0.05, Z score > 3.15)
Discussion
Previous DTI studies in individuals with ASD have reported that FA increases at an abnormally accelerated rate during early childhood development (Ben Bashat et al., 2007) while other studies have reported decreases in FA during adolescence and early adulthood (Alexander et al., 2007, Barnea-Goraly et al., 2004, Catani et al., 2008, Conturo et al., 2008, Lee et al., 2007, Sundaram et al., 2008, Thakkar et al., 2008). Here, we demonstrate an FA imbalance between control and ASD adolescent
Acknowledgments
The study was in part sponsored by the National Science Council (NSC 97-2410-H-010-003-MY2; NSC 98-2923-B-010 -001-MY3), the National Yang-Ming University Hospital (RD2008-015), the National Health Institute of Research (NHRI-EX98-9813EC) and the Healthy Department of Taipei City Hospital (97001-62-020). The authors thank the children and parents who participated in this study.
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