Increased Brain Size in Autism—What It Will Take to Solve a Mystery

The past decade has witnessed an explosion of research into the neurodevelopmental origins of Autism Spectrum Disorders (ASD). Magnetic resonance imaging (MRI) studies support the hypothesis that an increased brain size (BS) is the underlying cause of macrocephaly, which develops in approximately 20% of patients within the first two years of life (see (1) for a review). As compared to both typically-developing controls or non-autistic individuals with mental retardation, individuals with ASD have a 5-10% enlargement in total brain volume at 18 months-4 years of age. The increased BS was attributed to an increase in both the gray and white matter volumes. Differences in BS and head circumference appear most robust in early childhood. Whether the brain enlargement persists in ASD after age 5 is not clear, although several studies have reported a 6-12% increase in gray matter volume in adolescents and adults with ASD (see (1) for a review). While there are many unanswered questions regarding how the neuroanatomical perturbations seen in ASD lead to the cognitive and behavioral manifestations of these diseases, it is becoming increasingly clear that the altered trajectory of brain development in ASD is probably the most reliable biomarker in this disorder. In this issue of Biological Psychiatry, several articles confirm the increased BS in ASD and add intriguing details towards the underlying causes of autism. Freitag et al show that while ASD individuals have increased total brain volume (TBV), subcortical white matter volume (WMV) and gray matter volume (GMV), they also show decreased volume of the corpus callosum (CC). Furthermore, CC size was positively correlated with TBV, WMV and GMV in controls but not in autism. This study fits with earlier neuroimaging study (2, 3), which found a relative increase in the upper (radiate) cortical WM but not in the inner cortical WM, and decreased long-range tracts like the CC (Table). Freitag et al also suggest that positive correlations of brain volumetric indices with ASD diagnosis were primarily observed in ASD children with low IQ scores. Controlling for IQ poses a challenging conundrum for the interpretation of neuroimaging studies of ASD, for while lower IQ is part of the autistic phenotype, IQ is correlated with increased BS in the typically developing population. The authors confirm the finding that BS and IQ are positively correlated in normal children, whereas BS and IQ do not show any correlation in ASD children. This finding provides initial clues that the increase in BS in autism is not an adaptive phenomenon. Hardan et al. provide the first longitudinal data suggesting that ASD individuals exhibiting a greater GM volume also exhibit accelerated GM pruning in the periadolescent period. Coupled with the Freitag data, these findings suggest that both BS increase and excessive pruning may be part of the same maladaptive phenomenon, as greater decrease in volume (interpreted as pruning) was associated with more severe symptoms. Despite the low power, these findings confirm earlier suspicions based on cross sectional data (4) that the trajectory of brain development is fundamentally different in ASD. However, the biological underpinnings of the maladaptive growth and pruning phenomena are not understood. In normal development, genesis and pruning of connections (axons, dendrites, spines and synapses) occur concurrently, and either or both these phenomena may be altered in ASD. Thus, more research will be needed to understand the pathogenesis and implications of the BS dynamics in ASD.