On the Spectrum

General introduction
neuroimaging techniques have greatly expanded the possibilities to study brain development
in vivo, providing a promising route to unravelling the neurobiology of ASD. A better
understanding of the neurobiology of ASD could identify novel targets for early identification
and treatment of the disorder. Reconciling the phenotypic insights of a continuum in ASD
with modern neuroimaging techniques could help in the quest for such targets.
ASD is thought to be associated with differences in the brain, that occur at many different
levels (Parellada, Penzol, Pina, Moreno, Gonzalez-Vioque et al. 2014). In this thesis, we study
various aspects of the neurobiology of ASD from a quantitative trait perspective, focusing on
social impairment.
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Prenatal and postnatal structural brain development
One of the most prominent theories of the underlying neurobiology of ASD involves “early
brain overgrowth”. Traditionally, retrospective studies of brain growth in young children with
ASD have reported early brain overgrowth in the first year of life (Hazlett, Poe, Gerig, Smith,
Provenzale et al. 2005). More recently, the existence and exact timing of early brain growth
abnormalities have been disputed, as many studies used historic references and study samples
tend to suffer from ascertainment bias (Raznahan, Wallace, Antezana, Greenstein, Lenroot et
al. 2013). However, there seems to be at least some consensus that children with ASD show
subtle accelerated head growth in early life, which results in a greater head circumference
and brain volume by the age of two (Piven, Arndt, Bailey and Andreasen 1996; Courchesne,
Karns, Davis, Ziccardi, Carper et al. 2001; Constantino, Majmudar, Bottini, Arvin, Virkud et al.
2010). While it is thought that brain abnormalities in ASD may be present before birth, less is
known about prenatal head growth trajectories. The few studies available have small sample
sizes, typically depend on retrospectively collected ultrasound data, after a diagnosis of ASD
has been established and do not all include repeated measurements of growth.
In addition, it is unclear whether this potential ‘early overgrowth’ persists into later
development. Postnatal brain development has been the topic of numerous studies in ASD
since modern neuroimaging techniques became available in children (Amaral, Schumann and
Nordahl 2008). One of the proposed underlying mechanisms of ASD involves altered growth
and refinement of the cortex, as reflected by global and regional differences in the thickness
of the cortex. However, studies of cortical morphology in ASD have reported mixed results.
This may partly be explained by a developmental effect. Studies in older children (12 years
and up) point to a thinner cortex in subjects with ASD compared to controls (Hadjikhani,
Joseph, Snyder and Tager-Flusberg 2006; Wallace, Dankner, Kenworthy, Giedd and Martin
2010; Scheel, Rotarska-Jagiela, Schilbach, Lehnhardt, Krug et al. 2011), whereas studies in
younger children primarily show a thicker cortex (Hardan, Muddasani, Vemulapalli, Keshavan
and Minshew 2006; Schumann, Bloss, Barnes, Wideman, Carper et al. 2010; Raznahan,
Lenroot, Thurm, Gozzi, Hanley et al. 2012). In addition, measures of gyrification, or the
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