On the Spectrum

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Cortical morphology in children with autistic traits traits and confirmed ASD. Finally, we found less gyrification with more autistic traits and a comparable –though non-significant– effect when comparing a small sample of confirmed ASD cases to age and gender-matched controls. Taken together, these findings provide supportive evidence for the existence of a continuum, at least for some regions, in the neurobiology of autistic traits in children. While other studies of gyrification in ASD have not had the goal of evaluating whether traits are continuous in the population, they have evaluated gyrification abnormalities in ASD. Studies have found both decreased (Schaer et al. 2013) and increased (Kates et al. 2009; Wallace et al. 2013) gyrification in clinical cohorts with ASD. In a case/control study of ASD in 11 subjects (8 male) compared to typically developing controls aged 9-17 years, Schaer et al. found decreased gyrification in frontal brain regions (Schaer et al. 2013). However, using the same technique, Wallace et al. (Wallace et al. 2013) reported regions of increased gyrification in an all-male case control study of ASD (aged 12-23 years). The differences in the age and gender constellations of these studies could be responsible for the discrepancy in the findings. However, this is less intuitive since gyrification peaks early in childhood and, parallel with cortical pruning, decreases over time (White, Su, Schmidt, Kao and Sapiro 2010; Shaw, Malek, Watson, Sharp, Evans et al. 2012). Thus, factors such as heterogeneity in the features of ASD, small sample size, or sample selection differences could be responsible for the differences. Interestingly though, when Wallace et al. performed a subanalysis that included only the typically developing subjects, they found negative correlations between autistic traits and gyrification in a region showing marked overlap with our finding in the right superior temporal lobe. Gyrification is a poorly understood phenomenon that is thought to accommodate efficient neural processing in the brain (Van Essen 1997). Decreased gyrification could point to disruptions in fetal development, since the majority of gyrification takes place in the third trimester, at a time when the brain undergoes prolific growth. However, the many primary sulci are formed before that, between 20 and 28 weeks of gestational age (Habas, Scott, Roosta, Rajagopalan, Kim et al. 2012). Following Van Essen’s model (Van Essen 1997), decreased gyrification could reflect decreased short-range connectivity of the neurons within specific regions. Indeed, Schaer et al. recently found decreased gyrification in ASD to be related to decreased connectivity in the same regions (Schaer et al. 2013). In our study, decreased gyrification was not associated with decreased surface area. This decoupling of various aspects of the cortex is puzzling, but consistent with at least one other study in ASD (Wallace et al. 2013) and could potentially be understood by the fact that both features derive from distinct stages in gestation and that different aspects of the cortex are regulated by different genetic mechanisms (Panizzon, Fennema-Notestine, Eyler, Jernigan, Prom-Wormley et al. 2009). A disruption within a particular developmental window may interfere with the development of one feature, while leaving another preserved. 2 37
Chapter 2 While we found widespread regions of decreased gyrification, specific brain regions were more affected. Interestingly, the regions we found are functionally associated with capacities that are impaired in ASD. The frontal and posterior cingulate cortices both form components of the default mode network, a resting-state functional brain network thought to be involved in self-reflection (Fair, Cohen, Dosenbach, Church, Miezin et al. 2008). Additionally, the anterior cingulate cortex, the temporal lobes and superior temporal sulcus, have been related to ‘theory of mind’ (Gallagher and Frith 2003). The superior temporal sulcus, in which we found less gyrification and decreased sulcal depth, is recognized as a structure crucial to perception and processing of language, auditory stimuli, and specifically social stimuli (both visual and auditory) (Zilbovicius, Meresse, Chabane, Brunelle, Samson et al. 2006). Previous research has shown decreased gray matter (Hadjikhani, Joseph, Snyder and Tager- Flusberg 2006; Scheel et al. 2011), white matter volumes (von dem Hagen, Nummenmaa, Yu, Engell, Ewbank et al. 2011), and abnormal activation of the superior temporal region in ASD (Zilbovicius et al. 2006). We found larger volume and thicker cortex of the pericalcarine region, a region that is among the first to reach peak cortical thickness (Shaw, Kabani, Lerch, Eckstrand, Lenroot et al. 2008), around age 7 years, which falls within the age range in our study. Thicker occipital cortex has been found in school-aged children with ASD (Zielinski et al. 2014) and is in line with the early brain overgrowth hypothesis. Further, Magnetic Resonance Spectroscopy has revealed diminished levels of creatine (Levitt, O’Neill, Blanton, Smalley, Fadale et al. 2003). Thicker cortex in the pericalcarine area was exclusively found in boys, which potentially reflects gender specificity in brain development in children with autistic traits. Since females are generally underrepresented in clinical ASD samples, due to the low prevalence in females, it is possible that some findings arising from previous studies on cortical thickness are in fact driven by the males only. However, the regions where we found decreased gyrification were mostly overlapping across genders, in line with work that suggests similar brain differences in men and women with ASD (Craig, Zaman, Daly, Cutter, Robertson et al. 2007). Our study has a number of strengths. First we imaged children from a large, populationbased cohort with autistic traits across a broad spectrum. This provides the unique opportunity to test whether the underlying neurobiology of autistic traits extends into the general population. In addition, considerable information is available on potential confounding factors. Although autistic traits frequently co-occur with attention problems and lower IQ (Grzadzinski, Di Martino, Brady, Mairena, O’Neale et al. 2011), the brain correlates described here are specifically related to autistic traits independent of IQ and attention problems. Further, our results were independent of symptoms of aggression, anxiety and depression. There are several limitations to the study. First, the measurement of autistic traits and cortical morphology was not contemporaneous. However, autistic traits are relatively stable over time (Constantino, Abbacchi, Lavesser, Reed, Givens et al. 2009) and a sensitivity 38
Page 1 and 2: On the Spectrum the neurobiology of
Page 3 and 4: ISBN: 978-94-6233-336-9 © Laura Bl
Page 5 and 6: PROMOTIECOMMISSIE Promotoren Overig
Page 8: MANUSCRIPTS THAT FORM THE BASIS OF
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Page 13 and 14: Chapter 1 Cuthbert, Garvey, Heinsse
Page 15 and 16: Chapter 1 folding of the brain into
Page 17 and 18: Chapter 1 beneficial for treatment
Page 19 and 20: Chapter 1 REFERENCES Achenbach, T.
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Page 27 and 28: Chapter 2 ABSTRACT Objective: Recen
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Page 33 and 34: Chapter 2 Gyrification Six regions
Page 35 and 36: Chapter 2 The association remained
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Page 41 and 42: Chapter 2 REFERENCES Amaral, D. G.,
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Chapter 4 Table 4. TBSS: autistic t
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Chapter 4 of group differences rela
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Chapter 4 Cook, P. A., Y. Bai, S. N
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Chapter 4 White, T., H. El Marroun,
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5 From Chronnectivity To Chronnecto
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From Chronnectivity To Chronnectopa
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nalysis did not reveal any FDR-corr
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6 Cognitive functioning in children
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Cognitive functioning in children w
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Chapter 7 ABSTRACT Objectives: In c
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Chapter 7 profile analysis performe
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Chapter 7 have been demonstrated pr
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Chapter 7 Next, we examined associa
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Chapter 7 Table 2 Brain morphology
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Chapter 7 Table 3 Cortical thicknes
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Chapter 7 Our finding was suggestiv
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Chapter 7 Using empirically defined
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Chapter 7 Fischl, B. and A. M. Dale
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Chapter 7 Supplement Table 1 Brain
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IIIPart III
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Chapter 8 190
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Chapter 8 stable relationships, and
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Chapter 8 gyrification changes in p
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Chapter 8 genetic or environmental
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Chapter 8 diseases, according to th
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Chapter 8 ability may be even more
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Chapter 8 symptoms could be more sp
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Chapter 8 association of maternal v
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Chapter 8 REFERENCES Abrahams, B. S
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Chapter 8 Goddard, M. N., S. van Ri
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Chapter 8 Sebat, J., B. Lakshmi, D.
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SSummary Samenvatting
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Summary SUMMARY Despite evidence fr
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Summary along a continuum were used
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Samenvatting SAMENVATTING Genetisch
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Samenvatting jonge kinderen die zic
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Addendum Mous SE, Schoemaker NK, Bl
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Addendum Zoeken in andere databases
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Addendum School of Women’s and In
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Addendum Graag wil ik Dr. Marion Sm
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Addendum hebben. Dank in het bijzon
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On the Spectrum

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