The effect of age on vertex-based measures of the grey-white matter tissue contrast in autism spectrum disorder

Mann et al. Molecular Autism (2018) 9:49 https://doi.org/10.1186/s13229-018-0232-6 RESEARCH Open Access The effect of age on vertex-based measures of the grey-white matter tissue contrast in autism spectrum disorder Caroline Mann1* , Anke Bletsch1, Derek Andrews2, Eileen Daly3, Clodagh Murphy3, MRC AIMS Consortium, Declan Murphy3 and Christine Ecker1,3 Abstract Background: Histological evidence suggests that autism spectrum disorder (ASD) is accompanied by a reduced integrity of the grey-white matter boundary. This has also recently been confirmed by a structural neuroimaging study in vivo reporting significantly reduced grey-white matter tissue contrast (GWC) in adult individuals (18–42 years of age) with ASD relative to typically developing (TD) controls. However, it remains unknown whether the neuroanatomical differences in ASD at the grey-white matter boundary are stable across development or are age-dependent. Methods: Here, we examined differences in the neurodevelopmental trajectories of GWC in a cross-sectional sample of 77 male ASD individuals and 76 typically developing (TD) controls across childhood and early adulthood (from 7 to 25 years). Results: Using nested model comparisons, we first established that the developmental trajectory of GWC is complex in many regions across the cortex and includes linear and non-linear effects of age. Second, while ASD individuals have significantly reduced GWC overall, these differences are age-dependent and are most prominent during childhood (< 15 years). Conclusions: Taken together, our findings suggest that differences in GWC in ASD are unlikely to reflect atypical grey matter cytoarchitecture alone, but may also represent other aspects of the cortical architecture such as age-dependent variability in myelin integrity. Keywords: Autism spectrum disorder, Neurodevelopment, Structural MRI, Neuroimaging, Brain anatomy Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social communication, social reciprocity, and repetitive/stereotypic behaviour [1]. There is strong evidence to suggest that these core symptoms are accompanied by differences in grey matter (GM) neuroanatomy and white matter (WM) connectivity [2], which typically manifest during early infancy [3, 4]. Despite the large number of existing neuroimaging studies, however, the neurobiological * Correspondence: 1 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, Goethe University Frankfurt am Main, Deutschordenstrasse 50, 60528 Frankfurt am Main, Germany Full list of author information is available at the end of the article mechanisms that drive the atypical development of the brain in ASD remain poorly understood. To date, most neuroimaging studies examining atypical brain development in ASD have focused on measures of brain volume [5–7] and its two constituent components cortical thickness [8] and surface area [9, 10]. More recently, however, the attention of structural neuroimaging studies is shifting towards examining the grey-white matter boundary, as histological evidence suggests that the grey-white matter tissue contrast may be regionally less well defined (i.e. less distinct) in ASD [11]. Such ‘blurring’ of the grey-white matter transition zone seems to be caused by the presence of supernumerary neurons beneath the cortical plate, which—in turn—may result from migration deficits or failed apoptosis in the subplate region [12]. This finding also agrees with genetic investigations linking the © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mann et al. Molecular Autism (2018) 9:49 aetiology of ASD to atypical neuronal proliferation, migration, and maturation [13, 14]. For stratification purposes, and to capture aspects of ASD neuropathology that may be more closely linked to aetiological factors, it is therefore important to also investigate neuroimaging measures that map onto these particular characteristics of the cortical microstructure in vivo. With this aim in mind, we recently examined the contrast between grey and white matter (GWC) across different cortical layers in a sample of males and females with ASD and typically developing (TD) controls [15]. We found that the GWC was significantly reduced in ASD, particularly at the grey-white matter boundary, and in many brain regions that have previously been linked to autistic symptoms and traits [16]. Our in vivo finding of a reduced GWC is also consistent with prior postmortem reports of a less well-defined grey-white matter boundary in ASD [11, 12]. However, based on tissue contrast alone, it is not possible to disentangle whether the observed between-group effects are driven by (1) differences in grey matter cytoarchitecture, as suggested by the above histological studies, or by (2) local variations in myelin content. For instance, a recent neuroimaging study of typical ageing, examining a sample of healthy adults (with an age range of 20–84 years), suggests that the GWC typically declines with increasing age and most likely reflects local (i.e. region-dependent) age-related changes of myelin integrity in the superficial WM [17]. Thus, by studying the GWC in ASD across different developmental stages, it may be possible to gain in vivo insights into neurobiological processes that (1) should be completed around birth (e.g. migration deficits), (2) end during early childhood (e.g. apoptosis), and (3) that are ongoing (e.g. myelination). Here, we examined age-related changes in GWC in ASD individuals compared to TD controls during childhood and adolescence. In addition to between-group differences in GWC, the present study investigated age-by-group interactions in a cross-sectional sample of male individuals with ASD and matched TD controls using a spatially unbiased ‘vertex-wise’ approach (i.e. not restricted to regions of interest). We expected the differences in the contrast to be age-dependent (i.e. there are significant age × group interactions), which would suggest that differences observed during postnatal brain development are not exclusively driven by atypical grey matter cytoarchitecture. Furthermore, it has previously been shown that the trajectory of brain maturation for different morphological features is complex and cannot adequately be captured by linear effects alone. For example, the trajectory of total brain volum (...truncated)