White matter alterations at pubertal onset
Introduction
Puberty is a critical period of development, marking the transition from childhood to reproductive maturity (Dorn et al., 2006). Adrenarche describes the earliest phase of puberty, beginning between the ages of 6 – 9 in females, and approximately 1 year later in males (Grumbach and Styne, 1998). It is the period in which physical changes begin to manifest. Endocrine events tied to puberty such as activation of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes leads to increased production of adrenal and gonadal steroid hormones, which have been shown to enter the blood brain barrier and initiate remodelling of the brain in animal models (Sisk and Foster, 2004).
Quantifying these hormone levels in puberty, however, is inherently limited by individual variability and diurnal pattern of hormone concentrations, making it difficult to infer pubertal stage (Ankarberg and Norjavaara, 1999). The Pubertal Development Scale (PDS) is a non-invasive self or parent-report measure of pubertal stage that is highly correlated with hormones and physical exam (Shirtcliff et al., 2009).
A growing body of evidence suggests that the timing of pubertal onset can lead to differential patterns of grey and white matter development evidenced by Magnetic Resonance Imaging (MRI) (Blakemore et al., 2010, Byrne et al., 2016, Ladouceur et al., 2012). In the context of grey matter, there is converging evidence of a positive relationship between pubertal stage and pituitary volume (Whittle et al., 2012, Wong et al., 2014), global grey matter density (Peper et al., 2009), and amygdala volume (Goddings et al., 2014, Neufang et al., 2009).
In addition to physical indices of pubertal maturation, endogenous adrenal and sex steroid hormone levels have been associated with grey and white matter structure. In early puberty, corpus callosum body volume is higher with increased luteinizing hormone (LH) levels (Peper et al., 2008). Testosterone levels are associated with increased white matter volume (Perrin et al., 2008), as well as sex-dependent relationships in grey matter surface area (Herting et al., 2015) and corticospinal structure (Pangelinan et al., 2016).
Diffusion MRI techniques have allowed the in-vivo quantification of properties of white matter microstructure during this dynamic period of brain development. A number of diffusion tensor imaging (DTI) studies have revealed greater microstructural organisation with pubertal advancement (Asato et al., 2010, Herting et al., 2012, Menzies et al., 2015). Whilst DTI is the most commonly used technique to assess white matter microstructure, metrics such as fractional anisotropy (FA) are non-specific at distinguishing between white matter properties such as axon density, myelination, glial infiltration, crossing fibres, and partial voluming. These are all separate physio-anatomical properties of white matter that must be disentangled to fully understand the nature of white matter changes across development (Beaulieu, 2009).
Since chronological age and pubertal stage are highly correlated, highly sensitive as well as specific models that interrogate white matter microstructure at the fibre level are necessary to disentangle ‘pubertal age’, or pubertal contributions to white matter microstructure, from chronological age. Despite these advancements, disentangling age-related mechanisms of brain development from pubertal processes remains a challenge.
Recent advances have introduced more specific measures of axon density and fibre bundle cross-section (Groeschel et al., 2016). Neurite density index from NODDI (Zhang et al., 2012) can characterise the density of neurites by restricted diffusion by modelling the intra-cellular space (Sepehrband et al., 2015). Whilst more sensitive than DTI metrics to age-related differences in the developing brain (Genc et al., 2017), there has been some debate regarding its interpretation in areas in multiple crossing fibres, and the underlying assumptions of the model (Lampinen et al., 2017; Novikov et al., 2016).
Fixel-based analysis (FBA) (Raffelt et al., 2012, Raffelt et al., 2017) is a recently developed diffusion MRI analysis technique that uses fibre-population specific information to estimate fibre density and morphology for individual white matter fibre populations. A fixel is defined as a fibre-population within a voxel, and as such FBA allows for whole-brain comparisons of fibre-specific white matter properties. It produces metrics that assess fibre density (FD), fibre cross-section (FC), and the combined effect of fibre density and cross-section (FDC), where FD for a given fibre population is proportional to the volume of the intra-axonal compartment. FC reflects the cross-sectional area of the white matter fibre bundle, and FDC reflects the combined effect of FD and FC. Increases in FD can represent an increase in axonal count, or denser packing of axons, in a given fibre area, whereas increases in FC can suggest greater cross-sectional area of a fibre bundle.
In this study, we implement fixel-based analysis to estimate and compare white matter fibre density and morphology across two age-matched groups of children: pre-pubertal (no evidence of maturation of secondary sexual characteristics), and pubertal (evidence of pubertal maturation).
Section snippets
Participants
This paper reports on a subsample of typically developing children recruited as part of the Neuroimaging of the Children's Attention Project study (see Silk et al. (2016) for a detailed protocol). Briefly, children were recruited from 43 socio-economically diverse primary schools distributed across the Melbourne metropolitan area, Victoria, Australia. MR imaging was performed on 86 typically developing children. Of those, 8 participants were excluded owing to missing or motion-affected
Participant characteristics
The pre-pubertal and pubertal group did not differ in age, handedness, BMI, SES, or WASI matrix reasoning T-score (Table 1). Sex distribution significantly differed between the groups, as there was a higher proportion of girls in the pubertal group compared to the pre-pubertal group.
Fixel-based analysis
Fixel-based analyses revealed higher FD in the pubertal group, compared with the pre-pubertal group (pFWE <.001). The region of significantly higher fibre density was localised to the splenium of the corpus
Discussion
This study presents the first application of the recently developed fixel-based analysis technique to investigate white matter fibre architectural differences between age-matched children at pre- and early- stages of pubertal maturation. Previous research suggests that the onset of puberty contributes to the remodelling of white matter during the transition between childhood and adolescence, and the present study shows that fibre density is specifically altered.
The fixel-wise comparison between
Conclusion
In conclusion, we found that white matter apparent fibre density in the splenium is associated with pubertal onset. These findings suggest that pubertal onset is associated with increasing axon diameter, compared with age-matched pre-pubertal children. Together, we present evidence that white matter development and maturation may be influenced by pubertal onset itself, rather than solely the developmental processes associated with chronological age.
Acknowledgements
This study was funded by the National Medical Health and Research Council of Australia (NHMRC; project grant #1065895). This research was conducted within the Developmental Imaging research group, Murdoch Childrens Research Institute, and the Children's MRI Centre, The Royal Children's Hospital, Melbourne, Victoria. It was supported by the Murdoch Childrens Research Institute, The Royal Children's Hospital, The Department of Paediatrics at The University of Melbourne and the Victorian
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