Longitudinal patterns of white matter fibre density and morphology in children are associated with age and pubertal stage

AbstractPurposeWhite matter fibre development in childhood involves dynamic changes to microstructural organisation driven by increasing axon diameter, density, and myelination. However, there is a lack of longitudinal studies that have quantified advanced diffusion metrics to identify regions of accelerated fibre maturation, particularly across the early pubertal period. We applied a novel longitudinal fixel-based analysis (FBA) framework, in order to estimate microscopic and macroscopic white matter changes over time.MethodsDiffusion-weighted imaging (DWI) data were acquired for 59 typically developing children (27 female) aged 9 – 13 years at two time-points approximately 16 months apart (time-point 1: 10.4 ± 0.4 years, time-point 2: 11.7 ± 0.5 years). Whole brain FBA was performed using the connectivity-based fixel enhancement method, to assess longitudinal changes in fibre microscopic density and macroscopic morphological measures, and how these changes are affected by sex, pubertal stage, and pubertal progression. Follow-up analyses were performed in sub-regions of the corpus callosum to confirm the main findings using a Bayesian repeated measures approach.ResultsThere was a statistically significant increase in fibre density over time localised to medial and posterior commissural and association fibres, including the forceps major and bilateral superior longitudinal fasciculus. Increases in fibre cross-section were substantially more widespread. The rate of fibre development was not associated with age or sex. In addition, there was no significant relationship between pubertal stage or progression and longitudinal fibre development over time. Follow-up Bayesian analyses were performed to confirm the findings, which supported the null effect of the longitudinal pubertal comparison.ConclusionUsing a novel longitudinal fixel-based analysis framework, we demonstrate that white matter fibre density and fibre cross-section increased within a 16-month scan rescan period in specific regions. The observed increases might reflect increasing axonal diameter or axon count. Pubertal stage or progression did not influence the rate of fibre development in the early stages of puberty. Future work should focus on quantifying these measures across a wider age range to capture the full spectrum of fibre development across the pubertal period.

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White matter alterations at pubertal onset

10.1101/128165 ◽

2017 ◽

Author(s):

Sila Genc ◽

Marc L Seal ◽

Thijs Dhollander ◽

Charles B Malpas ◽

Philip Hazell ◽

...

Keyword(s):

White Matter ◽

Corpus Callosum ◽

Cross Section ◽

Pubertal Development ◽

B Value ◽

Imaging Data ◽

Pubertal Stage ◽

Fibre Density ◽

Pubertal Onset ◽

Post Hoc

Recent neurodevelopmental research supports the contribution of pubertal stage to local and global grey and white matter remodelling. Little is known, however, about white matter microstructural alterations at pubertal onset. This study investigated differences in white matter properties between pre-pubertal and pubertal children using whole brain fixel-based analysis (FBA) of the microscopic density and macroscopic cross-section of fibre bundles. Diffusion-weighted imaging data were acquired for 74 typically developing children (M=10.4, SD=0.43 years, 31 female) at 3.0T (60 diffusion gradient directions, b-value=2800 s/mm 2 ). Group comparisons of fibre density (FD) and fibre cross-section (FC) were made between age-matched pre-pubertal and pubertal groups, and post-hoc analyses were performed on regions of interest (ROIs) defined in the splenium, body and genu of the corpus callosum. Significant fixel-wise differences in FD were observed between the pubertal groups, where the pubertal group had significantly higher FD compared with age-matched pre-pubertal children, localised to the posterior corpus callosum. Post-hoc analyses on mean FD in the corpus callosum ROIs revealed group differences between the pubertal groups in the splenium, but not body or genu. The observed higher apparent fibre density in the splenium suggests that pubertal onset coincides with white matter differences explained by increasing axon diameter. This may be an important effect to account for over pubertal development, particularly for group studies where age-matched clinical and typical populations may be at various stages of puberty.

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Longitudinal white matter development in children is associated with puberty, attentional difficulties, and mental health

10.1101/607671 ◽

2019 ◽

Cited By ~ 4

Author(s):

Sila Genc ◽

Charles B Malpas ◽

Alisha Gulenc ◽

Emma Sciberras ◽

Daryl Efron ◽

...

Keyword(s):

Mental Health ◽

White Matter ◽

Pubertal Development ◽

Pubertal Stage ◽

Fibre Density ◽

Increased Risk ◽

White Matter Development ◽

Attentional Difficulties ◽

Higher Cognitive Functions ◽

The Right

ABSTRACTThe pubertal period involves dynamic white matter development. This period also corresponds with rapid gains in higher cognitive functions including attention, as well as increased risk of developing mental health difficulties. This longitudinal study comprised children aged 9-13 years (n=130). Diffusion magnetic resonance imaging (dMRI) data were acquired (b=2800 s/mm2, 60 directions) at two time-points. We derived measures of fibre density and morphology using the fixel-based analysis framework and performed a tract-based mixed-effects modelling analysis to understand patterns of white matter development with respect to age, pubertal stage, attentional difficulties, and internalising and externalising problems. We observed significant increases in apparent fibre density across a large number of white matter pathways, including major association and commissural pathways. We observed a linear relationship between fibre density and morphology with pubertal stage, in the right superior longitudinal fasciculus and in the right inferior longitudinal fasciculus. In terms of symptom severity, fibre density was positively associated with attentional dysfunction in the right uncinate fasciculus. Overall, white matter development across ages 9-13 years involved the expansion of major white matter fibre pathways, with key right-lateralised association pathways linked with pubertal development and attentional difficulties.

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Faculty Opinions recommendation of Investigating white matter fibre density and morphology using fixel-based analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726749306.793549543 ◽

2018 ◽

Author(s):

Serena Counsell

Keyword(s):

White Matter ◽

Fibre Density

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Development of white matter fibre density and morphology over childhood: A longitudinal fixel-based analysis

NeuroImage ◽

10.1016/j.neuroimage.2018.08.043 ◽

2018 ◽

Vol 183 ◽

pp. 666-676 ◽

Cited By ~ 24

Author(s):

Sila Genc ◽

Robert E. Smith ◽

Charles B. Malpas ◽

Vicki Anderson ◽

Jan M. Nicholson ◽

...

Keyword(s):

White Matter ◽

Fibre Density

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Long-term development of white matter fibre density and morphology up to 13 years after preterm birth: A fixel-based analysis

NeuroImage ◽

10.1016/j.neuroimage.2020.117068 ◽

2020 ◽

Vol 220 ◽

pp. 117068 ◽

Cited By ~ 1

Author(s):

Claire E. Kelly ◽

Deanne K. Thompson ◽

Sila Genc ◽

Jian Chen ◽

Joseph YM. Yang ◽

...

Keyword(s):

Preterm Birth ◽

White Matter ◽

Fibre Density

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Childhood conduct problems are associated with reduced white matter fibre density and morphology

10.1101/2020.05.29.123364 ◽

2020 ◽

Author(s):

Daniel T. Burley ◽

Sila Genc ◽

Timothy J. Silk

Keyword(s):

White Matter ◽

Conduct Problems ◽

Diffusion Tensor ◽

Community Sample ◽

Fibre Density ◽

Time Points ◽

White Matter Microstructure ◽

Childhood Conduct Problems ◽

Childhood Conduct ◽

Time Point

AbstractChildhood conduct problems are an important public health issue as these children are at-risk of adverse outcomes. Studies using diffusion Magnetic Resonance Imaging (dMRI) have found that conduct problems in adults are characterised by abnormal white-matter microstructure within a range of white matter pathways underpinning socio-emotional processing, while evidence within children and adolescents has been less conclusive based on non-specific diffusion tensor imaging metrics. Fixel-based analysis (FBA) provides measures of fibre density and morphology that are more sensitive to developmental changes in white matter microstructure. The current study used FBA to investigate whether childhood conduct problems were related both cross-sectionally and longitudinally to microstructural alterations within the fornix, inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and the uncinate fasciculus (UF). dMRI data was obtained for 130 children across two time-points in a community sample with high levels of externalising difficulties (age: time-point 1 = 9.47 – 11.86 years, time-point 2 = 10.67 −13.45 years). Conduct problems were indexed at each time-point using the Conduct Problems subscale of the parent-informant Strengths and Difficulties Questionnaire (SDQ). Conduct problems were related to lower fibre density in the fornix at both time-points, and in the ILF at time-point 2. We also observed lower fibre cross-section in the UF at time-point 1. The change in conduct problems did not predict longitudinal changes in white-matter microstructure across time-points. The current study suggests that childhood conduct problems are related to reduced fibre-specific microstructure within white matter fibre pathways implicated in socio-emotional functioning.

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Prospective associations, longitudinal patterns of childhood socioeconomic status, and white matter organization in adulthood

Human Brain Mapping ◽

10.1002/hbm.25031 ◽

2020 ◽

Vol 41 (13) ◽

pp. 3580-3593

Author(s):

Alexander J. Dufford ◽

Gary W. Evans ◽

Julia Dmitrieva ◽

James E. Swain ◽

Israel Liberzon ◽

...

Keyword(s):

Socioeconomic Status ◽

White Matter ◽

Longitudinal Patterns ◽

Childhood Socioeconomic Status

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IC-P-108: Apparent fibre density: A novel MRI approach that identifies specific white matter tracts affected in Alzheimer's disease and MCI

Alzheimer s & Dementia ◽

10.1016/j.jalz.2012.05.142 ◽

2012 ◽

Vol 8 (4S_Part_2) ◽

pp. P61-P61

Author(s):

David Raffelt ◽

J. Donald Tournier ◽

Stuart Crozier ◽

Kathryn Ellis ◽

Ralph Martins ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

White Matter Tracts ◽

Fibre Density

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Long-term development of white matter fibre density and morphology up to 13 years after preterm birth

10.1101/2020.04.01.20049585 ◽

2020 ◽

Author(s):

Claire E Kelly ◽

Deanne K Thompson ◽

Sila Genc ◽

Jian Chen ◽

Joseph YM Yang ◽

...

Keyword(s):

Risk Factors ◽

White Matter ◽

Corpus Callosum ◽

Childhood And Adolescence ◽

Fibre Tract ◽

Perinatal Risk Factors ◽

Perinatal Risk ◽

Fibre Density ◽

Individual Fibre

AbstractBackgroundIt is well documented that infants born very preterm (VP) are at risk of brain injury and altered brain development in the neonatal period, however there is a lack of long-term, longitudinal studies on the effects of VP birth on white matter development over childhood. Most previous studies were based on voxel-averaged, non-fibre-specific diffusion magnetic resonance imaging (MRI) measures, such as fractional anisotropy. In contrast, the novel diffusion MRI analysis framework, fixel-based analysis (FBA), enables whole-brain analysis of microstructural and macrostructural properties of individual fibre populations at a sub-voxel level. We applied FBA to investigate the long-term implications of VP birth and associated perinatal risk factors on fibre development in childhood and adolescence.MethodsDiffusion images were acquired for a cohort of VP (born <30 weeks’ gestation) and full-term (FT, ≥37 weeks’ gestation) children at two ages: mean (SD) 7.6 (0.2) years (n=138 VP and 32 FT children) and 13.3 (0.4) years (n=130 VP and 45 FT children). 103 VP and 21 FT children had images at both ages for longitudinal analysis. At every fixel (individual fibre population within an image voxel) across the white matter, we compared FBA metrics (fibre density (FD), cross-section (FC) and a combination of these properties (FDC)) between VP and FT groups cross-sectionally at each age, and longitudinally between ages. We also examined associations between perinatal risk factors and FBA metrics in the VP group.ResultsCompared with FT children, VP children had lower FD, FC and FDC throughout the white matter, particularly in the corpus callosum, tapetum, inferior fronto-occipital fasciculus, fornix and cingulum at ages 7 and 13 years, as well as the motor pathways at age 13 years. VP children also had slower FDC development in the corpus callosum and corticospinal tract between ages 7 and 13 years compared with FT children. Within VP children, earlier gestational age at birth, lower birth weight z-score, and neonatal brain abnormalities were associated with lower FD, FC and FDC throughout the white matter at both ages.ConclusionsVP birth and concomitant perinatal risk factors are associated with fibre tract-specific alterations to axonal development in childhood and adolescence.

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