Lifespan Trajectories of Asymmetry in White Matter Tracts

Abstract

ABSTRACT Asymmetry in white matter is believed to give rise to the brain's capacity for specialized processing and is involved in the lateralization of various cognitive processes, such as language and visuo‐spatial reasoning. Although studies of white matter asymmetry have been previously documented, they have often been constrained by limited age ranges, sample sizes, or the scope of the tracts and structural features examined. While normative lifespan charts for brain structures are emerging, comprehensive charts detailing white matter asymmetries across numerous pathways and diverse structural measures have been notably absent. This study addresses this gap by leveraging a large‐scale dataset of 35,120 typically developing and aging individuals, ranging from 0 to 100 years of age, from 50 primary neuroimaging studies. We generated comprehensive lifespan trajectories for 30 lateralized association and projection white matter tracts, examining six distinct microstructural and macrostructural features of these pathways. Our findings reveal that: (1) asymmetries are widespread across the brain's white matter and are present in all 30 pathways; (2) for a given pathway, the degree and direction of asymmetry differ between features of tissue microstructure and pathway macrostructure; (3) asymmetries vary across and within pathway types (association and projection tracts); and (4) these asymmetries are not static, following unique trajectories across the lifespan, with distinct changes during development, and a general trend of becoming more asymmetric with increasing age (particularly in later adulthood) across pathways. This study represents the most extensive characterization of white matter asymmetry across the lifespan to date, charting how lateralization patterns emerge, mature, and change throughout life. It provides a foundational resource for understanding the principles of white matter organization from early to late life, its relation to functional specialization and inter‐individual variability, and offers a key reference for interpreting deviations during healthy development and aging as well as those associated with clinical populations. (A) Large‐scale lifespan modeling of white matter asymmetry. Diffusion MRI data from 35,000+ individuals (0‐100 years) across 50 cohorts were used to generate normative lifespan trajectories of white matter asymmetry. Thirty bilateral tracts were segmented, and microstructural (FA, MD, AD, RD) and macrostructural (volume, length) features were extracted. A lateralization index (LI) was computed for each tract‐feature pair and modeled using a centile‐based normative framework (GAMLSS), enabling estimation of age‐specific population distributions. (B) Lateralization differs by tract and structural feature. Asymmetry was widespread but highly specific to tract and feature. Microstructural measures exhibited smaller magnitude asymmetries, whereas macrostructural features showed larger effects and greater inter‐individual variability. Individual tracts frequently demonstrated opposing asymmetry directions across features, underscoring distinct biological contributions of tissue microstructure and pathway geometry. Population‐level patterns ranged from strong, consistent lateralization to substantial heterogeneity within age groups. (C) Asymmetry is dynamic across the lifespan. White matter asymmetry varied continuously across development and aging, with tract‐ and feature‐specific trajectories. Patterns included early establishment, gradual strengthening or attenuation, and occasional direction reversals. Variability was greatest in early life and older adulthood, and many pathways showed increasing asymmetry magnitude with age. These results demonstrate that asymmetry is a dynamic property of white matter organization across the lifespan. graphical