Fang-Cheng Yeh

The two cerebral hemispheres specialize while remaining interconnected. Does greater structural asymmetry imply less connectivity, and does connectivity also relate to how asymmetry changes during development? We addressed these questions in three independent cohorts spanning birth to 22 years, measuring asymmetry as the magnitude of the left–right difference in association tract overlap across 74 homotopic cortical region pairs. The regional pattern of asymmetry was similar across cohorts. In all three cohorts, more asymmetric regions had lower connectional density to cortical and non-cortical targets. However, involvement of the corpus callosum, the major pathway connecting the hemispheres, showed no consistent inverse relationship with regional asymmetry across cohorts. Instead, callosal involvement conditioned the relationship between mean regional asymmetry and its age-related change. In the two older cohorts, greater mean asymmetry accompanied more positive age effects among regions with appreciable callosal overlap, whereas this relationship was weak or negative among regions with little callosal overlap (standardized interactions +0.42 and +0.56). The pattern replicated across the two cohorts at matched ages, and longitudinal region-mean estimates in the Adolescent Brain Cognitive Development cohort were similar in direction and magnitude. In the youngest cohort, regions converged toward the mean, narrowing the between-region spread by 12%, with no detected callosal moderation. More asymmetric regions have lower overall connectional density, whereas callosal involvement helps explain how regional asymmetry changes with age. Significance statement: The brain’s hemispheres differ in structure and function while remaining extensively connected. Does connectivity relate to how asymmetric a region is, how its asymmetry develops, or both? We distinguish these questions in three developmental cohorts. More asymmetric regions had lower overall connectional density. In contrast, involvement of the corpus callosum, the major pathway linking the hemispheres, showed no consistent inverse relationship with asymmetry across cohorts. Instead, it distinguished how mean regional asymmetry related to age-related change in the two older cohorts. A static comparison would miss this developmental relationship. These findings provide a framework for studying hemispheric development and investigating whether connectivity–asymmetry relationships are altered in neurodevelopmental conditions.

Translational neuroscience requires consistent anatomical frameworks to compare brain organization across species despite differences in size and specialization. Existing atlases are species-specific, limiting cross-species analyses. Here we developed a hierarchical common atlas delineating homologous cortical and subcortical gray matter regions across mouse, rat, marmoset, rhesus macaque, and human, built upon population-averaged minimal deformation templates and uniform tissue segmentation. We validated the atlas using four independent approaches: cross-atlas Dice similarity against established human parcellations, cross-scale containment against species-specific atlases, cross-species geometric consistency of regional positioning, and comparison of independent mouse and marmoset tracer connectivity. A per-region homology confidence index quantifies the strength of each regional assignment. Cross-species tracer comparison revealed a structured gradient of correspondence, with sensorimotor connections showing strong conservation and association connections showing progressive divergence. This freely available atlas provides a unified coordinate system for comparative neuroscience, enabling quantitative evaluation of where cross-species correspondence holds and where species-specific divergence emerges.

Childhood and adolescence are marked by protracted developmental remodeling of cortico-cortical structural connectivity. However, the spatiotemporal variability of white matter connectivity development across the human connectome and its relevance to cognition and psychopathology remains unclear. Using diffusion MRI data from three independent developmental cohorts spanning youth, we identified a robust divergence in structural connectivity maturation along a predefined sensorimotor-association (S-A) connectional axis during youth ( http://connectcharts.cibr.ac.cn ). This developmental continuum ranged from early childhood increases in sensorimotor-sensorimotor connectivity strength to late adolescent increases in association-association connectivity strength, with the transition occurring around age 15. The S-A connectional axis also captured spatial variations in the associations between structural connectivity and both higher-order cognition and general psychopathology. Moreover, group-level developmental trajectories of structural connectivity differed by cognitive and psychopathological levels, with psychopathological effects predominantly observed in association connections. These findings delineate a spatiotemporal continuum of structural connectivity development during youth, providing a normative reference for quantifying developmental variability in psychiatric disorders.

Structural topology develops non-linearly across the lifespan and is strongly related to cognitive trajectories. We gathered diffusion imaging from datasets with a collective age range of zero to 90 years old ( N = 4,216). We analyzed how 12 graph theory metrics of organization change with age and projected these data into manifold spaces using Uniform Manifold Projection and Approximation. With these manifolds, we identified four major topological turning points across the lifespan – around nine, 32, 66, and 83 years old. These ages defined five major epochs of topological development, each with distinctive age-related changes in topology. These lifespan epochs each have a distinct direction of topological development and specific changes in the organizational properties driving the age-topology relationship. This study underscores the complex, non-linear nature of human development, with unique phases of topological maturation, which can only be illuminated with a multivariate, lifespan, population-level perspective.

Translational neuroscience requires consistent anatomical frameworks to compare brain organization across species despite differences in size and specialization. Existing atlases are species-specific, limiting cross-species analyses. Here we developed a hierarchical common atlas delineating homologous cortical and subcortical gray matter regions across mouse, rat, marmoset, rhesus macaque, and human, built upon population-averaged minimal deformation templates and uniform tissue segmentation. The atlas was validated through cross-atlas Dice similarity against established human parcellations, cross-scale containment against species-specific atlases, cross-species geometric consistency of regional positioning, and comparison of independent mouse and marmoset invasive tracer connectivity, with a per-region homology confidence index quantifying the strength of each regional assignment. Cross-species tracer comparison revealed a structured gradient of correspondence, with sensorimotor connections showing strong conservation and association connections showing progressive divergence. This freely available atlas provides a unified coordinate system for comparative neuroscience, enabling quantitative evaluation of where cross-species correspondence holds and where species-specific divergence emerges.

Human cortical development follows a hierarchical, sensorimotor-to-association sequence. The brain’s capacity to enact this sequence indicates that it relies on unknown mechanisms to regulate regional differences in the timing of cortical maturation. Given evidence from animal systems that thalamic axons mechanistically regulate periods of cortical plasticity, here we evaluate in humans whether the development of structural connections between the thalamus and cortex aligns with cortical maturational heterochronicity. By deriving a new tractography atlas of human thalamic connections and applying it to diffusion data from three youth samples (8–23 years; total n = 2,676), we demonstrate that thalamocortical connectivity matures in a generalizable manner along the cortex’s sensorimotor–association axis. Associative cortical regions with thalamic connections that take the longest to mature exhibit neurochemical, structural and functional signatures of protracted developmental plasticity as well as heightened sensitivity to the socioeconomic environment. This work highlights the role of the thalamus in the expression of hierarchical periods of cortical developmental plasticity and environmental receptivity.

Atlases of the brain are critical resources that make it possible to share data in a common reference frame. Unexpectedly, there is no three-dimensional (3D) stereotaxic atlas of the mouse brain that provides whole brain coverage at macro to single-cell levels. Diffusion tensor images from five perfusion-fixed (in skull) specimens were acquired at 15 micrometers, the highest resolution ever reported. Diffusion tensor imaging yields multiple 3D volumes, each of which highlights unique cytoarchitecture. The averages were mapped into micro–computed tomography of the mouse skull to create external landmarks (bregma and lambda). Light sheet images of the same brains were coregistered, providing cell maps in the same stereotaxic space. The Allen Reference Atlas was registered to the volume to correct the geometric distortion in that atlas and bring it into the stereotaxic space. The resulting multiscalar (13 terabytes) atlas provides a common spatial framework to anneal data across molecular, structural, and functional studies of mice.