Biology subjects

Wagstyl, K.

Publications and source records attributed to Wagstyl, K..

At least 19 recordsLinked to original sources

bioRxiv2026

AI segmentation requires accounting for brain size to maintain performance on developmental MRI cohorts

The human brain undergoes rapid developmental changes through early life, underpinning the emergence of function but also marking a period of vulnerability to a range of neurodevelopmental disorders. With dynamic changes to brain size, morphology, and imaging contrast, consistent and accurate computational neuroanatomy remains a challenge. Deep learning tools for segmentation, like SynthSeg, offer robustness to heterogeneously acquired MRI contrast but remain unproven in early development. Here, we aggregated a large cohort (26k) of MRI scans spanning infant to adult development, and evaluated SynthSeg performance. Automated quality control scores, visual inspection, and spatial overlap with expert-segmented MRI scans revealed poor quality output segmentations during development. In the infant period only 36% of scans (1094/3069) passed automated QC. Rescaling infant scans to adult brain sizes significantly improved spatial overlap, and cropping scans to match adult fields of view retrieved automated quality control. Evaluation of the SynthSeg rescale + crop pipeline demonstrated visible and quantitative improvements in segmentation throughout infancy and childhood. There were marked increases in successful segmentations in infant scans, with 91% of scans now passing QC (2803/3069). These findings facilitate computational analysis of typical and disrupted neurodevelopment and should be considered when training the next generation of computational tools.

neuroscience↗

bioRxiv2026

Intracortical vessel density mapping at mesoscale reveals regionally specific angioarchitecture in the human brain

The metabolic demands of the human brain are met by a complex vascular architecture, yet our characterization of this network remains incomplete. While we have mapped the macroscopic vessels on the brains surface and the microscopic capillaries within small tissue samples, the mesoscopic scale consisting of the penetrating vessels that plunge through cortex remains an anatomical terra incognita. Mapping the interface between the macroscopic and microscopic scales is essential to understanding the critical vascular supply that sustains brain health. Here, we leveraged the BigBrain dataset and developed custom detection and tracing algorithms to reveal a whole-cortex record of the mesoscopic vascular network. We find that vascular density is not uniform across the cortex, but is a heterogeneous landscape that shows clear relationships to traditional areal boundaries. Our results constitute a reference for human mesoscopic angioarchitecture and demonstrates the power of repurposing high-resolution histological at-lases. Ultimately, this work lays the groundwork for validating recently developed in vivo MRI techniques for imaging the human cerebrovascular system at mesoscale.

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bioRxiv2025

Fractionation of sex differences in human cortical anatomy

Humans show reproducible sex differences in regional cortical volume (CV), but it remains unclear how these arise from underlying sex-biases in the two biologically dissociable determinants of CV: surface area (SA) and cortical thickness (CT). Moreover, limited access to experimental methods in humans has hindered direct studies of the causal drivers of regional sex differences in the human cortex, although rodent models have argued for both chromosomal and gonadal contributions to sex-biased mammalian cortical development. Here, we first use structural neuroimaging data in two independent human cohorts (combined N=1,754; 967 females) to quantify and spatially resolve the differential contributions of SA and CT to observed sex differences in CV. These dissociable facets of sex-biased cortical organization are highly reproducible and align with distinct functional networks and histo-molecular signatures. We then leverage complementary neuroimaging data in clinical case-control cohorts (combined N=313) featuring variations in X and Y chromosome dosage (sex chromosome aneuploidies) and testicular hormone production (isolated GnRH deficiency) to establish that regions of sex-biased CV, SA and CT in humans are enriched for congruent anatomical effects of X-chromosome dosage (e.g., primary sensory and insular cortices) and gonadal hormones (e.g. dorsomedial frontal and temporo-parietal-occipital regions). Taken together, these findings substantially advance both the breadth and granularity of our understanding regarding sex-biased cortical organization in humans - disambiguating sex effects on regional CV, SA and CT and nominating their potential genetic and endocrine causes.

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bioRxiv2025

Charting structural brain asymmetry across the human lifespan

Lateralization is a fundamental principle of structural brain organization. In vivo imaging of brain asymmetry is essential for deciphering lateralized brain functions and their disruption in neurodevelopmental and neurodegenerative disorders. Here, we present a normative framework for benchmarking brain asymmetry across the lifespan, developed from an aggregated sample of 128 primary neuroimaging studies, including 177,701 scans from 138,231 individuals, jointly spanning the age range from 20 post menstrual weeks to 102 years. This resource includes comprehensive, hemisphere-specific brain growth charts for multiple neuroimaging phenotypes: regional cortical grey matter volume, thickness, surface area, and subcortical volumes. Our findings reveal distinct spatial patterns of asymmetry, with early leftward asymmetry observed in association cortices and late rightward asymmetry in sensory regions. These trajectories support theories of the neuroplasticity of asymmetry and the role of both genetic and environmental factors in shaping brain lateralization. Additionally, we provide tools to generate asymmetry centile scores, which allow the quantification of individual deviations from typical asymmetry throughout the lifespan and can be applied to unseen data or clinical populations. We demonstrate the utility of these models by highlighting group-level differences in asymmetry in autism spectrum disorder, schizophrenia, and Alzheimers disease, and exploring genetic correlations with hemispheric specialization. To facilitate further research, we have made this normative framework freely available as an interactive open-access resource (upon publication), offering an essential tool to advance both basic and clinical neuroscience.

neuroscience↗

bioRxiv2023

A bipolar taxonomy of adult human brain sulcal morphology related to timing of fetalsulcation and trans-sulcal gene expression gradients

We developed a computational pipeline (now provided as a resource) for measuring morphological similarity between cortical surface sulci to construct a sulcal phenotype network (SPN) from each magnetic resonance imaging (MRI) scan in an adult cohort (N=34,725; 45-82 years). Networks estimated from pairwise similarities of 40 sulci on 5 morphological metrics comprised two clusters of sulci, represented also by the bipolar distribution of sulci on a linear-to-complex dimension. Linear sulci were more heritable and typically located in unimodal cortex; complex sulci were less heritable and typically located in heteromodal cortex. Aligning these results with an independent fetal brain MRI cohort (N=228; 21-36 gestational weeks), we found that linear sulci formed earlier, and the earliest and latest-forming sulci had the least between-adult variation. Using high-resolution maps of cortical gene expression, we found that linear sulcation is mechanistically underpinned by trans-sulcal gene expression gradients enriched for developmental processes.

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bioRxiv2023

The spatial arrangement of laminar thickness profiles in the human cortex scaffolds processing hierarchy

The human neocortex consists of tangentially organized layers with unique cytoarchitectural properties. These layers show spatial variations in thickness and cytoarchitecture across the neocortex, which is thought to support brain function through enabling targeted corticocortical connections. Here, leveraging maps of the six cortical layers in 3D human brain histology, we aimed to quantitatively characterize the systematic covariation of laminar structure in the cortex and its functional consequences. After correcting for the effect of cortical curvature, we identified a spatial pattern of changes in laminar thickness covariance from lateral frontal to posterior occipital regions, which differentiated the dominance of infra- versus supragranular layer thickness. Corresponding to the laminar regularities of cortical connections along cortical hierarchy, the infragranular-dominant pattern of laminar thickness was associated with higher hierarchical positions of regions, mapped based on resting-state effective connectivity in humans and tract-tracing of structural connections in macaques. Moreover, we show that regions with comparable laminar thickness patterns correspond to inter-regional structural covariance, maturational coupling, and transcriptomic patterning, indicating developmental relevance. In sum, here we characterize the association between organization of laminar thickness and processing hierarchy, anchored in ontogeny. As such, we illustrate how laminar organization may provide a foundational principle ultimately supporting human cognitive functioning.

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bioRxiv2022

3D reconstruction of ultra-high resolution neurotransmitter receptor atlases in human and non-human primate brains

Quantitative maps of neurotransmitter receptor densities are important tools for characterising the molecular organisation of the brain and key for understanding normal and pathologic brain function and behaviour. We describe a novel method for reconstructing 3-dimensional cortical maps for data sets consisting of multiple different types of 2-dimensional post-mortem histological sections, including autoradiographs acquired with different ligands, cell body and myelin stained sections, and which can be applied to data originating from different species. The accuracy of the reconstruction was quantified by calculating the Dice score between the reconstructed volumes versus their reference anatomic volume. The average Dice score was 0.91. We were therefore able to create atlases with multiple accurately reconstructed receptor maps for human and macaque brains as a proof-of-principle. Future application of our pipeline will allow for the creation of the first ever set of ultra-high resolution 3D atlases composed of 20 different maps of neurotransmitter binding sites in 3 complete human brains and in 4 hemispheres of 3 different macaque brains.

neuroscience↗

bioRxiv2022

The molecular genetic landscape of human brain size variation

Human brain size increases dynamically through early development, peaks in adolescence, and varies up to two-fold among adults. Although previous studies have elucidated changes in brain size across evolution, development, traits, and diseases, the molecular underpinnings of interindividual variation in brain size remain unknown. Here, we leverage postmortem brain RNA sequencing and estimates of brain weight (BW) in 2,531 individuals across three independent datasets, to identify 928 genes that show genome-wide significant associations with either higher or lower BW (BW+, BW-, respectively). These BW gene sets showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto developmental, functional and cellular axes of brain organization. Expression differences among evolutionarily conserved BW genes were predictive of interspecies differences in brain size, and functional annotation of BW genes revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses of in vivo neuroimaging phenotypes confirmed that the genetic regulation of BW-transcripts influences cortical surface area and volume, as well as behavioral traits related to brain function and disease. Cumulatively, our study represents a major step towards the goal of delineating the causal mechanisms of human brain size variation in health and disease.

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bioRxiv2022

Three transcriptional axes underpin anatomy, development, and disorders of the human cortex

Human brain organisation involves the coordinated expression of thousands of genes. For example, the first principal component (C1) of cortical transcription identifies a hierarchy from sensorimotor to association regions. Here, optimised processing of the Allen Human Brain Atlas revealed two new components of cortical gene expression architecture, C2 and C3, which are distinctively enriched for neuronal, metabolic and immune processes, specific cell-types and cytoarchitecture, and genetic variants associated with intelligence. Using additional datasets (PsychENCODE, Allen Cell Atlas, and BrainSpan), we found that C1-C3 represent generalisable transcriptional programmes that are coordinated within cells, and differentially phased during foetal and postnatal development. Autism spectrum disorder and schizophrenia were specifically associated with C1/C2 and C3, respectively, across neuroimaging, differential expression, and genome-wide association studies. Evidence converged especially in support of C3 as a normative transcriptional programme for adolescent brain development, which can lead to atypical supra-granular cortical connectivity in people at high genetic risk for schizophrenia.

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bioRxiv2022

Conserved whole-brain spatiomolecular gradients shape adult brain functional organization

Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, how these gradients relate to adult brain function, and whether they are maintained in the adult brain, remains unknown. Here we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately predicts the location of unseen brain tissue samples, ii) delineates known functional territories, and iii) explains the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical functional hierarchies differentiating primary sensory cortex from association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two non-human primate datasets, and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well known morphogens (e.g., PAX6 and SIX3), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.

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bioRxiv2022

Transcriptional Cartography Integrates Multiscale Biology of the Human Cortex

The cerebral cortex underlies many of our unique strengths and vulnerabilities - but efforts to understand human cortical organization are challenged by reliance on incompatible measurement methods at different spatial scales. Macroscale features such as cortical folding and functional activation are accessed through spatially dense neuroimaging maps, whereas microscale cellular and molecular features are typically measured with sparse postmortem sampling. Here, we integrate these distinct windows on brain organization by building upon existing postmortem data to impute, validate and analyze a library of spatially dense neuroimaging-like maps of human cortical gene expression. These maps allow spatially unbiased discovery of cortical zones with extreme transcriptional profiles or unusually rapid transcriptional change which index distinct microstructure and predict neuroimaging measures of cortical folding and functional activation. Modules of spatially coexpressed genes define a family of canonical expression maps that integrate diverse spatial scales and temporal epochs of human brain organization - ranging from protein-protein interactions to large-scale systems for cognitive processing. These module maps also parse neuropsychiatric risk genes into subsets which tag distinct cyto-laminar features and differentially predict the location of altered cortical anatomy and gene expression in patients. Taken together, the methods, resources and findings described here advance our understanding of human cortical organization and offer flexible bridges to connect scientific fields operating at different spatial scales of human brain research.

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bioRxiv2021

Mesoscopic Quantification of Cortical Architecture in the Living Human Brain

AO_SCPLOWBSTRACTC_SCPLOWMesoscopic (0.1-0.5 mm) interrogation of the living human brain is critical for advancing neuroscience and bridging the resolution gap with animal models. Despite the variety of MRI contrasts measured in recent years at the mesoscopic scale, in vivo quantitative imaging of T2* has not been performed. Here we provide a dataset containing empirical T2* measurements acquired at 0.35 x 0.35 x 0.35 mm3 voxel resolution using 7 Tesla MRI. To demonstrate unique features and high quality of this dataset, we generate flat map visualizations that reveal fine-scale cortical substructures such as layers and vessels, and we report quantitative depth-dependent T2* (as well as R2*) values in primary visual cortex and auditory cortex that are highly consistent across subjects. This dataset is freely available at https://doi.org/10.17605/OSF.IO/N5BJ7, and may prove useful for anatomical investigations of the human brain, as well as for improving our understanding of the basis of the T2* -weighted (f)MRI signal.

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bioRxiv2021

BigBrainWarp: Toolbox for integration of BigBrain 3D histology with mutlimodal neuroimaging

AO_SCPLOWBSTRACTC_SCPLOWNeuroimaging stands to benefit from emerging ultrahigh-resolution histological atlases of the human brain; the first of which is "BigBrain". Ongoing research aims to characterise regional differentiation of cytoarchitecture with BigBrain and to optimise registration of BigBrain with standard neuroimaging templates. Together, this work paves the way for multi-scale investigations of brain organisation. However, working with BigBrain can present new challenges for neuroimagers, including dealing with cellular resolution neuroanatomy and complex transformation procedures. To simplify workflows and support adoption of best practices, we developed BigBrainWarp, a toolbox for integration of BigBrain with multimodal neuroimaging. The primary BigBrainWarp function wraps multiple state-of-the-art deformation matrices into one line of code, allowing users to easily map data between BigBrain and standard MRI spaces. Additionally, the toolbox contains ready-to-use cytoarchitectural features to improve accessibility of histological information. The present article discusses recent contributions to BigBrain-MRI integration and demonstrates the utility of BigBrainWarp for further investigations.

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bioRxiv2020

The natural axis of transmitter receptor distribution in the human cerebral cortex

Transmitter receptors constitute a key component of the molecular machinery for inter-cellular communication in the brain. Recent efforts have mapped the density of diverse transmitter receptors across the human cerebral cortex with an unprecedented level of detail. Here, we distil these observations into key organizational principles. We demonstrate that receptor densities form a natural axis in the human cerebral cortex, reflecting decreases in differentiation at the level of laminar organization, and a sensory-to-association axis at the functional level. Along this natural axis, key organizational principles are discerned: progressive molecular diversity (increase of the diversity of receptor density), excitation/inhibition (increase of the ratio of excitatory-to-inhibitory receptor density) and mirrored, orderly changes of the density of ionotropic and metabotropic receptors. The uncovered natural axis formed by the distribution of receptors aligns with the axis that is formed by other dimensions of cortical organization, such as the myelo- and cytoarchitectonic levels. Therefore, the uncovered natural axis constitutes a unifying organizational feature linking multiple dimensions of the cerebral cortex, thus bringing order to the heterogeneity of cortical organization.

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bioRxiv2020

CIVET-Macaque: an automated pipeline for MRI-based cortical surface generation and cortical thickness in macaques

The MNI CIVET pipeline for automated extraction of cortical surfaces and evaluation of cortical thickness from in-vivo human MRI has been extended for processing macaque brains. Processing is performed based on the NIMH Macaque Template (NMT), as the reference template, with the anatomical parcellation of the surface following the D99 and CHARM atlases. The modifications needed to adapt CIVET to the macaque brain are detailed. Results have been obtained using CIVET-macaque to process the anatomical scans of the 31 macaques used to generate the NMT and another 95 macaques from the PRIME-DE initiative. It is anticipated that the open usage of CIVET-macaque will promote collaborative efforts in data collection and processing, sharing, and automated analyses from which the non-human primate brain imaging field will advance.

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bioRxiv2020

LAYNII: A software suite for layer-fMRI

High-resolution fMRI in the sub-millimeter regime allows researchers to resolve brain activity across cortical layers and columns non-invasively. While these high-resolution data make it possible to address novel questions of directional information flow within and across brain circuits, the corresponding data analyses are challenged by MRI artifacts, including image blurring, image distortions, low SNR, and restricted coverage. These challenges often result in insufficient spatial accuracy of conventional analysis pipelines. Here we introduce a new software suite that is specifically designed for layer-specific functional MRI: LayNii. This toolbox is a collection of command-line executable programs written in C/C++ and is distributed open-source and as pre-compiled binaries for Linux, Windows, and macOS. LayNii is designed for layer-fMRI data that suffer from SNR and coverage constraints and thus cannot be straightforwardly analyzed in alternative software packages. Some of the most popular programs of LayNii contain layerification and columnarization in the native voxel space of functional data as well as many other layer-fMRI specific analysis tasks: layer-specific smoothing, model-based vein mitigation of GE-BOLD data, quality assessment of artifact dominated sub-millimeter fMRI, as well as analyses of VASO data. HighlightsO_LIA new software toolbox is introduced for layer-specific functional MRI: LayNii. C_LIO_LILayNii is a suite of command-line executable C++ programs for Linux, Windows, and macOS. C_LIO_LILayNii is designed for layer-fMRI data that suffer from SNR and coverage constraints. C_LIO_LILayNii performs layerification in the native voxel space of functional data. C_LIO_LILayNii performs layer-smoothing, GE-BOLD deveining, QA, and VASO analysis. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/148080v3_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@e12e9org.highwire.dtl.DTLVardef@1fbb564org.highwire.dtl.DTLVardef@41da13org.highwire.dtl.DTLVardef@1545106_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

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bioRxiv2020

Relating quantitative 7T MRI across cortical depths to cytoarchitectonics, gene expression and connectomics: a framework for tracking neurodegenerative disease

Cortical layer-specific ultra-high field MRI has the potential to provide anatomically precise biomarkers and mechanistic insights into neurodegenerative disease. Here we compare cortical layer-specificity for a 7T multi-parametric mapping (MPM) 500m whole brain acquisition to the von Economo and Big Brain post-mortem histology atlases. We also investigate the relationship between 7T MPMs, layer-specific gene expression and Huntingtons disease related genes, using the Allen Human Brain atlas. Finally we link MPM cortical depth measures with white matter connections using high-fidelity diffusion tractography from a 300mT/m Connectom MRI system. We show that R2* across cortical depths is highly correlated with layer-specific cell number, cell staining intensity and gene expression. Furthermore white matter connections were highly correlated with grey matter R1 and R2* across cortical depths. These findings demonstrate the potential of combining 7T MPMs, gene expression and white matter connections to provide an anatomically precise framework for tracking neurodegenerative disease.

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bioRxiv2019

Estimates of cortical column orientation improveMEG source inversion

Determining the anatomical source of brain activity non-invasively measured from EEG or MEG sensors is challenging. In order to simplify the source localization problem, many techniques introduce the assumption that current sources lie on the cortical surface. Another common assumption is that this current flow is orthogonal to the cortical surface, thereby approximating the orientation of cortical columns. However, it is not clear which cortical surface to use to define the current source locations, and normal vectors computed from a single cortical surface may not be the best approximation to the orientation of cortical columns. We compared three different surface location priors and five different approaches for estimating dipole vector orientation, both in simulations and visual and motor evoked MEG responses. We show that models with source locations on the white matter surface and using methods based on establishing correspondences between white matter and pial cortical surfaces dramatically outperform models with source locations on the pial or combined pial/white surfaces and which use methods based on the geometry of a single cortical surface in fitting evoked visual and motor responses. These methods can be easily implemented and adopted in most M/EEG analysis pipelines, with the potential to significantly improve source localization of evoked responses.

neuroscience↗