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Seidlitz, J.

Publications and source records attributed to Seidlitz, J..

At least 19 recordsLinked to original sources
bioRxiv2026

Charting neuroimaging-based head circumference and cranial shape across development

Quantitative assessment of head growth supports early detection of neurological disease, yet current clinical practice relies on manual measurements that are variable, anatomically limited, and difficult to scale. Here we introduce a fully automated imaging-native framework (CranioTrace) that transforms routine neuroimaging into standardized, population-referenced markers of cranial development. By integrating topology-constrained segmentation, contour regularization, and geometry-based quality control for automated slice selection, CranioTrace robustly extracts head circumference and cranial morphology from heterogeneous MRI and CT data without manual intervention. The framework enabled construction of sex-specific population growth models across pediatric development in a dataset comprising 9,685 scans spanning birth to early adulthood across 25 cohorts. Imaging-derived head circumference shows strong agreement with tape measurements across independent datasets, high reproducibility (intraclass correlation up to 0.99), and consistent performance across modalities. Beyond conventional head circumference, CranioTrace quantifies cranial shape and asymmetry, capturing developmental dynamics that are not accessible through conventional measurements. Population modeling reveals rapid early-life expansion followed by nonlinear deceleration and stable sex differences. Application to neurogenetic cohorts identifies disease-consistent shifts in growth trajectories: head circumference was higher in neurofibromatosis type 1 and 16p11.2 deletion and lower in 22q11.2 deletion and 16p11.2 duplication. By converting clinical imaging archives into scalable cranial phenotypes linked to probabilistic reference models, CranioTrace provides a foundation for imaging-based growth charting, integrated skull-brain phenotyping, and precise assessment of neurodevelopment.

neuroscience↗
bioRxiv2026

Neuroanatomical Subtypes of Callous-Unemotional Traits in a Community Sample of Youth

ImportanceCallous Unemotional (CU) traits are associated with significant clinical and neurophysiological heterogeneity that may affect treatment effectiveness. ObjectiveTo uncover neuroanatomical subtypes of CU traits using weakly-supervised machine learning and assess whether emerging subtypes differ on relevant clinical, temperamental, and environmental constructs. Design, Setting, and ParticipantsImaging data was from the longitudinal Adolescent, Brain, Cognitive Development (ABCD) Study. Participants were 9-10 years old at baseline (M=9.925, 69.9% male) and included 222 children with CU traits and 234 typically developing controls matched on age, sex and income. Main Outcomes and MeasuresThe weakly-supervised heterogeneity through discriminative analysis (HYDRA) model was trained on grey matter (GM) volumes from 84 regions of interest (ROIs) and tested for reproducibility using cross-validation and permutation testing. Derived subtypes were compared cross-sectionally and prospectively on relevant clinical, temperamental, and environmental measures and subsequent GM volume at 2-year follow up. ResultsHYDRA revealed an optimal 2-subtype solution within children with CU traits. Subtypes showed comparable levels of aggression that were significantly higher than typically developing controls. At the same time, subtype 1 had larger GM volume, fewer internalizing symptoms, and less adversity exposure, while subtype 2 was characterized by smaller GM volume, more internalizing symptoms, and more adversity exposure. Conclusions and RelevanceThis study provides evidence of neuroanatomically distinct subtypes of CU traits characterized by different clinical and etiological profiles, with implications for diagnosis and treatment.

neuroscience↗
bioRxiv2026

Brain charts for neuroanatomical sex differences across the human lifespan

Population-level sex differences in human neuroanatomy have been highly debated, with prior literature limited by narrow age windows and assumptions about regions scaling with total brain size. Building on recent work charting brain structures across the lifespan, we use magnetic resonance imaging data from over 100,000 individuals (51.7% F) to model normative reference trajectories of 241 structural features capturing age-varying sex effects. Results show replicable age-varying sex differences in nearly all features, and sexs effects survive nonlinear correction for total brain size, with sex biases tending to increase across the lifespan. Notably, models are sensitive to atypicalities in six neuropsychiatric disorders. This work establishes and quantifies population-level sex biases in the largest-to-date study of sex differences in the human brain.

neuroscience↗
bioRxiv2026

Functional connectome harmonics capture early brain organization and maturity in neonates

The functional organization of the human brain is established early, yet the ontogeny of its large-scale functional gradients remains unclear. Using resting-state fMRI data from 714 neonates in the Developing Human Connectome Project, we mapped neonatal brain gradients via functional connectome harmonics (FCH). We identified adult-like sensory-to-multimodal and cognitive gradient patterns present at birth. Applying three FCH-derived metrics--entropy, power, and energy--we found that power and energy were higher in term-born compared to preterm neonates, while entropy was elevated in preterms. These metrics predicted up to ~30% of postmenstrual age, indicating their biological relevance. Our findings reveal that the neonatal brain possesses a robust gradient architecture underpinning early functional organization, offering novel biomarkers for assessing brain maturity and the impact of prematurity on neurodevelopment.

neuroscience↗
bioRxiv2026

Functional connectome harmonics and dynamic connectivity maps of the preadolescent brain

The maturation of large-scale functional brain networks during preadolescence underpins critical cognitive and behavioral development. However, the spatial and temporal organization of these networks in this age group remains incompletely characterized. Here we applied Functional Connectome Harmonics (FCH) and Leading Eigenvector Dynamics Analysis (LEiDA) to resting-state fMRI data from over 11,000 children aged 9-10 years in the ABCD Study. FCH revealed hierarchical spatial gradients spanning cortical and subcortical regions, while LEiDA identified recurrent dynamic brain states aligned with canonical intrinsic connectivity networks. Linking these spatial and temporal components, we established a low-dimensional harmonic scaffold constraining brain dynamics during this developmental window. These findings provide a large-scale spatiotemporal reference framework of preadolescent functional brain organization, offering a foundation for characterizing neurodevelopmental benchmarks and early neural markers relevant to adolescent mental health.

neuroscience↗
bioRxiv2026

Multi-modal and multi-region distance model for neuroimaging: Application to ABCD study

Large-scale neuroimaging studies often collect multiple modalities, such as task and resting-state functional MRI, diffusion MRI, and structural MRI. Joint inference across these modalities uses shared variation to improve statistical efficiency, increase replicability, and provide a more integrated view of brain-phenotype associations. In practice, however, such analyses are limited because complex cross-modality covariance cannot be flexibly modeled, which makes the resulting joint effects difficult to interpret. A recent distance-based ANOVA extension allows multimodal analysis and increases power for detecting group differences, but it cannot easily distinguish location from scale effects in distance space, offers only an omnibus pseudo-F test without interpretable parameters, and requires computationally intensive permutation inference. We propose a novel semiparametric, U-statistics-based Generalized Estimating Equation (UGEE) framework that unifies univariate and multivariate distance models. By regressing pairwise dissimilarities on covariates, this method yields interpretable regression coefficients that disentangle location and scale effects and quantify inter-modality differences, while flexibly accounting for correlations among modality distances. The estimator is based on efficient influence functions, ensuring asymptotic efficiency, robustness to misspecification, and computational scalability for large-scale data analysis. We evaluate the proposed method through extensive simulations and analyses of the Adolescent Brain Cognitive Development dataset. Results show that UGEE accurately estimates modality, group, and interaction effects and achieves a 100-fold speed-up compared with permutation-based approaches. This framework provides a general and computationally efficient tool for semiparametric inference on multimodal data, particularly suited for large neuroimaging applications.

neuroscience↗
bioRxiv2025

Conditional-longitudinal brain growth charts detect MRI changes with birth weight and psychopathology

ImportanceBrain maturation varies between individuals, particularly during dynamic developmental periods like adolescence. Directly assessing differences in longitudinal trajectories can reveal deviations from normative patterns. ObjectiveWe present novel conditional-longitudinal normative models that characterize variability in brain maturation. We utilize these models to examine whether differences in longitudinal trajectories are associated with birth weight (BW), gestational age (GA), and longitudinal psychopathology derived from behavioral assessments. DesignCross-sectional and conditional-longitudinal normative models were developed for brain volumes derived from the first two neuroimaging timepoints from the Adolescent Brain Cognitive Development (ABCD) Study. Conditional-longitudinal models index an individuals expected brain volume at follow-up conditioned on their baseline measurement. Models were fit with split-half cross-validation on demographically matched samples. SettingThe ABCD Study is a multi-site, population-based study ParticipantsParticipants were excluded based on imaging quality flags and missing data, leaving 10,830 at baseline and 7,262 at follow-up. ExposuresBW and GA were derived from parent-report questionnaires. General psychopathology scores were calculated using a bifactor model. Main Outcomes and MeasuresWe calculated cross-sectional and conditional-longitudinal centiles, respectively quantifying individual deviations in size and change between timepoints. Sensitivity analyses included covariates for parental income and education as well as current weight and height. ResultsThe sample was 10,830 at baseline (48.2% F,age 9-10y) and 7,262 at follow-up (46.6% F,age 11-13y). Conditional-longitudinal centiles were sensitive to individual differences in brain change between timepoints. Lower BW was associated with lower conditional-longitudinal centiles, suggesting larger decreases in brain volumes over time (27 regions pfdr<0.05, {beta}max=0.08). Lower conditional-longitudinal centiles were associated with greater increases in psychopathology scores, suggesting with increased psychopathology brain volumes show greater decrease (37 regions pfdr<0.05, {beta}max=0.06). Notably, changes in psychopathology were not related to brain size at either timepoint, indexed by cross-sectional centiles. Conclusions and RelevanceModels that capture individual-level deviations from expected growth trajectories, rather than static positions on a growth curve, are particularly informative for assessing developmental change. Novel conditional-longitudinal models address this gap in lifespan brain imaging. Using this framework, we demonstrate robust associations between individual trajectory deviations, perinatal adversity, and longitudinally assessed mental health symptoms. Condition-longitudinal models hold promise for applications across psychiatric neuroscience, from development to aging. Key Points QuestionHow do differences in brain maturation trajectories, quantified by novel conditional-longitudinal models, relate to perinatal factors and mental health in adolescence? FindingsIn this longitudinal analysis of neuroimaging data from the Adolescent Brain Cognitive Development (ABCD) Study, conditional-longitudinal normative models revealed that trajectories of brain maturation in adolescence are associated with birth weight, and with longitudinal changes in mental health. MeaningConditional longitudinal models detect inter-individual variability in brain maturation, which is related to both perinatal factors and concurrent changes in psychopathology.

neuroscience↗
bioRxiv2025

Improved Estimation of Correlation Accuracy for Machine Learning Brain-Phenotype Associations

Machine learning is used in neuroscience to examine brain-phenotype associations and facilitate individual prediction from high-dimensional brain imaging. For continuous phenotypes, Pearsons correlation between the observed and predicted phenotype is used to quantify model accuracy in testing data. However, recent research suggests millions of samples may be needed to reliably estimate the maximum achievable predictive accuracy (MAPA). We formally define the MAPA and show that Pearsons estimator is biased for this quantity and its confidence intervals fail to capture the target. We develop a semiparametric (double machine learning) one-step estimator that more accurately estimates the MAPA and yields valid confidence intervals across flexible machine learning settings. Analyzing data from the Reproducible Brain Charts dataset, we show that this estimator has smaller bias when estimating brain-phenotype associations of neuroimaging data with age and psychopathology phenotypes. We show that MAPA for psychopathology factor scores using machine learning models built on structural and functional imaging measures is not better than using demographic and nuisance covariates alone.

neuroscience↗
bioRxiv2025

Calibration of MRI-based reference intervals to new samples

Reference intervals, defined as intervals containing a new observation with a specified probability relative to reference data, would be clinically useful in assessing brain magnetic resonance imaging (MRI). Brain charts, which are estimates of MRI phenotypes across covariates such as age and sex, can be used to construct reference intervals. However, the reference data used to fit intervals often differs from a new sample in terms of study design, MRI acquisition, and image preprocessing. Application of MRI reference intervals to new samples remains a challenging problem. Here, we propose a new method called Reference interval calibration via conFormal prediction (ReForm) that adjusts reference intervals for a new sample. Our method builds on recent work in conformal prediction, which yields intervals with guaranteed coverage for new observations. Through resampling experiments in Lifespan Brain Chart Consortium cortical thickness data, we compare ReFormed reference intervals to refitting intervals, statistical harmonization methods, and model-based adjustment of intervals. Notably for patient privacy concerns, ReForm does not require sharing of reference data. Yet, our empirical results demonstrate that ReForm controls FPR similarly or better than alternative methods which require sharing reference data. Finally, we provide recommendations for practical applications of ReForm and an R package (https://github.com/andy1764/ReForm) for calibrating reference intervals using ReForm.

neuroscience↗
bioRxiv2025

skiftiTools: An R package for reading, writing, analysing, and visualising, tract-based spatial statistics (TBSS) derived diffusion MR images

skiftiTools processes three- and four-dimensional neuroimaging data, facilitating advanced statistical modelling with voxelwise data in any software of choice. Tract-Based Spatial Statistics (TBSS) is a conventionally used tool to make statistical calculations in voxel space for brain imaging data. While pre-existing software packages provide support for general linear model based statistics, there is a clear need for more sophisticated modeling. skiftiTools writes subject-per-volume NIfTI files as tab-separated value ASCII files, which are easily readable by most commonly used statistical tools such as R language (RStudio), SPSS, SAS, and GraphPad Prism. This facilitates a wide range of voxel-level statistical analyses from TBSS data, including estimation of standardised effect sizes, clustering, dimensionality reduction, non-linear and machine learning predictive modelling, which we showcase in this article using FinnBrain and developing Human Connectome Project diffusion MRI data. After statistical processing, the resulting ASCII data can then be read again for visualization. The package supports NIfTI image format, tab-separated ASCII format, and its own stand-alone format for efficient disk usage. It is open source (https://github.com/haanme/skiftiTools), built on R-language and has easy installation from Rs CRAN package repository. In addition, we provide basic functions available in Docker containers for further platform independence. HighlightsO_LIThe skiftiTools R package is an open-source, user-friendly interface for analysing voxelwise diffusion tensor imaging (DTI) data following tract-based spatial statistics (TBSS) processing C_LIO_LIIt supports reading, writing, visualization, mathematical operations, and data manipulation and thus allows comprehensive conventional and advanced statistics, including machine learning C_LIO_LIskiftiTools bridges a critical gap between statistical tools in R and voxelwise neuroimaging data - including comparable means to perform multiple comparison corrections and much needed possibility to use non-linear statistics C_LI

neuroscience↗
bioRxiv2025

ComBat-Predict enhances generalizability of neuroimaging models to new sites

Neuroimaging is vital in quantifying brain atrophy due to typical aging and due to neurodegenerative diseases. To collect large samples necessary to model lifespan brain development, research consortiums aggregate images acquired across multiple study sites. Previous studies have demonstrated that this multi-site study design can lead to site-related bias, necessitating harmonization of these "site effects". However, current methodologies are unable to generalize to new sites outside the original harmonized sample, limiting translation to new sites or clinical practice. Here, we propose a method called ComBat-Predict (CB-Predict) building upon the ComBat method for site effect adjustment, which extends to data from a new site with smaller sample sizes and unknown site effects. In data from the Alzheimers Disease Neuroimaging Initiative (ADNI), our proposed method mitigates bias and yields high accuracy in predicting cortical thickness measures when generalizing the model to new data. Furthermore, we demonstrate that our proposed harmonization method can reduce site-related variance in centile scores estimated using data from the Lifespan Brain Chart Consortium (LBCC). Altogether, our results demonstrate that CB-Predict effectively harmonizes new sites and thereby enables effective translation of neuroimaging models to additional samples.

neuroscience↗
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↗
bioRxiv2025

Comparing Brain-Behavior Relationships Across Dimensional, Tail-Sampled, and Propensity-Matched Models

Large population cohorts are needed to perform brain-wide association studies (BWAS), with evidence that sampling from the tails of a distribution increases effect sizes and improves reproducibility. However, studies rarely compare how variability in sample sociodemographic characteristics relates to imaging or behavioral phenotypes within BWAS. To address this gap, we derived estimates for brain-behavior associations using multivariate regression models, comparing effect sizes for dimensional, tail-sampled, and propensity matched groups. Data were obtained from the Adolescent Brain Cognitive Development (ABCD) Study(R). The independent variables were brain structural imaging phenotypes, with a range of biological and psychological outcomes as dependent variables. We found expected increases in the magnitude of effect sizes moving from full-sample dimensional models to tail-sampled group-based models. However, findings for the propensity-matched group models suggested a non-uniform impact on BWAS (i.e., both increased and decreased effect sizes). Results suggest that sampling from the tails of the distribution of measures of brain structure generally increases effect sizes across biological, clinical, and cognitive outcomes.

neuroscience↗
bioRxiv2025

Semiparametric Confidence Sets for Arbitrary Effect Sizes in Longitudinal Neuroimaging

The majority of neuroimaging inference focuses on hypothesis testing rather than effect estimation. With concerns about replicability, there is growing interest in reporting standardized effect sizes from neuroimaging group-level analyses. Confidence sets are a recently developed approach to perform inference for effect sizes in neuroimaging but are restricted to univariate effect sizes and cross-sectional data. Thus, existing methods exclude increasingly common multigroup or nonlinear longitudinal associations of biological brain measurements with inter- and intra-individual variations in diagnosis, development, or symptoms. We broadly generalize the confidence set approach by developing a method for arbitrary effect sizes in longitudinal studies. Our method involves robust estimation of the effect size image and spatial and temporal covariance function based on generalized estimating equations. We obtain more efficient effect size estimates by concurrently estimating the exchangeable working covariance and using a nonparametric bootstrap to determine the joint distribution of effect size across voxels used to construct confidence sets. These confidence sets identify regions of the image where the lower or upper simultaneous confidence interval is above or below a given threshold with high probability. We evaluate the coverage and simultaneous confidence interval width of the proposed procedures using realistic simulations and perform longitudinal analyses of aging and diagnostic differences of cortical thickness in Alzheimers disease and diagnostic differences of resting-state hippocampal activity in psychosis. This comprehensive approach along with the visualization functions integrated into the pbj R package offers a robust tool for analyzing repeated neuroimaging measurements.

neuroscience↗
bioRxiv2025

BabyPy: a brain-age model for infancy, childhood and adolescence

Withdrawal StatementThe authors have withdrawn this manuscript because during the peer-review process, they realised that their interpretation of the brain-age model presented in this paper was not fully accurate. While the analyses, statistics, and results remain valid, their interpretation of the internal test set performance metrics was inaccurate due to the non-linear shape of the distribution. In other words, although the overall R{superscript 2} is correctly reported as 0.80, this value does not capture the variability of the metrics across different age bins. For this reason, the authors are withdrawing the preprint. Therefore, the authors do not wish this work to be cited as reference for the project. The authors aim to re-run the analysis to provide a more robust version of the model and a new DOI will be linked on this page once the revised work is available. If you have any questions, please contact the corresponding author.

neuroscience↗
bioRxiv2024

dGAMLSS: An exact, distributed algorithm to fit Generalized Additive Models for Location, Scale, and Shape for privacy-preserving population reference charts

There is growing interest in estimating population reference ranges across age and sex to better identify atypical clinically-relevant measurements throughout the lifespan. For this task, the World Health Organization recommends using Generalized Additive Models for Location, Scale, and Shape (GAMLSS) which can model non-linear growth trajectories under complex distributions that address the heterogeneity in human populations. Fitting GAMLSS models requires large, generalizable sample sizes, especially for accurate estimation of extreme quantiles, but obtaining such multi-site data can be challenging due to privacy concerns and practical considerations. In settings where patient data cannot be shared, privacy-preserving distributed algorithms for federated learning can be used, but no such algorithm exists for GAMLSS. We propose distributed GAMLSS (dGAMLSS), a distributed algorithm which can fit GAMLSS models across multiple sites without sharing patient-level data. We demonstrate the effectiveness of dGAMLSS in constructing population reference charts across clinical, genomics, and neuroimaging settings.

bioinformatics↗
bioRxiv2024

The genetic architecture of cortical similarity networks

The genetic architecture of human brain networks is central to understanding the organization and evolution of the cortex, the causal relationships between brain structure and function, and the pathogenesis of heritable neuropsychiatric disorders. However, the current understanding of the genetics of brain networks remains fragmented. Here, we investigated common genetic effects on Morphometric INverse Divergence (MIND), a biologically-validated, heritable, and multimodal MRI metric of inter-areal similarity and connectivity. Using a discovery dataset (N>30,000 adults), we estimated subject-specific MIND networks from the multivariate distributions of four MRI features at each of 23 cortical areas and performed genome-wide association studies (GWAS) at each of the 276 inter-areal edges. These edge-level genetic effects were highly replicated by parallel GWAS of an independent validation dataset (N>18,000 adults). We found that strong genetic correlations between multiple edges were largely reducible to two gradients of genetically-determined cortical similarity, each of which was aligned with geodesic distance from one of the two phylogenetically primitive areas (paleocortex and archicortex) predicted by the dual origin theory of cortical evolution. Genetic MIND gradients were more heritable than comparable gradients derived from GWAS of functional MRI connectivity networks; and the paleocortical trend was genetically correlated with, and causally predictive of, functional connectivity. Finally, we identified multiple global and local genetic correlations between both MIND gradients and nine clinical diagnoses or biomedical traits, indicating that the normative genetic architecture of human brain networks is pleiotropically associated with inherited risk of neuropsychiatric disorders and systemic metabolic and immune traits. These results provide fresh insight into the dual origins of the human cortex and their implications for brain function and health.

neuroscience↗