Biology subjects

Dorfschmidt, L.

Publications and source records attributed to Dorfschmidt, L..

14 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

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

Associations between the environment, brain, mental health, and cognition across adolescence

Adolescence is a critical period for the development of the brain, cognition, and mental health, which are shaped by a wide range of environmental factors. In the present study, we analysed the Adolescent Brain and Cognitive Development (ABCD) dataset to examine how a range of proximal (e.g., socioeconomic status, familial circumstances) and distal (e.g., neighbourhood conditions, access to healthcare and education) environmental factors are associated with changes in centile-based measures of brain structure, and whether these brain differences subsequently mediate variations in cognition and mental health. We analysed these associations both at baseline (N = 6,911; 3,605 M, 3,606 F; mean age = 9.93) and longitudinally across three timepoints (N = 1,628; 879 M, 749 F; ages 8-15). At baseline, a more advantaged proximal and distal environment was associated with larger volumes across the whole brain relative to age- and sex-matched peers, which, in turn, mediated better mental health outcomes and cognitive performance. In the longitudinal analysis, the childhood environment predicted changes in brain structure across adolescence, and these structural changes predicted changes in mental health and cognition. The childhood environment also predicted cognitive but not mental health changes across adolescence, suggesting that these associations may already be established early in adolescence. These findings provide insight into how environmental and neural factors shape adolescent mental health and cognition, with potential implications for early intervention strategies aimed at promoting positive developmental outcomes.

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

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

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↗

bioRxiv2024

Development and early life stress sensitivity of the rat cortical microstructural similarity network

Understanding how early life experiences shape brain network development is a key challenge in the neuroscience of mental health disorders. To address this, we used magnetic resonance imaging (MRI) similarity network analysis to study the effects of stress in the rat, an important animal model in neuropsychiatry. We measured magnetization transfer ratio (MTR) at each of 53 distinct cortical areas and estimated a cortical similarity network for each individual scan, in two independent experimental datasets. We first characterized normative network development in rats scanned repeatedly between postnatal days 20 (weanling) and 290 (mid-adulthood) (N=47), and then contrasted these findings with a cohort exposed to early life stress in the form of repeated maternal separation (RMS, N=40). The normative rat cortical similarity network exhibited biologically meaningful organization, aligning with prior cytoarchitectonic and tract-tracing data, and displayed complex topological features, including rich club organization. During postnatal and adolescent development, brain regions became more similar, including an early phase of fronto-hippocampal convergence. Early increases in inter-areal similarity were reversed in a later phase of fronto-hippocampal divergence in mid-adulthood. RMS exposure altered inter-areal similarity, especially between frontal and parahippocampal regions, that were also most active developmentally and in aging. Our results reveal how normative cortical network changes in the developing brain are influenced by early life stress. These findings suggest a new translational framework for elucidating how environmental risk factors lead to atypical development of cortical networks.

neuroscience↗

bioRxiv2024

Heterogeneous, temporally consistent, and plastic brain development after preterm birth

The current view of neurodevelopment after preterm birth presents a strong paradox: diverse neurocognitive outcomes suggest heterogeneous neurodevelopment, yet numerous brain imaging studies focusing on average dysmaturation imply largely uniform aberrations across individuals1. Here we show both, spatially heterogeneous individual brain abnormality patterns (IBAPs) but with consistent underlying biological mechanisms of injury and plasticity. Using cross-sectional structural magnetic resonance imaging data from preterm neonates and longitudinal data from preterm children and adults in a normative reference framework2, we demonstrate that brain development after preterm birth is highly heterogeneous in both severity and patterns of deviations. Individual brain abnormalities were also consistent for their extent and location along the life course, associated with glial cell underpinnings, and plastic for influences of the early social environment. Thus, IBAPs of preterm birth are spatially heterogenous, temporally consistent for extent, spatial location, and cellular underpinnings, and plastic for social-environmental impacts. Our findings extend conventional views of preterm neurodevelopment, revealing a nuanced landscape of individual variation, with consistent commonalities between subjects. This integrated perspective of preterm neurodevelopment implies more targeted theranostic intervention strategies, specifically integrating brain charts2 and imaging at birth, as well as social interventions during early development3.

neuroscience↗

bioRxiv2024

ComBatLS: A location- and scale-preserving method for multi-site image harmonization

Recent work has leveraged massive datasets and advanced harmonization methods to construct normative models of neuroanatomical features and benchmark individuals morphology. However, current harmonization tools do not preserve the effects of biological covariates including sex and age on features variances; this failure may induce error in normative scores, particularly when such factors are distributed unequally across sites. Here, we introduce a new extension of the popular ComBat harmonization method, ComBatLS, that preserves biological variance in features locations and scales. We use UK Biobank data to show that ComBatLS robustly replicates individuals normative scores better than other ComBat methods when subjects are assigned to sex-imbalanced synthetic "sites". Additionally, we demonstrate that ComBatLS significantly reduces sex biases in normative scores compared to traditional methods. Finally, we show that ComBatLS successfully harmonizes consortium data collected across over 50 studies. R implementation of ComBatLS is available at https://github.com/andy1764/ComBatFamily.

neuroscience↗

bioRxiv2024

Sex Differences in Human Brain Structure at Birth

Sex differences in human brain anatomy have been well-documented; however, their underlying causes remain controversial. Neonatal research offers a pivotal opportunity to address this long-standing debate. Given that postnatal environmental influences (e.g., gender socialisation) are minimal at birth, any sex differences observed at this stage can be more readily attributed to prenatal influences. Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed higher total cortical gray matter volumes, whilst males showed higher total white matter volumes. After controlling for total brain volume in regional comparisons, females had increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and left caudate nucleus. Males had increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. While postnatal experiences likely amplify sex differences in the brain, our findings demonstrate that several global and regional on-average sex differences are already present at birth.

neuroscience↗

bioRxiv2024

Microstructural asymmetry in the human cortex

While macroscale brain asymmetry and its relevance for human cognitive function have been consistently shown, the underlying neurobiological signatures remain an open question. Here, we probe layer-specific microstructural asymmetry of the human cortex using intensity profiles from post-mortem cytoarchitecture. An anterior-posterior cortical pattern of left-right asymmetry was found, varying across cortical layers. A similar anterior-posterior pattern was observed using in vivo microstructural imaging, with in vivo asymmetry showing the strongest similarity with layer III. Microstructural asymmetry varied as a function of age and sex and was found to be heritable. Moreover, asymmetry in microstructure corresponded to asymmetry of intrinsic function, in particular in sensory areas. Last, probing the behavioral relevance, we found differential association of language and markers of mental health with asymmetry, illustrating a functional divergence between inferior-superior and anterior-posterior microstructural axes anchored in microstructural development. Our study highlights the layer-based patterning of microstructural asymmetry of the human cortex and its functional relevance.

neuroscience↗

bioRxiv2023

Human adolescent brain network development is different for paralimbic versus neocortical systems

Adolescent development of human brain structural and functional networks is increasingly recognised as fundamental to emergence of typical and atypical adult cognitive and emotional processes. We analysed multimodal magnetic resonance imaging (MRI) data collected from N [~] 300 healthy adolescents (51%; female; 14-26 years) each scanned repeatedly in an accelerated longitudinal design, to provide an analyzable dataset of 469 structural scans and 448 functional MRI scans. We estimated the morphometric similarity between each possible pair of 358 cortical areas on a feature vector comprising six macro- and micro-structural MRI metrics, resulting in a morphometric similarity network (MSN) for each scan. Over the course of adolescence, we found that morphometric similarity increased in paralimbic cortical areas, e.g., insula and cingulate cortex, but generally decreased in neocortical areas; and these results were replicated in an independent developmental MRI cohort (N [~] 304). Increasing hubness of paralimbic nodes in MSNs was associated with increased strength of coupling between their morphometric similarity and functional connectivity. Decreasing hubness of neocortical nodes in MSNs was associated with reduced strength of structure-function coupling and increasingly diverse functional connections in the corresponding fMRI networks. Neocortical areas became more structurally differentiated and more functionally integrative in a metabolically expensive process linked to cortical thinning and myelination; whereas paralimbic areas specialised for affective and interoceptive functions became less differentiated, as hypothetically predicted by a developmental transition from peri-allocortical to pro-isocortical organization of cortex. Cytoarchitectonically distinct zones of human cortex undergo distinct neurodevelopmental programmes during typical adolescence.

neuroscience↗

bioRxiv2020

Sexually dimorphic development of depression-related brain networks during healthy human adolescence

We hypothesized that there are sexual differences in human brain network development underlying the female > male divergence in adolescent depression. We tested for sex differences in parameters of brain network development (accelerated longitudinal fMRI, N=298 healthy adolescents, each scanned 1 to 3 times). Sexually divergent development of functional connectivity was located in default mode network (DMN), limbic cortex, and subcortical nuclei. Females had a more "disruptive" pattern of development, where weak functional connectivity at age 14 became stronger during adolescence. This fMRI-derived map of divergent adolescent development was co-located with (i) a map of functional dysconnectivity associated with adult major depressive disorder (MDD); and (ii) an adult brain gene expression pattern enriched for genes on the X chromosome, neurodevelopmental genes, and risk genes for MDD. Sexual divergence in disruptive development of DMN, limbic and subcortical functional networks is potentially relevant to the increased risk of depression in adolescent females.

neuroscience↗