Biology subjects

Seidlitz, J.

Publications and source records attributed to Seidlitz, J..

At least 37 records · Page 2Linked to original sources

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

A protective role for the cerebellum in cognitive aging

BackgroundBrain reserve -- the brains resilience to age-related change or damage -- provides protection against cognitive decline. The cerebellum is relatively unstudied as a contributor to brain reserve. This study investigates cerebellar brain reserve in the largest cohort to date. MethodsWe used data from the Human Connectome Project (n=708, 36-100yrs), UK Biobank (n=45,013, 44-81yrs), and ADNI (n=1,423, 56-95yrs). ADNI participants were cognitively normal or had a diagnosis of mild cognitive impairment or Alzheimers disease (AD) dementia. We examined associations between cerebellar tissue volume, age, Montreal Cognitive Assessment (MoCA) scores, global PET amyloid burden, and APOE genotype. FindingsHCP-Aging data revealed heterogenous aging-associated changes in cerebellar volume, with the greatest effects in posterior hemispheric regions (crus I) (Bonferroni-corrected, p<0{middle dot}05). MoCA scores were associated with higher tissue density in the cerebellum (p<0{middle dot}0001) to the same extent as neocortex, and MoCA scores coupled most strongly with posterior cerebellar cortex. Strikingly, greater volume in MoCA visuospatial-related cerebellar cortex protected against aging-related cognitive decline (p=0{middle dot}0001). We replicated tissue aging results in the UK Biobank with the greatest aging-related effects in posterior cerebellum (p<0{middle dot}0001), and an association of greater cerebellar volumes with less cognitive decline (Trails Making-B: p<0{middle dot}00001; Digit Symbol Substitution: p=0{middle dot}034). AD patients with low amyloid-beta burden (A{beta}-) exhibited the strongest cerebellar association with MoCA (volume x group, A{beta}- AD: p=0{middle dot}0001). In A{beta}- individuals, APOE {varepsilon}4/{varepsilon}4 carriers showed the greatest effect with MoCA (volume x APOE, {varepsilon}4/{varepsilon}4: p=0{middle dot}017). InterpretationOur large-scale study demonstrates a potentially strong role for the cerebellum in mitigating cognitive decline. The persistence of this protection in APOE {varepsilon}4/{varepsilon}4 carriers reshapes our understanding of reserve and AD risk. Our findings open the cerebellum as a novel target for future clinical research on brain reserve in aging populations. FundingNational Science Foundation, National Academies of Sciences, Engineering and Medicine, National Institutes of Health. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and GoogleScholar between August 12, 2023, and September 25, 2024 for articles irrespective of language or date of publication, relating to measures of cortical and cerebellar aging. Search terms included "cerebellum", "cognitive aging", "cerebellar reserve", "Alzheimers disease", "covariance", "retrogenesis", and "connectivity". Prior research demonstrated that the cerebellum may play a role in cognitive function. Studies have shown that cerebellar development is spatially heterogenous, with posterior regions undergoing the most protracted change in structure and function. Brain reserve has been predominantly studied in the neocortex, with some studies suggesting the cerebellum may contribute to cognitive changes in diseases like Alzheimers disease (AD) dementia. Cerebellar volume differences between young and older adults have been noted, as well as between healthy adults and neurodegenerative conditions like Parkinsons disease. However, the cerebellums contribution to cognitive reserve, particularly in healthy aging and individuals with a clinical diagnosis of mild cognitive impairment or AD dementia, had not been explored especially in large population-based datasets. Added value of this studyTo our knowledge, this study is the largest to date looking into how cerebellar structures contribute to cognitive outcomes in both healthy older adults, and those with mild cognitive impairment or AD dementia. We leverage three large neuroimaging datasets -- HCP-Aging, UK Biobank, and ADNI -- and demonstrate that cerebellar aging is spatially heterogeneous, with posterior regions showing the greatest age-related decline. We further establish a significant link between larger cerebellar volumes and better cognitive outcomes, suggesting that the cerebellum plays a role in cognitive resilience. Additionally, we identify how cerebellar structures predict cognitive performance and interact with amyloid-beta brain pathology and APOE genotype, particularly in those with low amyloid brain burden and those at greatest risk of AD such as in homozygous APOE e4 allele carriers. Implications of all the available evidenceThe aging of the global population raises the challenge of maintaining cognitive health in older age. Our research focuses on the cerebellum as a novel mediator of preserved cognitive function in old age and clinical dementia. Our findings have profound implications, given that individuals with robust cerebellar structures may be missed during cognitive and clinical screenings. Greater cerebellum volume seems to be most advantageous in those at higher risk for Alzheimers disease based on APOE4 status and those who have yet to accumulate substantial amyloid-beta brain pathology. Our study underscores the importance of the cerebellum as a novel brain reserve mechanism in aging populations.

neuroscience↗

bioRxiv2024

Reproducible Sex Differences in Personalized Functional Network Topography in Youth

BackgroundA key step towards understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organization at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organization of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex. AimsWe aimed to evaluate the impact of sex on the spatial organization of person-specific functional brain networks. MethodWe leveraged person-specific atlases of functional brain networks defined using non-negative matrix factorization in a sample of n = 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalized additive models to uncover associations between sex and the spatial layout ("topography") of personalized functional networks (PFNs). Next, we trained support vector machines to classify participants sex from multivariate patterns of PFN topography. Finally, we leveraged transcriptomic data from the Allen Human Brain Atlas to evaluate spatial correlations between sex differences in PFN topography and gene expression. ResultsSex differences in PFN topography were greatest in association networks including the fronto-parietal, ventral attention, and default mode networks. Machine learning models trained on participants PFNs were able to classify participant sex with high accuracy. Brain regions with the greatest sex differences in PFN topography were enriched in expression of X-linked genes as well as genes expressed in astrocytes and excitatory neurons. ConclusionsSex differences in PFN topography are robust, replicate across large-scale samples of youth, and are associated with expression patterns of X-linked genes. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence.

neuroscience↗

bioRxiv2024

Brain Charts for the Rhesus Macaque Lifespan

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

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

A sensorimotor-association axis of thalamocortical connection development

Human cortical development follows a sensorimotor-to-association sequence during childhood and adolescence1-6. The brains capacity to enact this sequence over decades indicates that it relies on intrinsic mechanisms to regulate inter-regional differences in the timing of cortical maturation, yet regulators of human developmental chronology are not well understood. Given evidence from animal models that thalamic axons modulate windows of cortical plasticity7-12, here we evaluate the overarching hypothesis that structural connections between the thalamus and cortex help to coordinate cortical maturational heterochronicity during youth. We first introduce, cortically annotate, and anatomically validate a new atlas of human thalamocortical connections using diffusion tractography. By applying this atlas to three independent youth datasets (ages 8-23 years; total N = 2,676), we reproducibly demonstrate that thalamocortical connections develop along a maturational gradient that aligns with the cortexs sensorimotor-association axis. Associative cortical regions with thalamic connections that take longest to mature exhibit protracted expression of neurochemical, structural, and functional markers indicative of higher circuit plasticity as well as heightened environmental sensitivity. This work highlights a central role for the thalamus in the orchestration of hierarchically organized and environmentally sensitive windows of cortical developmental malleability.

neuroscience↗

bioRxiv2024

Molecular signatures of cortical expansion in the human fetal brain

The third trimester of human gestation is characterised by rapid increases in brain volume and cortical surface area. A growing catalogue of cells in the prenatal brain has revealed remarkable molecular diversity across cortical areas.1,2 Despite this, little is known about how this translates into the patterns of differential cortical expansion observed in humans during the latter stages of gestation. Here we present a new resource, Brain, to facilitate knowledge translation between molecular and anatomical descriptions of the prenatal developing brain. Built using generative artificial intelligence, Brain is a three-dimensional cellular-resolution digital atlas combining publicly-available serial sections of the postmortem human brain at 21 weeks gestation3 with bulk tissue microarray data, sampled across 29 cortical regions and 5 transient tissue zones.4 Using Brain, we evaluate the molecular signatures of preferentially-expanded cortical regions during human gestation, quantified in utero using magnetic resonance imaging (MRI). We find that differences in the rates of expansion across cortical areas during gestation respect anatomical and evolutionary boundaries between cortical types5 and are founded upon extended periods of upper-layer cortical neuron migration that continue beyond mid-gestation. We identify a set of genes that are upregulated from mid-gestation and highly expressed in rapidly expanding neocortex, which are implicated in genetic disorders with cognitive sequelae. Our findings demonstrate a spatial coupling between areal differences in the timing of neurogenesis and rates of expansion across the neocortical sheet during the prenatal epoch. The Brain atlas is available from: https://garedaba.github.io/micro-brain/ and provides a new tool to comprehensively map early brain development across domains, model systems and resolution scales.

neuroscience↗

bioRxiv2023

Structural covariation between cerebellum and cerebral cortex is atypically modulated by thalamus in autism spectrum disorder

Despite its strong interconnectivity with the cerebral cortex, the influence of the human cerebellum on neocortical structure and its role in the development of neuropsychiatric disorders is unclear. Because cerebellar damage in early postnatal life creates a high risk for autism spectrum disorder (ASD), we investigated inter-relationships in cerebello-cerebral morphology. Leveraging a large structural brain MRI dataset in neurotypical children (n=375) and those diagnosed with ASD (n=373), we examined whether volumetric variation in cerebellar structure across individuals was correlated with neocortical variation during development, modeling the thalamus as a moderating coupling factor. We found negative covariation between cerebellar cortical regions and thalamic/sensorimotor neocortical regions, and positive covariation between thalamic and sensorimotor neocortical regions. This pattern aligned with the major disynaptic path of cerebellar inhibition to thalamocortical excitation. Examining the dependence of this structural covariation on ASD diagnosis, we found that neurotypical and ASD children displayed inverted hemispheric biases. In ASD, the thalamus moderated structural associations between the left cerebellum and right sensorimotor cortex. For neurotypical children, right cerebellum and left sensorimotor cortex were coupled. Notably, structural coupling between cerebellum, thalamus, and neocortex was strongest in younger childhood and waned by early adolescence, a time during which behavioral differences were smallest between typically developing and autistic children. In addition to the sensorimotor cortex, cerebellar dentate nuclei in ASD displayed greater coupling to broad neocortical regions, and these nuclei related to cognitive function differently such that greater dentate nuclear volume was associated with greater behavioral impairment in ASD but not in controls. Graph analyses demonstrated that the cerebello-thalamocortical network was more densely and less prolifically interconnected in ASD than in typical development. Taken as a whole, our study reveals a developmental interplay between the cerebellum, thalamus, and neocortex which differs in ASD from neurotypical children. This pattern is consistent with a model of ASD in which early developmental influences of cerebellar output on brain maturation are specifically moderated by cerebello-thalamocortical pathways.

neuroscience↗

bioRxiv2023

The overlapping genetic architecture of psychiatric disorders and cortical brain structure

Both psychiatric vulnerability and cortical structure are shaped by the cumulative effect of common genetic variants across the genome. However, the shared genetic underpinnings between psychiatric disorders and brain structural phenotypes, such as thickness and surface area of the cerebral cortex, remains elusive. In this study, we employed pleiotropy-informed conjunctional false discovery rate analysis to investigate shared loci across genome-wide association scans of regional cortical thickness, surface area, and seven psychiatric disorders in approximately 700,000 individuals of European ancestry. Aggregating regional measures, we identified 50 genetic loci shared between psychiatric disorders and surface area, as well as 26 genetic loci shared with cortical thickness. Risk alleles exhibited bidirectional effects on both cortical thickness and surface area, such that some risk alleles for each disorder increased regional brain size while other risk alleles decreased regional brain size. Due to bidirectional effects, in many cases we observed extensive pleiotropy between an imaging phenotype and a psychiatric disorder even in the absence of a significant genetic correlation between them. The impact of genetic risk for psychiatric disorders on regional brain structure did exhibit a consistent pattern across highly comorbid psychiatric disorders, with 80% of the genetic loci shared across multiple disorders displaying consistent directions of effect. Cortical patterning of genetic overlap revealed a hierarchical genetic architecture, with the association cortex and sensorimotor cortex representing two extremes of shared genetic influence on psychiatric disorders and brain structural variation. Integrating multi-scale functional annotations and transcriptomic profiles, we observed that shared genetic loci were enriched in active genomic regions, converged on neurobiological and metabolic pathways, and showed differential expression in postmortem brain tissue from individuals with psychiatric disorders. Cumulatively, these findings provide a significant advance in our understanding of the overlapping polygenic architecture between psychopathology and cortical brain structure.

genetics↗

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↗

bioRxiv2023

A Molecular Basis of Human Brain Connectivity

Neuroimaging is commonly used to infer human brain connectivity, but those measurements are far-removed from the molecular underpinnings at synapses. To uncover the molecular basis of human brain connectivity, we analyzed a unique cohort of 98 individuals who provided neuroimaging and genetic data contemporaneous with dendritic spine morphometric, proteomic, and gene expression data from the superior frontal and inferior temporal gyri. Through cellular contextualization of the molecular data with dendritic spine morphology, we identified hundreds of proteins related to synapses, energy metabolism, and RNA processing that explain between-individual differences in functional connectivity and structural covariation. By integrating data at the genetic, molecular, subcellular, and tissue levels, we bridged the divergent fields of molecular biology and neuroimaging to identify a molecular basis of brain connectivity. One-Sentence SummaryDendritic spine morphometry and synaptic proteins unite the divergent fields of molecular biology and neuroimaging.

neuroscience↗

bioRxiv2023

Study design features that improve effect sizes in cross-sectional and longitudinal brain-wide association studies

Brain-wide association studies (BWAS) are a fundamental tool in discovering brain-behavior associations. Several recent studies showed that thousands of study participants are required for good replicability of BWAS because the standardized effect sizes (ESs) are much smaller than the reported standardized ESs in smaller studies. Here, we perform analyses and meta-analyses of a robust effect size index using 63 longitudinal and cross-sectional magnetic resonance imaging studies from the Lifespan Brain Chart Consortium (77,695 total scans) to demonstrate that optimizing study design is critical for increasing standardized ESs and replicability in BWAS. A meta-analysis of brain volume associations with age indicates that BWAS with larger variability in covariate have larger reported standardized ES. In addition, the longitudinal studies we examined reported systematically larger standardized ES than cross-sectional studies. Analyzing age effects on global and regional brain measures from the United Kingdom Biobank and the Alzheimers Disease Neuroimaging Initiative, we show that modifying longitudinal study design through sampling schemes improves the standardized ESs and replicability. Sampling schemes that improve standardized ESs and replicability include increasing between-subject age variability in the sample and adding a single additional longitudinal measurement per subject. To ensure that our results are generalizable, we further evaluate these longitudinal sampling schemes on cognitive, psychopathology, and demographic associations with structural and functional brain outcome measures in the Adolescent Brain and Cognitive Development dataset. We demonstrate that commonly used longitudinal models can, counterintuitively, reduce standardized ESs and replicability. The benefit of conducting longitudinal studies depends on the strengths of the between-versus within-subject associations of the brain and non-brain measures. Explicitly modeling between-versus within-subject effects avoids averaging the effects and allows optimizing the standardized ESs for each separately. Together, these results provide guidance for study designs that improve the replicability of BWAS.

neuroscience↗

bioRxiv2023

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites1. Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus, provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage2. Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and -ketoglutarate-KG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo. Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

neuroscience↗

bioRxiv2022

Two differentiated brain systems micro-structurally associated with obesity

The relationship between obesity and brain structure is incompletely understood. Using diffusion-weighted MRI from [~]30,000 UK Biobank participants we test the hypothesis that obesity (waist-to-hip ratio, WHR) is associated with regional differences in two micro-structural MRI metrics: isotropic volume fraction (ISOVF), an index of free water, and intra-cellular volume fraction (ICVF), an index of neurite density. We observed significant associations with obesity in two coupled but distinct brain systems: a prefrontal-temporal-striatal system associated with ISOVF and a medial temporal-occipital-striatal system associated with ICVF. The ISOVF[~]WHR system colocated with expression of genes enriched for innate immune functions, decreased glial density, and high mu opioid (MOR) and other neurotransmitter receptor density. Conversely, the ICVF[~]WHR system co-located with expression of genes enriched for G-protein coupled receptors and decreased density of MOR and other receptors. To test whether these distinct brain phenotypes might differ in terms of their underlying shared genetics or relationship to maps of the inflammatory marker C-reactive Protein (CRP), we estimated the genetic correlations between WHR and ISOVF (rg = 0.026, P = 0.36) and ICVF (rg = 0.112, P < 9 x 10-4) as well as comparing correlations between WHR maps and equivalent CRP maps for ISOVF and ICVF (p<0.05). These correlational results are consistent with a two-way mechanistic model whereby genetically determined differences in neurite density in the medial temporal system may contribute to obesity, whereas water content in the prefrontal system could reflect a consequence of obesity mediated by innate immune system activation.

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.

neuroscience↗

bioRxiv2022

MIND Networks: Robust Estimation of Structural Similarity from Brain MRI

Structural similarity networks are a central focus of magnetic resonance imaging (MRI) research into human brain connectomes in health and disease. We present Morphometric INverse Divergence (MIND), a robust method to estimate within-subject structural similarity between cortical areas based on the Kullback-Leibler divergence between the multivariate distributions of their structural features. Compared to the prior approach of morphometric similarity networks (MSNs) on N>10,000 data from the ABCD cohort, MIND networks were more consistent with known cortical symmetry, cytoarchitecture, and (in N=19 macaques) gold-standard tract-tracing connectivity, and were more invariant to cortical parcellation. Importantly, MIND networks were remarkably coupled with cortical gene co-expression, providing fresh evidence for the unified architecture of brain structure and transcription. Using kinship (N=1282) and genetic data (N=4085), we characterized the heritability of MIND phenotypes, identifying stronger genetic influence on the relationship between structurally divergent regions compared to structurally similar regions. Overall, MIND presents a biologically-validated lens for analyzing the structural organization of the cortex using readily-available MRI measurements.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗