Biology subjects

Bethlehem, R. A. I.

Publications and source records attributed to Bethlehem, R. A. I..

At least 37 records · Page 2Linked to original sources

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.

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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.

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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.

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bioRxiv2024

Moving towards precision TMS? Evaluating individual differences and reproducibility of personalized stimulation targets in UK Biobank

ObjectivePersonalized transcranial magnetic stimulation (TMS) targeting, guided by functional connectivity (FC), shows potential in treating depression. The present study aims to map individual FC peak location using UK Biobank, to evaluate individual differences and reproducibility of FC-based targets. MethodsWe analyzed UK Biobank resting-state fMRI (rfMRI) of 35,423 participants, identifying individual FC peak locations on the dorsolateral prefrontal cortex (DLPFC) that functionally connected to the subcallosal cingulate, amygdala, and ventromedial prefrontal cortex, respectively. Euclidean distance between each participants individual peak and group-average peak was calculated. With follow-up rfMRI of 1341 participants, within-subject FC peak location changes were calculated. We also compared common TMS targets and random locations for their median distance to individual peaks in a permutation test. ResultsSeed-based FC analyses revealed large differences in the individual FC peak location on DLPFC: the mean distance from the individual peaks to group-average peak ranged from 14.24 to 29.92mm; 70% to 94% of participants were >10mm away from the group-average peak and potentially located outside of the TMS effective area with common TMS coils. Similar variability was observed in within-subject peak locations across two fMRI assessments. Common TMS targets and the group-average FC peak showed no significant difference in median distances to individual FC peaks when compared to random locations. ConclusionsFC peak location shows wide inter- and intra-individual variability. We emphasize a role for individualized TMS neuronavigation targeting but emphasize the need for more reliable biomarker studies.

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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.

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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.

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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.

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bioRxiv2023

Pervasive inter-individual differences in the sensorimotor-association axis of cortical organization

In humans, many neurobiological features of the cortex--including gene expression patterns, microstructure, and functional connectivity--vary systematically along a sensorimotor-association (S-A) axis of brain organisation. To date, it is still poorly understood whether inter-individual differences in patterns of S-A axis capture these robust spatial relationships across neurobiological properties observed at the group-level. Here, we examine inter-individual differences in structural and functional properties of the S-A axis, namely cortical microstructure, geodesic distances, and the functional gradient, in a sample of young adults from the Human Connectome Project (N = 992, including 328 twins). We quantified heritable variation associated with inter-individual differences in the S-A axis, and assessed whether structural and functional properties that are highly spatially correlated at the group-level also share genetic underpinnings. To consider measurement errors in resting-state functional connectivity data and their impact on properties of the S-A axis, we used a multivariate twin design capable of disentangling individual-level variation in both intra- and inter-individual differences. After accounting for some of the intra-individual variation, we found average heritable individual differences in both the functional gradient (htwin2 = 57%), cortical microstructure (htwin2 = 43%), and geodesic distances (htwin2 = 34%). However, these genetic influences were mostly distinct and deviated from group-level patterns. In particular, we found no significant genetic correlation between the functional gradient and microstructure, while we found both positive and negative genetic associations between the functional gradient and geodesic distances. Our approach highlights the complexity of genetic contributions to brain organisation and may have potential implications for understanding cognitive variability within the S-A axis framework.

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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.

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bioRxiv2023

Diverging asymmetry of intrinsic functional organization in autism

Autism is a neurodevelopmental condition involving atypical sensory-perceptual functions together with language and socio-cognitive deficits. Previous work has reported subtle alterations in the asymmetry of brain structure and reduced laterality of functional activation in individuals with autism relative to non-autistic individuals (NAI). However, whether functional asymmetries show altered intrinsic systematic organization in autism remains unclear. Here, we computed inter- and intra-hemispheric asymmetry of intrinsic functional gradients capturing connectome organization along three axes, stretching between sensory-default, somatomotor-visual, and default-multiple demand networks, to study system-level hemispheric imbalances in autism. We observed decreased leftward functional asymmetry of language network organization in individuals with autism, relative to NAI. Whereas language network asymmetry varied across age groups in NAI, this was not the case in autism, suggesting atypical functional laterality in autism may result from altered developmental trajectories. Finally, we observed that intra-but not inter-hemispheric features were predictive of the severity of autistic traits. In sum, our findings illustrate how regional and patterned functional lateralization is altered in autism at the system level. Such differences may be rooted in altered developmental trajectories of functional organization asymmetry in autism.

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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.

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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.

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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.

neuroscience↗

bioRxiv2022

The genetics of cortical organisation and development: a study of 2,347 neuroimaging phenotypes

Our understanding of the genetic architecture of the human cerebral cortex is limited both in terms of the diversity of brain structural phenotypes and the anatomical granularity of their associations with genetic variants. Here, we conducted genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,843 individuals from the UK Biobank and the ABCD cohorts. These phenotypes include cortical thickness, surface area, grey matter volume, and measures of folding, neurite density, and water diffusion. We identified 4,349 experiment-wide significant loci associated with global and regional phenotypes. Multiple lines of analyses identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with surface area and volume specifically are associated with cephalic disorders. Finally, we identified complex inter-phenotype and inter-regional genetic relationships among the 13 phenotypes which reflect developmental differences among them. These analyses help refine the role of common genetic variants in human cortical development and organisation. One sentence summaryGWAS of 2,347 neuroimaging phenotypes shed light on the global and regional genetic organisation of the cortex, underlying cellular and developmental processes, and links to neurodevelopmental and cephalic disorders.

neuroscience↗

bioRxiv2021

Asymmetry of cortical functional hierarchy in humans and macaques suggests phylogenetic conservation and adaptation

The human cerebral cortex is symmetrically organized along large-scale axes but also presents inter-hemispheric differences in structure and function. The quantified contralateral homologous difference, i.e., asymmetry, is a key feature of the human brain left-right axis supporting functional processes, such as language. Here, we assessed whether the asymmetry of cortical functional organization is heritable and phylogenetically conserved between humans and macaques. Our findings indicate asymmetric organization along an axis describing a hierarchical functional trajectory from perceptual/action to abstract cognition. Whereas language network showed leftward asymmetric organization, frontoparietal network showed rightward asymmetric organization. These asymmetries were heritable and comparable between humans and macaques, suggesting (phylo)genetic conservation. However, both language and frontoparietal networks showed a qualitatively larger asymmetry in humans relative to macaques and variable heritability in humans. This may reflect an evolutionary adaptation allowing for experience-dependent specialization, linked to higher-order cognitive functions uniquely developed in humans.

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bioRxiv2021

Adolescent development of multiscale cortical wiring and functional connectivity in the human connectome

AO_SCPLOWBSTRACTC_SCPLOWAdolescence is a time of profound changes in the physical wiring and function of the brain. Here, we analyzed structural and functional brain network development in an accelerated longitudinal cohort spanning 14-25 years (n = 199). Core to our work was an advanced in vivo model of cortical wiring incorporating MRI features of cortico-cortical proximity, microstructural similarity, and white matter tractography. Longitudinal analyses assessing age-related changes in cortical wiring identified a continued differentiation of multiple cortico-cortical structural networks in youth. Studying resting-state functional MRI measures in the same participants at baseline, we found that regions with more similar structural wiring were more likely to be functionally coupled. Moreover, longitudinal structural wiring changes, particularly between sensory/unimodal and default mode networks, were reflected in tendencies for increased differentiation in brain function. These longitudinal findings provide new insights into adolescent development of human brain structure and function, illustrating how structural wiring interacts with the maturation of macroscale functional hierarchies.

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bioRxiv2021

Brain charts for the human lifespan

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here, we built an interactive resource to benchmark brain morphology, www.brainchart.io, derived from any current or future sample of magnetic resonance imaging (MRI) data. With the goal of basing these reference charts on the largest and most inclusive dataset available, we aggregated 123,984 MRI scans from 101,457 participants aged from 115 days post-conception through 100 postnatal years, across more than 100 primary research studies. Cerebrum tissue volumes and other global or regional MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3; showed high stability of individual centile scores over longitudinal assessments; and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared to non-centiled MRI phenotypes, and provided a standardised measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In sum, brain charts are an essential first step towards robust quantification of individual deviations from normative trajectories in multiple, commonly-used neuroimaging phenotypes. Our collaborative study proves the principle that brain charts are achievable on a global scale over the entire lifespan, and applicable to analysis of diverse developmental and clinical effects on human brain structure. Furthermore, we provide open resources to support future advances towards adoption of brain charts as standards for quantitative benchmarking of typical or atypical brain MRI scans.

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