Brain charts for the human lifespan

Abstract

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 assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. 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 individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Fig. 1. Human brain charts.

a, MRI data were aggregated from over 100 primary studies comprising 123,984 scans that collectively spanned the age range from mid-gestation to 100 postnatal years. Box–violin plots show the age distribution for each study coloured by its relative sample size (log-scaled using the natural logarithm for visualization purposes). b, Non-centiled, ‘raw’ bilateral cerebrum tissue volumes for grey matter, white matter, subcortical grey matter and ventricles are plotted for each cross-sectional control scan as a function of age (log-scaled); points are coloured by sex. c, Normative brain-volume trajectories were estimated using GAMLSS, accounting for site- and study-specific batch effects, and stratified by sex (female, red; male, blue). All four cerebrum tissue volumes demonstrated distinct, non-linear trajectories of their medians (with 2.5% and 97.5% centiles denoted as dotted lines) as a function of age over the lifespan. Demographics for each cross-sectional sample of healthy controls included in the reference dataset for normative GAMLSS modelling of each MRI phenotype are detailed in Supplementary Table 1.2–1.8. d, Trajectories of median between-subject variability and 95% confidence intervals for four cerebrum tissue volumes were estimated by sex-stratified bootstrapping (see Supplementary Information 3 for details). e, Rates of volumetric change across the lifespan for each tissue volume, stratified by sex, were estimated by the first derivatives of the median volumetric trajectories. For solid (parenchymal) tissue volumes, the horizontal line (y = 0) indicates when the volume at which each tissue stops growing and starts shrinking and the solid vertical line indicates the age of maximum growth of each tissue. See Supplementary Table 2.1 for all neurodevelopmental milestones and their confidence intervals. Note that y axes in b–e are scaled in units of 10,000 mm³ (10 ml).

Fig. 2. Extended global and regional cortical morphometric phenotypes.

a, Trajectories for total cerebrum volume (TCV), total surface area and mean cortical thickness. For each global cortical MRI phenotype, the following sex-stratified results are shown as a function of age over the lifespan. From top to bottom: raw, non-centiled data; population trajectories of the median (with 2.5% and 97.5% centiles (dotted lines)); between-subject variance (with 95% confidence intervals); and rate of growth (the first derivatives of the median trajectory and 95% confidence intervals). All trajectories are plotted as a function of log-scaled age (x axis) and y axes are scaled in units of the corresponding MRI metrics (10,000 mm³ for TCV, 10,000 mm² for surface area and mm for cortical thickness). b, Regional variability of cortical volume trajectories for 34 bilateral brain regions, as defined by the Desikan–Killiany parcellation, averaged across sex (see Supplementary Information 7,8 for details). Since models were generated from bilateral averages of each cortical region, the cortical maps are plotted on the left hemisphere purely for visualization purposes. Top, a cortical map of age at peak regional volume (range 2–10 years). Middle, a cortical map of age at peak regional volume relative to age at peak GMV (5.9 years), highlighting regions that peak earlier (blue) or later (red) than GMV. Bottom, illustrative trajectories for the earliest peaking region (superior parietal lobe, blue line) and the latest peaking region (insula, red line), showing the range of regional variability relative to the GMV trajectory (grey line). Regional volume peaks are denoted as dotted vertical lines either side of the global peak, denoted as a dashed vertical line, in the bottom panel. The left y axis on the bottom panel refers to the earliest peak (blue line); the right y axis refers to the latest peak (red line).

Fig. 3. Neurodevelopmental milestones.

Top, a graphical summary of the normative trajectories of the median (50th centile) for each global MRI phenotype, and key developmental milestones, as a function of age (log-scaled). Circles depict the peak rate of growth milestones for each phenotype (defined by the maxima of the first derivatives of the median trajectories (Fig. 1e)). Triangles depict the peak volume of each phenotype (defined by the maxima of the median trajectories); the definition of GMV:WMV differentiation is detailed in Supplementary Information 9.1. Bottom, a graphical summary of additional MRI and non-MRI developmental stages and milestones. From top to bottom: blue shaded boxes denote the age range of incidence for each of the major clinical disorders represented in the MRI dataset; black boxes denote the age at which these conditions are generally diagnosed as derived from literature (Methods); brown lines represent the normative intervals for developmental milestones derived from non-MRI data, based on previous literature and averaged across males and females (Methods); grey bars depict age ranges for existing (World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC)) growth charts of anthropometric and ultrasonographic variables. Across both panels, light grey vertical lines delimit lifespan epochs (labelled above the top panel) previously defined by neurobiological criteria. Tanner refers to the Tanner scale of physical development. AD, Alzheimer’s disease; ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder (including high-risk individuals with confirmed diagnosis at a later age); ANX, anxiety or phobic disorders; BD, bipolar disorder; MDD, major depressive disorder; RMR, resting metabolic rate; SCZ, schizophrenia.

Fig. 4. Case–control differences and heritability of centile scores.

a, Centile score distributions for each diagnostic category of clinical cases relative to the control group median (depicted as a horizontal black line). The median deviation of centile scores in each diagnostic category is overlaid as a lollipop plot (white lines with circles corresponding to the median centile score for each group of cases). Pairwise tests for significance were based on Monte Carlo resampling (10,000 permutations) and P values were adjusted for multiple comparisons using the Benjamini–Hochberg false discovery rate (FDR) correction across all possible case–control differences. Only significant differences from the control group (CN) median (with corrected P < 0.001) are highlighted with an asterisk. For a complete overview of all pairwise comparisons, see Supplementary Information 10, Supplementary Table 3. Groups are ordered by their multivariate distance from the CN group (see c and Supplementary Information 10.3). b, The CMD is a summary metric that quantifies the aggregate atypicality of an individual scan in terms of all global MRI phenotypes. The schematic shows segmentation of four cerebrum tissue volumes, followed by estimation of univariate centile scores, leading to the orthogonal projection of a single participant’s scan (Sub_x) onto the four respective principal components of the CN (coloured axes and arrows). The CMD for Sub_x is then the sum of its distances from the CN group mean on all four dimensions of the multivariate space. c, Probability density plots of CMD across disorders. Vertical black line depicts the median CMD of the control group. Asterisks indicate an FDR-corrected significant difference from the CN group (P < 0.001). d, Heritability of raw volumetric phenotypes and their centile scores across two twin studies (Adolescent Brain Cognitive Development (ABCD) and Human Connectome Project (HCP)); Supplementary Information 19), see Supplementary Information 13 for a full overview of statistics for each individual feature in each dataset. Data are mean ± s.e.m. (although some confidence intervals are too narrow to be seen). MCI, mild cognitive impairment. See Fig. 3 for other diagnostic abbreviations. FDR-corrected significance: *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 5. Schematic overview of brain charts, highlighting methods for out-of-sample centile scoring.

Top, brain phenotypes were measured in a reference dataset of MRI scans. GAMLSS modelling was used to estimate the relationship between (global) MRI phenotypes and age, stratified by sex, and controlling for technical and other sources of variation between scanning sites and primary studies. Bottom, the normative trajectory of the median and confidence interval for each phenotype was plotted as a population reference curve. Out-of-sample data from a new MRI study were aligned to the corresponding epoch of the normative trajectory, using maximum likelihood to estimate the study specific offsets (random effects) for three moments of the underlying statistical distributions: mean ($\mu$), variance ($\sigma$), and skewness (ν) in an age- and sex-specific manner. Centile scores of each phenotype could then be estimated for each scan in the new study, on the same scale as the reference population curve, while accounting for study-specific ‘batch effects’ on technical or other sources of variation (see Supplementary Information 1.8 for details). MLE, maximum likelihood estimation.