A global multicohort study to map subcortical brain development and cognition in infancy and early childhood

Ann M Alex¹, Fernando Aguate^{1

2}, Kelly Botteron³, Claudia Buss^{4

5

6}, Yap-Seng Chong^{7

8}, Stephen R Dager⁹, Kirsten A Donald^{10

11}, Sonja Entringer^{4

5

6}, Damien A Fair¹², Marielle V Fortier^{8

13}, Nadine Gaab¹⁴, John H Gilmore¹⁵, Jessica B Girault^{15

16}, Alice M Graham¹⁷, Nynke A Groenewold^{10

18

19

20}, Heather Hazlett^{16

17}, Weili Lin²¹, Michael J Meaney⁹, Joseph Piven^{16

17}, Anqi Qiu^{22

23

24

25

26

27}, Jerod M Rasmussen^{5

6}, Annerine Roos^{10

11

28}, Robert T Schultz²⁹, Michael A Skeide³⁰, Dan J Stein^{19

28}, Martin Styner^{16

31}, Paul M Thompson³², Ted K Turesky¹⁴, Pathik D Wadhwa^{5

6

33}, Heather J Zar^{18

20}, Lilla Zöllei³⁴, Gustavo de Los Campos^{1

2

35}, Rebecca C Knickmeyer^{36

37}; ENIGMA ORIGINs group

Affiliations

¹ Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI, USA.
² Departments of Epidemiology & Biostatistics, Michigan State University, East Lansing, MI, USA.
³ Mallinickrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Department of Medical Psychology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁵ Department of Pediatrics, University of California Irvine, Irvine, CA, USA.
⁶ Development, Health and Disease Research Program, University of California Irvine, Irvine, CA, USA.
⁷ Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁸ Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore.
⁹ Department of Radiology, University of Washington Medical Center, Seattle, WA, USA.
¹⁰ Division of Developmental Paediatrics, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa.
¹¹ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹² Masonic Institute for the Developing Brain, University of Minnesota Medical School, Minneapolis, MN, USA.
¹³ Department of Diagnostic & Interventional Imaging, KK Women's and Children's Hospital, Singapore, Singapore.
¹⁴ Harvard Graduate School of Education, Harvard University, Cambridge, MA, USA.
¹⁵ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Carboro, NC, USA.
¹⁷ Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA.
¹⁸ South African Medical Research Council (SA-MRC) Unit on Child & Adolescent Health, University of Cape Town, Cape Town, South Africa.
¹⁹ Department of Psychiatry, University of Cape Town, Cape Town, South Africa.
²⁰ Department of Paediatrics and Child Health, University of Cape Town, Faculty of Health Sciences, Cape Town, South Africa.
²¹ Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²² Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore.
²³ NUS (Suzhou) Research Institute, National University of Singapore, Suzhou, China.
²⁴ The N.1 Institute for Health, National University of Singapore, Singapore, Singapore.
²⁵ Institute of Data Science, National University of Singapore, Singapore, Singapore.
²⁶ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
²⁷ Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, China.
²⁸ SAMRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town, South Africa.
²⁹ Center for Autism Research, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA, USA.
³⁰ Research Group Learning in Early Childhood, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
³¹ Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³² Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of University of Southern California, Marina del Rey, CA, USA.
³³ Departments of Psychiatry and Human Behavior, Obstetrics & Gynecology, Epidemiology, University of California, Irvine, Irvine, CA, USA.
³⁴ A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
³⁵ Department of Statistics & Probability, Michigan State University, East Lansing, MI, USA.
³⁶ Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI, USA. knickmey@msu.edu.
³⁷ Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA. knickmey@msu.edu.

PMID: 37996530
PMCID: PMC10774128
DOI: 10.1038/s41593-023-01501-6

A global multicohort study to map subcortical brain development and cognition in infancy and early childhood

Ann M Alex et al. Nat Neurosci. 2024 Jan.

. 2024 Jan;27(1):176-186.

doi: 10.1038/s41593-023-01501-6. Epub 2023 Nov 23.

Authors

Affiliations

¹ Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI, USA.
² Departments of Epidemiology & Biostatistics, Michigan State University, East Lansing, MI, USA.
³ Mallinickrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Department of Medical Psychology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁵ Department of Pediatrics, University of California Irvine, Irvine, CA, USA.
⁶ Development, Health and Disease Research Program, University of California Irvine, Irvine, CA, USA.
⁷ Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁸ Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore.
⁹ Department of Radiology, University of Washington Medical Center, Seattle, WA, USA.
¹⁰ Division of Developmental Paediatrics, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa.
¹¹ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹² Masonic Institute for the Developing Brain, University of Minnesota Medical School, Minneapolis, MN, USA.
¹³ Department of Diagnostic & Interventional Imaging, KK Women's and Children's Hospital, Singapore, Singapore.
¹⁴ Harvard Graduate School of Education, Harvard University, Cambridge, MA, USA.
¹⁵ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Carboro, NC, USA.
¹⁷ Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA.
¹⁸ South African Medical Research Council (SA-MRC) Unit on Child & Adolescent Health, University of Cape Town, Cape Town, South Africa.
¹⁹ Department of Psychiatry, University of Cape Town, Cape Town, South Africa.
²⁰ Department of Paediatrics and Child Health, University of Cape Town, Faculty of Health Sciences, Cape Town, South Africa.
²¹ Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²² Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore.
²³ NUS (Suzhou) Research Institute, National University of Singapore, Suzhou, China.
²⁴ The N.1 Institute for Health, National University of Singapore, Singapore, Singapore.
²⁵ Institute of Data Science, National University of Singapore, Singapore, Singapore.
²⁶ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
²⁷ Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, China.
²⁸ SAMRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town, South Africa.
²⁹ Center for Autism Research, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA, USA.
³⁰ Research Group Learning in Early Childhood, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
³¹ Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³² Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of University of Southern California, Marina del Rey, CA, USA.
³³ Departments of Psychiatry and Human Behavior, Obstetrics & Gynecology, Epidemiology, University of California, Irvine, Irvine, CA, USA.
³⁴ A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
³⁵ Department of Statistics & Probability, Michigan State University, East Lansing, MI, USA.
³⁶ Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI, USA. knickmey@msu.edu.
³⁷ Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA. knickmey@msu.edu.

PMID: 37996530
PMCID: PMC10774128
DOI: 10.1038/s41593-023-01501-6

Abstract

The human brain grows quickly during infancy and early childhood, but factors influencing brain maturation in this period remain poorly understood. To address this gap, we harmonized data from eight diverse cohorts, creating one of the largest pediatric neuroimaging datasets to date focused on birth to 6 years of age. We mapped the developmental trajectory of intracranial and subcortical volumes in ∼2,000 children and studied how sociodemographic factors and adverse birth outcomes influence brain structure and cognition. The amygdala was the first subcortical volume to mature, whereas the thalamus exhibited protracted development. Males had larger brain volumes than females, and children born preterm or with low birthweight showed catch-up growth with age. Socioeconomic factors exerted region- and time-specific effects. Regarding cognition, males scored lower than females; preterm birth affected all developmental areas tested, and socioeconomic factors affected visual reception and receptive language. Brain-cognition correlations revealed region-specific associations.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Fig. 1. The effect of sex on the developmental trajectory of ICV.**
The lines represent the fitted growth curve for the male and female sex from the nonlinear mixed model regression (number of individuals = 1,835, number of observations = 3,168). Males (blue line) have significantly larger ICV than females (red line) throughout the age range studied (the P values derived from two-sided t-tests are 1.68 × 10^–12 at intercept and 1.88 × 10^–60 at asymptote; the Bonferroni-corrected P value threshold for significance was <0.0001). Circles represent individual data points, and colors represent the cohorts; BCP, Baby Connectome Project; Boston, Boston Children’s Hospital/Harvard Medical School; CAPET, Drakenstein Child Health Study, Cape Town; GUSTO, Growing Up in Singapore Towards Healthy Outcomes, Singapore; IBIS, Infant Brain Imaging Study Network; UCI, University of California, Irvine; UNC, University of North Carolina Early Brain Development Study.

**Fig. 2. Heat map of the correlation between brain volumes and cognitive scores.**
a,b, Correlation assessed between the predicted values for brain volumes and cognitive and motor scores at age 2 using Pearson’s correlations in children born full term (a) and preterm (b). In full-term children, the significant correlations are ICV–gross motor score (P = 0.0000), amygdala–gross motor score (P = 0.001), ICV–fine motor score (P = 0.0002), caudate–visual reception score (P = 0.001) and globus pallidus–visual reception score (P = 0.0005). In preterm children, the significant correlation is hippocampus–visual reception score (P = 0.0007). Brain volume–cognitive score correlations are highlighted in the dashed rectangle. The squares marked with an asterisk (*) represent significant correlations (P < 0.0015, which is the threshold for significance after Bonferroni correction for multiple comparisons). Data were analyzed by two-tailed t-tests; TLM, thalamus; CDT, caudate; PTM, putamen; PLD, globus pallidus; HPS, hippocampus; AGD, amygdala; GM, gross motor score; VR, visual reception score; FM, fine motor score; RL, receptive language score; EL, expressive language score.

**Fig. 3. Causal mediation analyses for children born full term.**
a–d, Causal mediation analysis reveals partial mediation effects of the caudate and globus pallidus on the association between sociodemographic factors (sex, maternal education and family income) and visual reception scores in children born full term. a,b, Mediation by the caudate on the effect of sex (a; P = 0.0052) and low family income (b; P = 0.015) on visual reception scores (N = 760). c,d, Mediation by the globus pallidus on the effect of sex (c; P = 0.0004) and low maternal education (d; P = 0.0012) on visual reception scores (N = 659). Bootstrapping was used to estimate P values; *P < 0.05; ***P < 0.001. No correction for multiple comparisons was performed.

**Fig. 4. Causal mediation analyses for children born preterm.**
a,b, Causal mediation analysis reveals the partial mediation effects of hippocampal volume on the association between sociodemographic factors (sex and maternal education) and visual reception scores in children born preterm. Mediation by the hippocampus on the effect of sex (a; P = 0.01) and low maternal education (b; P = 0.041) on visual reception scores (N = 269). Bootstrapping was used to estimate P values; *P < 0.05; ***P < 0.001. No correction for multiple comparisons was performed.

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A global multicohort study to map subcortical brain development and cognition in infancy and early childhood

Affiliations

A global multicohort study to map subcortical brain development and cognition in infancy and early childhood

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous