New digital atlas reveals detailed stages of human fetal brain maturation

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In a recently published study, Dr the natureResearchers have created a comprehensive digital atlas of fetal brain maturation from a large cohort, detailing structural growth and folding from early pregnancy to two years after birth and presenting a benchmark for normal brain development.

Study: Normal spatiotemporal fetal brain maturation with satisfactory development at 2 years. Image Credit: - Yuri A/Shutterstock.comStudy: Normal spatiotemporal fetal brain maturation with satisfactory development at 2 years. Image Credit: – Yuri A/


Human fetal brain development, mapping its structural organization to function, has been explored primarily using postmortem data. These data highlight a determined progression of cortical folding and growth, mostly beginning in the second trimester.

This growth is characterized by increased complexity of cortical surface structures and ongoing changes after birth. Inherent cellular events are essential for functional specialization in adults. Disruption of these early processes can result in significant deformities and loss of function, as seen in Zika virus infection.

Although magnetic resonance imaging (MRI) studies confirm postmortem data and highlight developmental patterns, they are limited by small sample sizes and inconsistent methods; Meanwhile, traditional two-dimensional ultrasound (2D US) provides insight but lacks comprehensive, large-scale mapping of fetal brain maturation internationally.

Further research is essential to understand the impact of deviations from this ideal fetal brain maturation atlas on long-term cognitive and developmental outcomes.

About the study

Between 2009 and 2016, the INTERGROWTH-21st project collected three-dimensional ultrasound scans of fetal heads in eight global urban areas. Only women who started prenatal care before the 14th week of low-risk pregnancy were included.

Using a rigorous protocol, 899 healthy singletons were scanned, and after birth, their growth was compared to World Health Organization (WHO) standards. At two years of age, children underwent a comprehensive neurodevelopmental assessment using the internationally recognized Inter-NDA tool.

The study thoroughly curated high-quality US images, which emphasized clear brain structures. These images underwent alignment, brain extraction and structural enhancement using convolutional neural networks and manual adjustments.

Using manual and automated segmentation, the study created a 4D atlas detailing fetal brain development across gestational ages.

Studies have observed asymmetry of the cerebral hemispheres of the fetus. Most images display the left hemisphere, aligning with the known fetal position in utero. Only one cerebral area exhibited significant volume asymmetry between hemispheres.

Increased variability among participants was observed as the fetal brain developed. The research was conducted ethically, the results and tools are available on GitHub.

Results of the study

Volumetric US images from eight international study sites provide a comprehensive view of the human fetal brain at submillimeter resolution. The project included 1,059 3D US volumes from 899 precisely dated embryos.

These images span the weekly stages of fetal brain maturation between weeks 14 and 31 of pregnancy. However, the data contribution fluctuates at different locations due to differences in image quality.

With an impressive spatial resolution, the atlas was able to depict the microstructure of cerebral laminations based on gestational age. This depth rivals what is seen on magnetic resonance images and histological sections, depicting structures such as cortical plates, ventricular zones, and more.

The atlas, week by week, stands shoulder to shoulder with the MRI-based atlas from the Computational Radiology Laboratory (CRL). Despite the inherent differences between 3D US and MRI techniques, the similarities in tissue boundaries and shapes were quite striking.

In order to ensure the credibility of the combined image data, careful validation process was employed. The two main techniques, variance component analysis, and standardized mean site differences, revealed only minute variability that could be traced back to site-based differences.

Further analysis revealed that while morphological variation was present, it appeared to increase with advancing gestational age. This suggests that combining data across different sites was a sound decision.

The underlying dynamics of the healthy mature brain were uncovered, highlighting specific time periods for different brain regions. An overwhelming majority of these developmental changes occurred between 14 and 31 weeks.

During this window, regions associated with language, such as the insular cortex, show significant development. Meanwhile, a detailed assessment across 34 cortical regions illustrated subtle variability in their maturation trajectories.

Regarding sex differences, male and female fetuses did not show significant discrepancies in brain structure until the 31st week. This finding suggests that pronounced sex characteristics in the brain have not yet been revealed.

A landmark observation related to the asymmetric structure and growth rate of the fetal brain. There were pronounced size differences between the hemispheres, with the choroid plexus volume (ChPV) of the left hemisphere predominating from the 14th week onwards.

This dominance decreases as pregnancy progresses. Despite the apparent bilateral symmetry, unique regional differences become evident at various developmental milestones.

For brain growth, there was a significant increase in total brain volume. This increase correlates well with established head circumference benchmarks. Also, there were consistent growth rates between brain hemispheres.

To further substantiate the research claims, brain scans were initially excluded due to moderate quality. These scans aligned well with the primary data, reinforcing the findings of the study.

Finally, a two-year follow-up of the children showed that most of them aligned well with WHO standards for growth, cognitive abilities, motor skills and behavior. Only a small fraction deviated in visual acuity and contrast sensitivity, proving the reliability of the study.

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