Biophysical basis for brain folding and misfolding patterns in ferrets and humans
Department of Mathematics, The Chinese University of Hong Kong, China
School of Engineering and Applied Sciences, Harvard University, United States
Department of Cell Biology, Duke University, United States
Department of Pharmacology, Feinberg School of Medicine, Northwestern University, United States
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, United States
Boston Children’s Hospital, United States
Department of Organismic and Evolutionary Biology, Harvard University, United States
Department of Physics, Harvard University, United States
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Morphogenesis and morphometry of brain folding patterns across species
Biophysical basis for brain folding and misfolding patterns in ferrets and humans
study characterizes the morphogenesis of cortical folding in the ferret and human cerebral cortex using complementary physical and computational modeling. Notably, these approaches are applied to charting, in the ferret model, known abnormalities of cortical folding in humans. The study finds
evidence that variation in cortical thickness and expansion accounts for deviations in morphology and supports these findings using cutting-edge approaches from both physical gel models and numerical simulations. The study will be of broad interest to the field of developmental neuroscience.
https://doi.org/10.7554/eLife.107141.3.sa0
: Findings that have theoretical or practical implications beyond a single subfield
: Appropriate and validated methodology in line with current state-of-the-art
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A mechanistic understanding of neurodevelopment requires us to follow the multiscale processes that connect molecular genetic processes to macroscopic cerebral cortical formations and thence to neurological function. Using MRI of the brain of the ferret, a model organism for studying cortical morphogenesis, we create in vitro physical gel models and in silico numerical simulations of normal brain gyrification. Using observations of genetically manipulated animal models, we identify cerebral cortical thickness and cortical expansion rate as the primary drivers of dysmorphogenesis and demonstrate that in silico models allow us to examine the causes of aberrations in morphology and developmental processes at various stages of cortical ontogenesis. Finally, we explain analogous cortical malformations in human brains, with comparisons with human phenotypes induced by the same genetic defects, providing a unified perspective on brain morphogenesis that is driven proximally by genetic causes and affected mechanically via variations in the geometry of the brain and differential growth of the cortex.
The wrinkled and folded surface of the human brain is both iconic and familiar. These folds allow a large cortical surface area to fit inside the skull and are essential for healthy brain function. The folds form during development when the brain’s outer layer – the cerebral cortex – grows faster than the tissue beneath it, causing the surface to buckle.
When this process is disrupted, the brain can develop abnormal folding patterns known as malformations of cortical development. In humans, these conditions are associated with epilepsy, intellectual disability and developmental delay. Studying how such malformations arise is challenging because human brain folding occurs before birth.
To address this, researchers use animal models. The ferret is particularly valuable because its brain develops folds similar to those in humans, and many genes linked to human cortical malformations produce comparable folding defects in ferrets. Choi et al. wanted to find out whether the wide range of brain folding abnormalities seen in ferrets and their homologs in humans could be explained by changes in just a few physical properties of the developing brain. Specifically, they tested whether mutations linked to human cortical malformations alter the thickness or growth rate of the cortex. This question is important because different genetic syndromes often result in surprisingly similar brain shapes.
By combining brain imaging, computer simulations, and physical gel models of brains that fold when their surfaces absorb solvents and swell (similar to how fingertips swell and wrinkle when wetted for a while), Choi et al. showed that normal brain folding in ferrets can be explained by mechanical forces generated during cortical growth.
Both physical experiments with gels and computer simulations of brains with varying cortical thickness or growth rates reproduced folding patterns seen in both healthy and genetically altered ferret brains and their human homologs. Local thinning of the cortex generated many small, tightly packed folds, resembling polymicrogyria, a condition linked to mutations such as those affecting the gene
, which encodes instructions to form a sodium channel. Reducing overall growth produced smaller, less folded brains similar to microcephaly, which is associated with genes such as
. In contrast, weaker folding with shallow grooves – characteristic of lissencephaly – emerged when growth was reduced and cortical thickness increased, as seen with disruptions to genes such as
These results suggest that diverse human genetic disorders converge on common physical mechanisms that shape the brain. The work of c provides a unifying framework linking specific genes to brain shape through physical growth processes. The ferret provides a useful model organism with direct implications for human brain development and misfolding. In the future, it could help researchers interpret human brain scans and understand why different genetic disorders lead to similar malformations. However, before such insights can inform clinical practice, the models will need to incorporate additional biological detail and examine how altered folding affects brain function. More broadly, the paper also raises the question of how variations in brain folding patterns arise in non-human brains, which is the subject of a related study.
Understanding the growth and form of normal and abnormal cortical convolutions (gyri and sulci) is important for the study of human neurodevelopmental diseases (
). During early brain development, the cortical plate expands tangentially relative to the underlying white matter (
). This pattern of growth is the central cause of gyrification; indeed, tangential cortical expansion creates compressive forces on the faster-growing outer layer of the cortex and tensile forces on the attached slower-growing inner layer, and the relative-growth induced forces cause cortical folding as suggested more than a century ago (
) and first quantitatively elucidated nearly 50 years ago (
). At a molecular and cellular level, neurogenesis, neuronal migration, and neuronal differentiation all contribute to the tangential growth of the developing cortex via processes such as an increase in either the number or size of cells (
). Recent models that take these facts into account attempt to explain gyrification in terms of a simple mechanical instability, termed sulcification (
), shows that tangential expansion of the gray matter constrained by the white matter can explain a range of different morphologies seen in the brains of different organisms (
). Furthermore, when deployed over developmental time to simulate normal human cortical convolution, the results can capture a substantial range of features seen in normal human fetal brain morphogenesis (
). However, these and other simil