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Microcephaly: diving into the folds and creases of the brain

People afflicted with microcephaly have undersized brains. Researchers from the CEA-I2BM have developed a mathematical analysis of MRI images that can discriminate variations in cortical folding complexity. This is a methodological step towards a more effective diagnostic approach, as well as a better understanding of cerebral development. ​

Published on 7 April 2015

Unfolded, the surface of the human cortex can reach more than 2 m2. Within the skull, the cortex is folded, forming a complex terrain whose geometry varies between individuals. Microcephaly1 is frequently associated with cerebral malformations. However, in certain cases the brain has a normal architectural aspect despite a strong reduction in volume. Researchers from the CEA-I2BM, in collaboration with the CNRS of Marseille and several teaching hospitals2, took an interest in this latter type of microcephaly. Aiming to characterize it better, the researchers developed a method to mathematically analyze the cortical curvature using spectral analysis, similar to analytical methods for the oscillations of a sound signal. This method calls upon computer-assisted neuroimaging to quantitatively understand the complexity of folding (an otherwise very subjective data point) by revealing the interweaving primary, secondary and tertiary folds of the cortex. The researchers then modeled the general effect of brain size on folding complexity, in order to explore brains this small in the best manner.

This method was tested in 3 groups of adolescents and young adults presenting a microcephaly linked to one of three different causes, including: fetal alcohol syndrome; mutation of the ASPM gene that causes an autosomal recessive microcephaly; and mutation of the PQB1 gene that is responsible for a syndromic microcephaly linked to the X chromosome. It appears that these microcephalies display different degrees of cortical fold simplification. For microcephalies associated with fetal alcohol syndrome, the level of simplification was as expected for the brain volume. In contrast, microcephalies linked to mutations of the ASPM gene display a simplification in cortical folding that is greater than expected, while those linked to mutations in the PQB1 gene show a less pronounced simplification.

Spectral analysis (bottom) of three MRI images (top) from patients with a microcephaly due to one of three distinct causes. On the left, a microcephaly linked to mutations in the ASPM gene; in the center, one linked to fetal alcohol syndrome; and on the right, one linked to mutations in the PQB1 gene.

Spectral analysis images of the cortex by MRI thus revealed that there are variations in the folding complexity beyond what is mechanically induced by variations in brain volume, and that these subtle variations could be specific to certain causes of microcephaly. The researchers were therefore able to demonstrate something that the eye alone cannot distinguish. Currently, they are working on applying this tool to the analysis of cerebral development in fetuses and premature babies, in order to improve the characterization of early stages of cortical development and to obtain new early markers that are characteristic of both proper and defective brain growth.

  1. Microcephaly refers to when the cranial circumference is at least 3 standard deviations smaller than the mean established measurement for age and gender.
  2. The Hôpital Robert Debré in Paris, Hôpital Femme Mère Enfant in Lyon, and the CHU of Réunion.

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