Malformations of cortical development as models of altered brain excitability

Abstract

The developmental organisation of the human cerebral cortex is among the most complex processes known in biology. The process includes the migration of neuronal precursors from the cortical endplate to the future outer boundary of the brain, a consistent organisation in layers from the inside to the outside, the differentiation of principal neurons and a wide spectrum of inhibitory neuronal types focusing information processing and controlling excitability, and the precision wiring of neurons within cortical columns and in extended projections. This process results in an efficient, stable, and functional small-world brain network. Unsurprisingly, the complex sequences and interactions contributing to this cortical development are liable to minor and major disturbances. Progress in brain imaging and in the histological analysis of brain specimens, particularly from humans undergoing neurosurgical resections of brain areas considered pathological, has considerably increased knowledge from the spectrum of malformations of cortical development. Such malformations can be extensive (eg, the formation of a double cortex or absent cortical layering, or altered gyrification, such as in pachygyria, or can be circumscribed (as with focal cortical dysplasia), or can be space occupying (as with a developmental tumour). Abnormal neuronal migration, differentiation, and wiring will often affect the intricate balance of excitability and inhibition in the affected brain region, resulting in epilepsy. Improved high resolution brain imaging, including computer-assisted postprocessing of 3D data sets, 1 Gill RS Lee HM Caldairou B et al. Multicenter validation of a deep learning detection algorithm for focal cortical dysplasia. Neurol. 2021; (published online Sep 14)https://doi.org/10.1212/WNL.0000000000012698 Crossref Scopus (10) Google Scholar , 2 Demerath T Rubensdörfer L Schwarzwald R et al. Morphometric MRI analysis: improved detection of focal cortical dysplasia using the MP2RAGE sequence. AJNR Am J Neuroradiol. 2020; 41: 1009-1014 Crossref PubMed Scopus (12) Google Scholar has provided evidence that discrete focal brain malformations are the most common cause of focal epilepsy in people, and particularly of focal epilepsy that responds insufficiently to anti-seizure medication and thus requires surgical treatment. 3 Fauser S Essang C Altenmüller DM et al. Long-term seizure outcome in 211 patients with focal cortical dysplasia. Epilepsia. 2015; 56: 66-76 Crossref PubMed Scopus (113) Google Scholar , 4 Blümcke I Spreafico R Haaker G et al. EEBB Consortium. Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med. 2017; 377: 1648-1656 Crossref PubMed Scopus (370) Google Scholar Neocortical development and epilepsy: insights from focal cortical dysplasia and brain tumoursDuring the past decade, there have been considerable advances in understanding of the genetic and morphogenic processes underlying cortical malformations and developmental brain tumours. Focal malformations are caused by somatic (postzygotic) variants in genes related to cell growth (ie, in the mTOR pathway in focal cortical dysplasia type 2), which are acquired in neuronal progenitors during neurodevelopment. In comparison, developmental brain tumours result from somatic variants in genes related to cell proliferation (eg, in the MAP-kinase pathway in ganglioglioma), which affect proliferating glioneuronal precursors. Full-Text PDF