Functional Connectivity and Genetic Profile of a “Double-Cortex”-Like Malformation

Abstract

Laminar heterotopia is a rare condition consisting in an extra layer of gray matter under properly migrated cortex; it configures an atypical presentation of periventricular nodular heterotopia (PNH) or a double cortex (DC) syndrome. We conducted an original functional MRI (fMRI) analysis in a drug-resistant epilepsy patient with “double-cortex”-like malformation to reveal her functional connectivity (FC) as well as a wide genetic analysis to identify possible genetic substrates. Heterotopias were segmented into region of interests (ROIs), whose voxel-wise FC was compared to that of (i) its normally migrated counterpart, (ii) its contralateral homologous, and (iii) those of 30 age-matched healthy controls. Extensive genetic analysis was conducted to screen cortical malformations-associated genes. Compared to healthy controls, both laminar heterotopias and the overlying cortex showed significant reduction of FC with the contralateral hemisphere. Two heterozygous variants of uncertain clinical significance were found, involving autosomal recessive disease-causing genes, FAT4 and COL18A1. This first FC analysis of a unique case of “double-cortex”-like malformation revealed a hemispheric connectivity segregation both in the laminar cortex as in the correctly migrated one, with a new pattern of genes’ mutations. Our study suggests the altered FC could have an electrophysiological and functional impact on large-scale brain networks, and the involvement of not yet identified genes in “double-cortex”-like malformation with a possible role of rare variants in recessive genes as pathogenic cofactors.

Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats

“…25 Because we have observed a slower progression towards fully mature SWDs upon manipulation of excitability of both the SBH, and the normotopic cortex, this suggests that the two regions contribute to the maturation of electrographic patterns. Interestingly, reciprocal connections between the SBH and the normotopic cortex were described in SBH patients, 28 in PVNH patients, 27,35,36 To conclude, our longitudinal monitoring of epilepsy progression in rats with bilateral SBH reveals a gradual evolution of seizure properties and patterns during the course of epileptogenesis, before finally reaching a fully developed discharge pattern. Further, through timed and spatially targeted manipulation of neuronal excitability, we demonstrate that a complex combination of developmental alterations in both the SBH and the cortex preprint (which was not certified by peer review) is the author/funder.…”

“…This is in line with neuroimaging studies in patients with various types of MCDs, revealing widespread structural and functional circuit reorganization in focal cortical dysplasia (FCD), 26 in periventricular nodular heterotopia (PVNH) 27 and in SBH. 28 In the present study, early manipulation of neuronal excitability has led to strikingly different consequences depending on the targeted area. These differences likely reflect distinct pathological mechanisms contributing to epileptogenesis in SBH -in which the causative mutation is the main contributor, and in the overlying cortex -in which secondary circuit-level reorganizations are prevailing as we demonstrated in Plantier et al 25 If both regions do concur to creating seizure-prone circuits, the weight of the SBH (and that of the causative gene) appears greater than that of the overlying cortex, as illustrated by a more favorable outcome of SBH-targeting manipulation.…”

“…This is in line with neuroimaging studies in patients with various types of MCDs, revealing widespread structural and functional circuit reorganization in focal cortical dysplasia (FCD), 26 in periventricular nodular heterotopia (PVNH) 27 and in SBH. 28…”

“…25 Because we have observed a slower progression towards fully mature SWDs upon manipulation of excitability of both the SBH, and the normotopic cortex, this suggests that the two regions contribute to the maturation of electrographic patterns. Interestingly, reciprocal connections between the SBH and the normotopic cortex were described in SBH patients, 28 in PVNH patients, 27,35,36 and in murine models of SBH and PVNH (Vermoyal, Hardy et al ., unpublished work) in keeping with this idea.…”

Realistic modeling of mesoscopic ephaptic coupling in the human brain

“…Symptoms may include unusual facial appearance, difficulty swallowing, failure to thrive, muscle spasms, seizures, and severe psychomotor retardation. Laminar heterotopia is a rare condition consisting in an extra layer of gray matter underlying properly migrated cortex, usually associated with epileptiform activity, cognitive deficits and alterations of functional connectivity patterns [72,73]. Polymicrogyria is PLOS COMPUTATIONAL BIOLOGY a condition in which the brain has an overly convoluted cortex.…”