Multimodal mapping of regional brain vulnerability to focal cortical dysplasia

Abstract

Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbor FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with 1) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain, 2) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan and 3) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick gray matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of inter-regional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicates that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.

Molecular signatures of cortical expansion in the human fetal brain

“…47 Spatially-embedded gene expression atlases of the adult human 35,68 and mouse 70,161 have proven exceptionally powerful in recent years, bridging resolution gaps to common neuroimaging modalities 162,163 and providing insight into the molecular correlates of structural 26,42,164 and functional neuroanatomy, 36,165,166 brain development, [167][168][169] disease and disorder. 47,170,171 In such studies, comparisons with in vivo neuroanatomy can only be fully realised through threedimensional localisation of tissue samples within a common coordinate space. 62,68,70 To date, a limitation of this approach has been either the sampling of a narrow age range outside of key developmental periods 35,69 or, in developmental datasets, a lack of 3D spatial information 3 and relatively coarse anatomical sampling.…”

Functional gradient perturbation in Wilson disease correlates with structural lesions and transcriptomic specializations

“…We calculated the enrichment ratio (ER) for each PLS component. The ER is defined as the difference between the mean bootstrap weight of the candidate gene and the mean bootstrap weight of the same number of randomly permuted genes, which was further divided by the standard deviation weight of the permuted genes 35 . Significance was determined by the percentile of the bootstrap weight of the candidate genes relative to the bootstrap weights of randomly selected genes from 10,000 permutations.…”

A scoping review of the functional magnetic resonance imaging‐based functional connectivity of focal cortical dysplasia‐related epilepsy

“…3 A large recent multicenter study of 337 patients with FCD type II used multimodal mapping to show a preferential lesion location to the frontal lobe, and found FCD transcriptomic associations with prenatal neuroglial and proliferation genes, as well as genes related to postnatal synaptogenesis and circuit development. 6 Despite the localized nature of histopathological abnormalities in FCD, and often normal-appearing cortex elsewhere, there is ample evidence for considering FCD-related epilepsy a network disease. [7][8][9] This network-based pathogenesis model is not limited to FCD; however, not all cortical lesions show the same epileptogenesis potential and person-to-person variability in network involvement.…”

“…There is a growing literature in the understanding of the genetic basis of FCD, with evidence for postnatal somatic mutations that associate FCD types IIA and IIB with the mammalian target of rapamycin (mTOR) pathway, FCD type III with the mitogen‐activated protein kinase (MAPK) pathway, and FCD type I with glysolyation 5 as well as transcriptomic errors 3 . A large recent multicenter study of 337 patients with FCD type II used multimodal mapping to show a preferential lesion location to the frontal lobe, and found FCD transcriptomic associations with prenatal neuroglial and proliferation genes, as well as genes related to postnatal synaptogenesis and circuit development 6 …”