Abstracts

Rationale: Malformations of cortical development (MCD) are a major cause of drug-resistant focal epilepsy (Barkovich et al., 2012). While emerging evidence suggests distributed pathological substrates exceeding the primary lesion (Hong et al., 2016; Rugg-Gunn et al., 2005), large-scale brain network organization has so far not been systematically assessed. Methods: Analyzing structural and resting-state functional MRIs, we built multimodal brain connectomes in 154 MCD patients and 41 closely-matched healthy controls. Structural networks were derived from inter-regional cortical thickness covariance patterns and functional networks from fMRI correlations. Statistical comparisons of group-level network matrices and multiple graph-theoretical topological parameters (i.e., clustering coefficient [Cp], shortest path length [Lp], rich-club indices) assessed differences in network topology in patients and controls. We subdivided the MCD cohort into subtypes based on a classification that adheres to their putative time course (Barkovich et al., 2012): focal cortical dysplasias (cell proliferation), heterotopias (neuronal migration), and polymicrogyrias (cortical organization). Following separate analysis of structural/functional connectomes, we evaluated network-level coupling. Results: Compared to controls, in all MCD subtypes, overall structural networks showed atypical patterns characterized by markedly increased intra-hemispheric connectivity at the expense of inter-hemispheric connections (Fig 1A). Networks also showed a more regularized topology (i.e., increased Cp and Lp; Fig 1B), with a gradual change across MCD subtypes: cortical dysplasias showed only subtle changes, while effects were more marked in heterotopias, and maximal in polymicrogyrias. A similar gradient was observed at the level of functional networks; yet contrary to structural networks, functional topology showed a random topology (i.e., decreased Cp, increased Lp; Fig 2A). Diverging patterns were supported by a gradual structure-function decoupling in patients, with a maximal decrease in polymicrogyrias (Fig 2B). Conclusions: In MCD, the severity of alterations of whole-brain structural and functional network organization is modulated by the time course of corticogenesis. More marked effects of polymicrogyrias relative to focal cortical dysplasias and heterotopias suggest increased sensitivity during late neurodevelopmental stages, when the majority of cortico-cortical connections are established (Takahashi et al., 2012). Funding: This work was supported by the Canadian Institutes of Health Research (CIHR, MOP-57840 and 123520). SJH and BCB received Jeanne Timmins Costello and CIHR fellowships, respectively.