Objective: Drug-resistant temporal lobe epilepsy (TLE) is typically associated with hippocampal pathology. However, widespread network alterations are increasingly recognized and suggested to perturb cognitive function in multiple domains. Here we tested (1) whether TLE shows atypical cortical hierarchical organization, differentiating sensory and higher order systems; and (2) whether atypical hierarchy predicts cognitive impairment. Methods:We studied 72 well-characterized drug-resistant TLE patients and 41 healthy controls, statistically matched for age and sex, using multimodal magnetic resonance imaging analysis and cognitive testing. To model cortical hierarchical organization in vivo, we used a bidirectional stepwise functional connectivity analysis tapping into the differentiation between sensory/unimodal and paralimbic/transmodal cortices. Linear models compared patients to controls.Finally, we assessed associations of functional anomalies to cortical atrophy and microstructural anomalies, as well as clinical and cognitive parameters.Results: Compared to controls, TLE presented with bidirectional disruptions of sensory-paralimbic functional organization. Stepwise connectivity remained segregated within paralimbic and salience networks at the top of the hierarchy, and sensorimotor and dorsal attention at the bottom. Whereas paralimbic segregation was associated with atypical cortical myeloarchitecture and hippocampal atrophy, dysconnectivity of sensorimotor cortices reflected diffuse cortical thinning. The degree of abnormal hierarchical organization in sensory-petal streams covaried, with broad cognitive impairments spanning sensorimotor, attention, fluency, and visuoconstructional ability and memory, and was more marked in patients with longer disease duration and Engel I outcome.

Highlights Consensus clustering of MRI contrasts maps focal cortical dysplasia lesional variability. Lesions were parcellated into four classes with distinct structural profiles. FCD classes reflected typical functional and histopathological characteristics. Class membership was replicated in two independent datasets. Class-informed detection algorithm outperformed a class-naïve paradigm.

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.