Dataset Information

Macroscale and microcircuit dissociation of focal and generalized human epilepsies.

ABSTRACT: Thalamo-cortical pathology plays key roles in both generalized and focal epilepsies, but there is little work directly comparing these syndromes at the level of whole-brain mechanisms. Using multimodal imaging, connectomics, and computational simulations, we examined thalamo-cortical and cortico-cortical signatures and underlying microcircuits in 96 genetic generalized (GE) and 107 temporal lobe epilepsy (TLE) patients, along with 65 healthy controls. Structural and functional network profiling highlighted extensive atrophy, microstructural disruptions and decreased thalamo-cortical connectivity in TLE, while GE showed only subtle structural anomalies paralleled by enhanced thalamo-cortical connectivity. Connectome-informed biophysical simulations indicated modest increases in subcortical drive contributing to cortical dynamics in GE, while TLE presented with reduced subcortical drive and imbalanced excitation-inhibition within limbic and somatomotor microcircuits. Multiple sensitivity analyses supported robustness. Our multiscale analyses differentiate human focal and generalized epilepsy at the systems-level, showing paradoxically more severe microcircuit and macroscale imbalances in the former.

SUBMITTER: Weng Y

PROVIDER: S-EPMC7234993 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Macroscale and microcircuit dissociation of focal and generalized human epilepsies.

Weng Yifei Y Larivière Sara S Caciagli Lorenzo L Vos de Wael Reinder R Rodríguez-Cruces Raúl R Royer Jessica J Xu Qiang Q Bernasconi Neda N Bernasconi Andrea A Thomas Yeo B T BT Lu Guangming G Zhang Zhiqiang Z Bernhardt Boris C BC

Communications biology 20200518 1

Thalamo-cortical pathology plays key roles in both generalized and focal epilepsies, but there is little work directly comparing these syndromes at the level of whole-brain mechanisms. Using multimodal imaging, connectomics, and computational simulations, we examined thalamo-cortical and cortico-cortical signatures and underlying microcircuits in 96 genetic generalized (GE) and 107 temporal lobe epilepsy (TLE) patients, along with 65 healthy controls. Structural and functional network profiling ...[more]

PMID: 32424317

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Project description:Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Dataset Information

Macroscale and microcircuit dissociation of focal and generalized human epilepsies.

Publications

Macroscale and microcircuit dissociation of focal and generalized human epilepsies.

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