Connectivity levels co-segregate genetic generalized epilepsy patients and asymptomatic siblings

Abstract

Idiopathic/genetic generalized epilepsy (IGE/GGE) is a common epilepsy syndrome. Aberrant brain network synchronization during rest¹ and strong evidence for a genetic aetiology of IGE/GGE has been reported². Disease mechanisms remain vague and a complex polygenetic interplay is presumed. The study of relatives not suffering from epilepsy may provide means to seek for traits that are closer to the genetic substrate than the full disease. Potential confounds such as disease activity and medication effects can be mitigated. We used magnetencephalography (MEG) to investigate resting-state in 25 IGE/GGE patients (16 females, age mean 30±11 SD years), 18 unaffected related siblings (10 females, age 31±12 years), and 45 controls (28 females, age 31±10 years). We analyzed 5 minutes of data without epileptiform discharges. Whole-brain functional connectivity (imaginary part of coherency) was assessed between MEG sources (2338 vertices) and in six frequency bands. Compared with controls, IGE/GGE patients showed significantly increased functional connectivity in most of the frequency bands studied and over widespread bilateral medio-frontal, temporal and parietal regions (theta to gamma, pFWE < 0.05). Mean connectivity levels of siblings fell between IGE/GGE patients and healthy controls. After corrections for multiple comparisons, siblings significantly differed from IGE/GGE patients only in alpha and beta2 frequency bands (pFWE < 0.05), but not from controls (pFWE > 0.05). In accordance with previous studies using comparable methods¹, IGE/GGE patients showed elevated connectivity levels during rest. Asymptomatic siblings presented with a weaker but similar trend across the frequency spectrum. The observed network phenotype in IGE/GGE patients may point to genetically mediated conditions of IGE/GGE. Our findings can be further elaborated using imaging genetics to identify associated genes and elucidate neurobiological underpinnings of the disease. ¹e.g. Hegner, Y. et al. Brain Topography 2018. 31(5), 863-874. ²Berkovic, S. et al. Annals of Neurology 1998. 43(4), 435-445.