Juvenile myoclonic epilepsy heterogeneity uncovered: Z-mapped imaging endophenotypes of cortical and subcortical structures and their clinical, cognitive, and psychiatric features

Abstract To identify imaging endophenotypes in Juvenile Myoclonic Epilepsy (JME) using individualized Z-maps of cortical/subcortical regions and examine their relationships with cognitive, psychiatric, and epilepsy-related variables. 62 JME patients (aged 12–25 years) and 41 age-and sex-matched healthy controls (HC) underwent 3T MRI, neuropsychological assessment, psychiatric evaluation, and clinical interviews. Cortical thickness and subcortical volumes were processed with FreeSurfer, adjusted for age, sex, and brain volume. Kolmogorov-Smirnov tests were used to compare regional distributions. Z-scores were calculated relative to HC, and K-means clustering identified endophenotypes. In JME, there were reduced subcortical volumes most prominently in motor-related thalamus (p<0.001) and greater variability in cortical thickness in the frontal/parietal regions. Three endophenotypes emerged: Subcortical Reduction (n = 27, 43.5%), Increased Cortical Thickness (n = 21, 33.9%), and Decreased Cortical Thickness (n = 14, 22.6%). Subcortical Reduction showed marked motor thalamic and subcortical gray matter loss. Increased Cortical Thickness exhibited frontal and parietal cortical thickening with associated subcortical reduction. Decreased Cortical Thickness showed less subcortical change, but overall reduced cortical thickness. Cognitive differences were notable: Increased Cortical Thickness was the most impaired cognitively, suggesting a disruption of neurodevelopment, while Decreased Cortical Thickness performed the best, particularly in Speed/Response Inhibition—consistent with the least disruption of brain maturation and dysregulation of synaptic pruning. Seizure burden, socioeconomic status, age of onset, and psychiatric diagnoses did not show any differences between groups. JME exhibits heterogeneous imaging endophenotypes, with motor thalamic and subcortical reductions and variability cortical thickness in the frontal and parietal regions, reflecting neurodevelopmental dysregulation with cognitive consequences.