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

## TL;DR

This study identifies three distinct brain imaging patterns in juvenile myoclonic epilepsy patients, showing how brain structure differences relate to cognitive performance.

## Contribution

The study introduces Z-mapped imaging endophenotypes to uncover heterogeneity in juvenile myoclonic epilepsy.

## Key findings

- Three endophenotypes were identified: subcortical reduction, increased cortical thickness, and decreased cortical thickness.
- Increased cortical thickness was linked to the worst cognitive performance, suggesting neurodevelopmental disruption.
- Decreased cortical thickness showed the best cognitive performance, particularly in speed and response inhibition.

## Abstract

To identify imaging endophenotypes in juvenile myoclonic epilepsy using individualized Z-maps of cortical/subcortical regions and examine their relationships with cognitive, psychiatric and epilepsy-related variables. Sixty-two juvenile myoclonic epilepsy patients (aged 12–25 years) and 41 age- and sex-matched healthy controls 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 healthy controls, and K-means clustering identified endophenotypes. In juvenile myoclonic epilepsy, 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 grey 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. Juvenile myoclonic epilepsy 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.

Struck et al. applied individualized Z-maps to MRI in 62 juvenile myoclonic epilepsy patients versus 41 controls, revealing motor thalamic/subcortical reductions and three imaging endophenotypes. The increased cortical thickness subgroup showed the poorest cognition, suggesting neurodevelopmental dysregulation, whereas decreased cortical thickness performed best; seizure burden and psychiatric diagnoses did not differ.

Graphical Abstract