Juvenile Myoclonic Epilepsy Imaging Endophenotypes and Relationship With Cognition and Resting-State EEG

Structural neuroimaging studies of patients with Juvenile Myoclonic Epilepsy (JME) typically present two findings: 1-volume reduction of subcortical gray matter structures, and 2-abnormalities of cortical thickness. The general trend has been to observe increased cortical thickness primarily in medial frontal regions, but heterogeneity across studies is common, including reports of decreased cortical thickness. These differences have not been explained. The cohort of patients investigated here originates from the Juvenile Myoclonic Epilepsy Connectome Project, which included comprehensive neuropsychological testing, 3 T MRI, and high-density 256-channel EEG. 64 JME patients aged 12-25 and 41 age and sex-matched healthy controls were included. Data-driven approaches were used to compare cortical thickness and subcortical volumes between the JME and control participants. After differences were identified, supervised machine learning was used to confirm their classification power. K-means clustering was used to generate imaging endophenotypes, which were then correlated with cognition, EEG frequency band lagged coherence from resting state high-density EEG, and white and grey matter based spatial statistics from diffusion imaging. The volumes of subcortical gray matter structures, particularly the thalamus and the motor-associated thalamic nuclei (ventral anterior), were found to be smaller in JME. In addition, the right hemisphere (primarily) sulcal pre-motor cortex was abnormally thicker in an age-dependent manner in JME with an asymmetry in the pre-motor cortical findings. These results suggested that for some patients JME may be an asymmetric disease, at least at the cortical level. Cluster analysis revealed three discrete imaging endophenotypes (left, right, symmetric). Clinically, the groups were not substantially different except for cognition, where left hemisphere disease was linked with a lower performance on a general cognitive factor ("g"). HD-EEG demonstrated statistically significant differences between imaging endophenotypes. Tract-based spatial statistics showed significant changes between endophenotypes as well. The left dominant disease group exhibited diffuse white matter changes. JME patients present with heterogeneity in underlying imaging endophenotypes that are defined by the presence and laterality of asymmetric abnormality at the level of the pre-motor sulcal cortex; these endophenotypes are linked to orderly relationships with cognition, EEG, and white matter pathology. The relationship of JME's adolescent onset, age-dependent cortical thickness loss, and seizure upon awakening all suggest that synaptic pruning may be a key element in the pathogenesis of JME. Individualized treatment approaches for neuromodulation are needed to target the most relevant cortical and subcortical structures as well as develop disease-modifying and neuroprotective strategies.