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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\u2009T MRI, and high\u2010density 256\u2010channel EEG. 64 JME patients aged 12\u201325 and 41 age and sex\u2010matched healthy controls were included. Data\u2010driven 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\u2010means clustering was used to generate imaging endophenotypes, which were then correlated with cognition, EEG frequency band lagged coherence from resting state high\u2010density 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\u2010associated thalamic nuclei (ventral anterior), were found to be smaller in JME. In addition, the right hemisphere (primarily) sulcal pre\u2010motor cortex was abnormally thicker in an age\u2010dependent manner in JME with an asymmetry in the pre\u2010motor 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 (\u201cg\u201d). HD\u2010EEG demonstrated statistically significant differences between imaging endophenotypes. Tract\u2010based 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\u2010motor sulcal cortex; these endophenotypes are linked to orderly relationships with cognition, EEG, and white matter pathology. The relationship of JME's adolescent onset, age\u2010dependent 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\u2010modifying and neuroprotective strategies.<\/jats:p>","DOI":"10.1002\/hbm.70226","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T08:52:37Z","timestamp":1747299157000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Juvenile Myoclonic Epilepsy Imaging Endophenotypes and Relationship With Cognition and Resting\u2010State <scp>EEG<\/scp>"],"prefix":"10.1002","volume":"46","author":[{"given":"Aaron F.","family":"Struck","sequence":"first","affiliation":[{"name":"Department of Neurology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Department of Radiology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"William S Middleton 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