Neurobehavioral Signatures of Epileptogenesis: Molecular Programs, Trait-like Phenotypes, and Translational Biomarkers Beyond Seizures.

Epileptogenesis is commonly defined by the emergence of spontaneous seizures after an initial insult; however, convergent experimental and clinical evidence indicates that the underlying disease process begins well before seizures become clinically detectable. During this pre-seizure phase, persistent molecular cascades remodel synaptic plasticity, circuit architecture, and glial-immune signaling. These processes are associated with trait-like alterations in cognition, affect, and behavior. Despite their clinical relevance, these neurobehavioral signatures remain poorly integrated into molecular models of epileptogenesis and are rarely considered as translational biomarkers of disease progression. This review synthesizes evidence linking core epileptogenic molecular cascades-maladaptive synaptic plasticity, glial-immune signaling, oxidative-metabolic stress, and activity-dependent gene regulation-to reproducible alterations in executive control, cognitive flexibility, emotional regulation, and motivational-social behavior. We outline an integrative framework in which these phenotypes are conceptualized as system-level readouts of progressive network reconfiguration rather than nonspecific "comorbidities" or mere consequences of recurrent seizures. Within this perspective, neurobehavioral markers can complement electrophysiological and molecular measures by capturing disease-relevant changes during windows when anti-epileptogenic interventions would be most effective. To increase mechanistic specificity, we provide representative pathway and gene-level anchors across epileptogenesis stages, a structured molecular-to-neurobehavioral mapping, and an operational biomarker panel specifying confounders and minimal controls. These anchors are included to ground the framework in experimentally documented molecular nodes with stage-dependent relevance; examples are representative rather than exhaustive, and evidence strength is indicated as preclinical mechanistic versus associative human observations. Finally, we discuss methodological requirements for biomarker validity (specificity, temporal anchoring, and cross-model consistency) and outline how integrating molecular and neurobehavioral trajectories may refine target discovery and improve the translation of anti-epileptogenic strategies. Conceptualizing epileptogenesis as a progressive disease process with measurable pre-seizure neurobehavioral signatures may broaden biomarker strategies beyond seizure occurrence and support the development of disease-modifying interventions.