Behavior Decoding Delineates Seizure Microfeatures and Associated Sudden Death Risks in Mouse Models of Epilepsy.

Abstract

OBJECTIVE: Behavior and motor manifestations are distinctive yet often overlooked features of epileptic seizures. Seizures can result in transient disruptions in motor control, often organized into specific behavioral sequences that can inform seizure types, onset zones, and outcomes. However, refined analysis of behaviors in epilepsy remains challenging. Current manual video inspection approaches are subjective, time-consuming, and often overlook the intricate behavioral dynamics and action kinematics. This study investigates whether artificial intelligence (AI)-aided tools can unravel complex behavior repertoire that can delineate seizure outcomes in a data-driven manner. METHODS: We utilized two AI-aided tools, DeepLabCut (DLC) and Behavioral Segmentation of Open Field in DLC (B-SOiD), to decode underexplored behavior and action domains of induced seizures in a population of 32 inbred mouse strains that mimic human genetic diversity and a mouse model of Angelman syndrome. RESULTS: Our automated behavior classification tool identified 63 interpretable behavior groups. Analysis of these behavior groups demonstrates significant differential behavior usage and complexity that can delineate distinct seizure states, unravel intrinsic seizure progression over time, and inform mouse sex, strain backgrounds, and specific pathogenic mutations. We also identified seizure behavior transition dynamics and action/subaction kinematics, like hindlimb motions, that can determine the risks of sudden unexpected death in epilepsy (SUDEP). INTERPRETATION: These behavior microfeatures can facilitate preclinical mechanistic studies and antiseizure medication screening at scales. These findings also underscore the translational potential of video-based seizure behavior decoding in both inpatient and outpatient settings, including analyzing videos captured by home surveillance devices and ubiquitous smartphones. ANN NEUROL 2026;99:231-247.