SBIR-STTR Award

There is an urgent need for research into treatment options for epilepsy and other seizure disorders. Animal models are increasingly used to understand disease mechanisms and to screen promising therapeutic approaches. Animal epilepsy model use typically requires expensive and labor-intensive experimentation, with invasive EEG measurements being the preferred method of validation. This severely limits the pace and scale of investigation. In models of acquired epilepsy, animals usually undergo treatment to induce status epilepticus— a period of unremitting seizure—followed by a latent period during which the brain rewires itself to generate spontaneously recurring seizures, evidence of chronic epilepsy. The duration of the latent period and the likelihood that an animal will develop epilepsy are both uncertain. Animals must be observed for weeks to confirm epilepsy before they are ready for experimentation. During this latent period, seizures are commonly documented by visual observation or video review, which are tedious and prone to error. A commercial system for automated noninvasive seizure detection would therefore be attractive to epilepsy researchers. Signal Solutions, LLC, has developed technology based on piezoelectric sensors for noninvasive, high- throughput behavioral monitoring of rodents that is currently used by research groups around the world to identify genes related to sleep and circadian rhythms. The system discriminates sleep from wakefulness with over 90% accuracy. The Sunderam Lab at the University of Kentucky has further demonstrated using EEG analysis that these piezo sensors can be used to label REM and NREM stages of sleep in mice. In this STTR proposal, PI Sunderam and co-investigator Bauer will work with Signal Solutions to develop methods based on the piezo technology for accurate noninvasive seizure screening in rodent models of epilepsy. The result will be a validated system that minimizes the need for invasive and resource-intensive EEG analysis or tedious video monitoring. The objectives of the project are the following: 1. Test the feasibility of coarse detection of epilepsy onset in rodents using a noninvasive piezo sensor; 2. Train a piezo classifier to accurately detect and quantify seizures in rodents with confirmed epilepsy; and 3. Test the utility of a miniature piezo sensor for seizure screening and an infrared imager for seizure verification and severity assessment. The envisioned product is a turnkey system for convenient and noninvasive seizure screening in small animal models of epilepsy in custom or commercial cages. Potential customers include academic research labs as well as labs in the pharmaceutical sector engaged in high-volume screening of antiepileptic drugs.

Public Health Relevance Statement:
The development of treatments for epilepsy depends heavily on laboratory animal studies in which the effect of treatment on seizures is measured. Seizures are rare and unpredictable, and monitoring animals for seizures requires tedious observation or review of video recordings; the alternative is to record brain signals, which requires invasive surgery to implant electrodes. A new technology is proposed here that would enable completely noninvasive detection of seizures in animals. The accuracy of this method will be compared with EEG analysis in an animal model of epilepsy.

Project Terms:
Aftercare; Algorithms; Alzheimer's Disease; Animal Experimentation; Animal Model; Animals; Antiepileptic Agents; base; Behavior; Behavior monitoring; Behavioral; Brain; Cataplexy; Chronic; Circadian Rhythms; commercialization; Communities; Computer software; Convulsants; Custom; Detection; Development; Devices; Disease; dravet syndrome; Drug Screening; Electroencephalography; Environment; Epilepsy; Epileptogenesis; Evaluation; Floor; Frontal Lobe Epilepsy; Funding; Genes; Genetic Models; Government; Image; imager; implantation; Implanted Electrodes; Industrialization; interest; Investigation; Kentucky; Knock-out; Label; Laboratory Animals; Lafora Disease; Measurement; Measures; Methods; Modeling; Monitor; Mus; Narcolepsy; natural hypothermia; neonatal stroke; new technology; Operative Surgical Procedures; Outcome; perinatal stroke; Persons; Pharmacologic Substance; Phase; Post-Traumatic Epilepsy; Pre-Clinical Model; pressure; Research; Research Personnel; Resources; respiratory; Rodent; Rodent Model; screening; Seizures; sensor; Severities; Signal Transduction; Sleep; Sleep Stages; Small Business Technology Transfer Research; Status Epilepticus; System; Technology; Temporal Lobe Epilepsy; Testing; Therapeutic; therapy development; Time; Training; trait; treatment effect; United States National Institutes of Health; Universities; Validation; Video Recording; Visual; voltage; Wakefulness; Work

EpiZode: Noninvasive Seizure Screening in Preclinical Models of Epilepsy There is an urgent need for research into treatment options for epilepsy and other seizure disorders. Animal models are increasingly used to understand disease mechanisms and to screen promising therapeutic approaches. Animal epilepsy model use typically requires expensive and labor-intensive experimentation, with invasive EEG measurements being the preferred method of validation. This severely limits the pace and scale of investigation. In models of acquired epilepsy, animals usually undergo treatment to induce status epilepticus— a period of unremitting seizure—followed by a latent period during which the brain rewires itself to generate spontaneously recurring seizures, the hallmark of chronic epilepsy. The duration of the latent period and the likelihood that an animal will develop epilepsy are both uncertain. Animals must be observed for weeks to confirm epilepsy before they are ready for experimentation. During this latent period, seizures are commonly documented by visual observation or video review, which are tedious and prone to error. A commercial system for automated noninvasive seizure detection would therefore be invaluable to epilepsy researchers. Signal Solutions, LLC, has developed piezoelectric sensor technologies for noninvasive, high-throughput behavioral monitoring in rodents. This is being used by sleep/circadian researchers around the world, and discriminates sleep from wakefulness with >90% accuracy. The Sunderam Lab at the University of Kentucky has further demonstrated that these piezo sensors can distinguish REM and NREM stages of sleep in mice. To address the needs of epilepsy researchers, we performed a Phase I STTR study to: 1. Test the feasibility of epilepsy onset detection in rodents using noninvasive piezo film sensors; 2. Validate piezo detections against simultaneous EEG recordings in rodents with epilepsy; and 3. Test the feasibility of using smaller profile piezo sensors and an infrared imager for seizure screening and verification. The study successfully confirmed the feasibility of these aims. In this Phase II STTR proposal, we will further develop methods for accurate noninvasive seizure screening in rodent models through the following objectives: 1. Develop algorithms for detection of both overt and subtle seizures using small form factor piezo sensors; 2. Send a prototype system out for beta testing on different animal models and refine the system based on feedback; 3. Develop and validate novel sensor configurations algorithms for accurate seizure detection and attribution in group-housed epileptic animals. The envisioned product is a turnkey system for convenient noninvasive seizure screening in small animal models of epilepsy in custom or commercial cages that minimizes the need for invasive and resource-intensive EEG analysis. Potential customers include academic research labs as well as labs in the pharmaceutical sector engaged in high-volume screening of antiepileptic drugs.

Public Health Relevance Statement:
The development of drugs and other treatments for epilepsy depends heavily on laboratory animal studies in which their effect on seizures is measured. Seizures are rare and unpredictable, and monitoring animals for seizures in person or from video recordings is tedious; the alternative is to record brain signals, which requires invasive and expensive recordings using electrodes. A new noninvasive technology is proposed for detecting seizures in lab animals used for epilepsy research.

Project Terms:
Acute; Address; Aftercare; Algorithms; Animal Experimentation; Animal Model; Animals; Antiepileptic Agents; base; Behavior; Behavior monitoring; Behavioral; Brain; Chronic; circadian; Circadian Rhythms; Communities; Computer software; Convulsants; Custom; Detection; Development; Disease; dravet syndrome; drug development; Drug Screening; Electrodes; Electroencephalography; Epilepsy; Epileptogenesis; Essential Tremor; Evaluation; Family; Feedback; Film; Floor; Frontal Lobe Epilepsy; Funding; Genes; Genetic Models; Government; Harmaline; imager; Industrialization; interest; Investigation; kainate; Kentucky; Knock-out; Laboratory Animals; Lafora Disease; Measurement; Measures; Methods; Modeling; Monitor; Mus; natural hypothermia; non rapid eye movement; non-invasive monitor; novel; Outcome; perinatal stroke; Persons; Pharmacologic Substance; Phase; Post-Traumatic Epilepsy; Pre-Clinical Model; pressure; prototype; Rattus; relating to nervous system; Research; Research Personnel; Resources; respiratory; Rodent; Rodent Model; Sampling; SCN8A gene; screening; Seizures; sensor; sensor technology; Signal Transduction; Sleep; Sleep Stages; Small Business Technology Transfer Research; social; source localization; Status Epilepticus; success; System; Technology; Temporal Lobe Epilepsy; Testing; Therapeutic; Time; Tonic - clonic seizures; trait; treatment effect; Tremor; United States National Institutes of Health; Universities; Validation; Video Recording; Visual; voltage; Wakefulness