Non-pharmacological intervention to ameliorate epilepsy and its comorbidities

University Of Washington, Seattle WA

Investigators

Linked publications, trials & patents

Abstract

SUMMARY Epilepsy is among the most common neurological disorders globally. Symptoms in severe childhood epilepsies such as Dravet syndrome (DS) are not limited to seizures but typically involve increased anxiety, autism spectrum disorder, intellectual disability, and circadian and sleep disorders. Most treatments for epilepsies target seizure severity and frequency but do not necessarily focus on remaining symptoms, which greatly diminish the quality of life of patients and caregivers. In this proposal we test the hypothesis that improving circadian and sleep regulation in DS will not only result in decreased seizure frequency and severity but also in an improvement of other symptoms of the disease. To test predictions of this hypothesis we capitalize on a mouse model of DS. As DS patients, DS mice have a heterozygous loss-of-function mutation in the SCN1A gene, which codes for the primary voltage-gated Na+ channel in adult GABAergic neurons. DS mice show most symptoms of the disease including febrile and spontaneous seizures, increased anxiety, autistic behavior, cognitive deficits and dysregulation of circadian rhythms and sleep. Thus, DS mice represent a reliable genotypic and phenotypic model of the disease. Here we propose to increase the 24-h temporal structure of the environment to improve both circadian and homeostatic regulation of sleep, and in turn to determine whether these improvements result in reduced seizure severity and frequency, reduced anxiety, improved social behavior and cognitive performance. Aim 1 will assess the ability of wheel-running restriction to the dark phase, food restriction to the dark phase or a combination of both routines, to improve behavioral, physiological and molecular circadian rhythms, to increase sleep hygiene, and to reduce seizure frequency in both male and female DS mice. Aim 2 will determine whether the best routine in improving these outcomes will be also effective in reducing anxiety, increasing social behavior and improving memory consolidation. Until now, most treatments of childhood epilepsies, including DS, involve pharmacological treatments that seek to reduce seizure severity and frequency. Many of these treatments are ineffective in treating DS and the development of non-pharmacological, non-invasive treatments that improve symptoms holistically offers great promise to improve the quality of life of DS patients as well as patients with other forms of severe epilepsy. Our proposal exploits a reliable animal model of DS to test potential treatments that, because of their minimal invasiveness, could be implemented in DS patients.