Mechanisms of Sleep-Seizure Interactions in Tuberous Sclerosis Complex
Abstract
This proposal addresses two of the three FY21 TSCRP Idea Development Focus Areas of preventing epilepsy, improving treatment, and mitigating neurodevelopmental outcomes associated with TSC-related seizures and understanding the features of TSC-Associated Neuropsychiatric Disorders (TAND) and reducing their impact, including pharmacological and behavioral interventions. Epilepsy and sleep disorders are both common disabling problems in tuberous sclerosis complex (TSC) and often occur together in the same TSC patients. Epilepsy occurs in up to 90% of TSC patients and is intractable to treatment in the majority of cases, often leading to lifelong disabling seizures. Sleep disorders, such as difficulty sleeping (insomnia) and early awakening, are frequently reported TAND symptoms (~50% of TSC patients) and a significant source of decreased quality of life for both the patient and family/caregivers, with limited available treatments. In addition to commonly occurring together, there is a strong interaction between epilepsy and sleep, with seizures being triggered during sleep and sleep, in turn, being disrupted by the seizures. Understanding the basis for this sleep-seizure relationship in the brain may lead to better therapies simultaneously for both epilepsy and sleep problems in TSC. Thus, the overall goal of this project is to understand the brain mechanisms involved in the interactions between sleep and seizures, utilizing this knowledge to develop more effective, targeted treatments for epilepsy and sleep disorders in TSC. Toward achieving this goal, we will first identify and characterize mouse models of TSC that demonstrate interactions between seizures and sleep. Then, we will use these TSC mouse models to study the brain abnormalities underlying these interactions and test novel treatments targeting these abnormalities. One particularly novel aspect of this proposal is that we will focus on an area deep within the brain, called the hypothalamus, which traditionally regulate hormones in the body, but also regulates sleep function and possibly seizures. Furthermore, we will study a special neurochemical selectively located in the hypothalamus, orexin, as potentially being responsible for linking sleep disorders and epilepsy in TSC. Finally, we will test the effect of drugs targeting orexin (orexin antagonists) on epilepsy and seizure-related sleep dysfunction in the TSC mouse models. The proposed research has the potential to help a large proportion of TSC patients, including those with epilepsy or sleep disorders, which again are both very common in TSC. A novel treatment that is simultaneously effective for both epilepsy and sleep disorders would be doubly impactful. As some orexin antagonists are already U.S. Food and Drug Administration (FDA)-approved for insomnia, the time and path to testing and bringing a treatment to TSC patients could be relatively short.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210227
Entities
People
- Michael Wong
Organizations
- United States Army
- Washington University in St. Louis