The second focus of the UWIN fellow research series is Raymond Sanchez, a graduate student in the UW Neuroscience Program and Department of Biology. Ray is advised by Horacia de la Iglesia, and received a UWIN fellowship in 2017. His research focuses on sleep disturbances related to seizures, and methods of detection and prevention of seizures during sleep.
Epilepsy is among the most common neurological disorders in the world, and are typically accompanied by sleep and circadian rhythm disturbances. These disturbances include waking up during the night, difficulty maintaining a consistent sleep cycle, and tiredness throughout the waking day. These disturbances tend to increase the likelihood and severity of seizures and other associated cognitive and developmental deficits. Additionally, frequent nocturnal seizures put patients at high risk for sudden unexpected death, particularly in children.
Investigating Sleep Disturbances
Dravet syndrome is a specific type of epilepsy syndrome that begins in infancy or early childhood, and is caused by a brain wide change in the SCN1A gene (which controls the sodium-ion exchange that is crucial in the action of a nervous system). Due to the specific gene mutation, Dravet syndrome can be induced in animal models and studied in specific locations of the brain. This allows for isolation of the modification of the SCN1A gene in the sleep section of the brain, clarifying the relationship between sleep and epilepsy.
Using existing techniques in mice, a gene can be tagged, modified, and removed, in this case, inducing physiological changes associated with Dravet syndrome in the sleep section of the brain. This allows these mice to act as Dravet syndrome models in research. With these mice models available, Ray is able to directly study the repercussions of Dravet syndrome in long scale sleep studies that can lend information about how environmental changes modify sleep architecture. Determining the sleep architecture of a night’s rest is important; while the total amount of sleep and the types of each sleep cycle is important, the order in which each sleep stage occurs also matters.
One of the most consistent observations of caretakers of individuals with Dravet syndrome is that travel is very hard to recover from, specifically jet lag and the transition to a new time zone or circadian rhythm. Ray looked into this phenomenon by observing the sleep regularity within two sets of mice, one with the Dravet syndrome mutation, the other without, while the light schedule was changed to simulate a time-zone change.
A way of visually depicting circadian sleep cycles is using an actogram. The actogram above is double plotted, meaning that the current day is plotted beside the previous day, allowing for an easier comparison from day to day. This plot compares the time and duration of activity during the day (x-axis) over the course of a 30 day (y-axis) observational period. The light gray shading represents the period ‘night’ time with lights off, while the light areas indicate the ‘day’ hours or lights on. During the day, an ECoG/EMG recording is taken of each mouse, with the black sections showing the sleeping times of the mouse, and the white gaps showing active times. This experiment was conducted for both a Wild Type control mouse (left) and a Dravet Syndrome model mouse (right), and observed sleep patterns as a “jet lag” time shift occurred. Visually, the common sleep disturbances with the Dravet Syndrome are present: inconsistent sleep during the night and tiredness or more resting though the day. These long-term sleep studies over multiple days are useful for understanding the severity and the circadian cycle adjustment needs over the Wild type and the Dravet Syndrome mice.
Sleep Stage Detection
An important distinction in the sleep architecture lies in what type of sleep stage is occurring. There are five different sleep stages, REM sleep, stage 1 and 2 (light sleep stages), stages 3 and 4 (deep sleep stages). These stages all serve a different purpose during a night’s rest, with the deep sleep stages encouraging the body to recover and rest during the night. This includes heart health, immune health, and brain help, even aiding the transfer of short-term memories into long term storage.
Patients with Dravet Syndrome often find it hard to get enough total sleep or enough of the deeper sleep cycles. This lack of sleep often serves as a future seizure trigger. The mouse studies have been useful in determining correlations in sleep and seizure activities, but due to the length of the study (multiple days), analyzing the data can be challenging.
To aid in this data analysis, Ray is currently developing a machine learning model for sleep stage classification. This will allow him to process long term sleep recordings with the same accuracy as a human, but automated and much quicker. This model is the first step in predicting when a seizure might occur. The ability to detect the type of sleep stage allows for a device to identify if there is a sleep stage that has been skipped, or ended early. This also allows the program to check large scale correlations for artifacts in the readings that are specific to a specific stage before a seizure occurs.
Once the data analysis is automated, Ray is looking towards how to detect, prevent, and interrupt night seizures. In order to accurately predict when a night seizure is going to occur, there needs to be identification and automatic detection of pre-markers of the seizures. While the seizure prediction models are still in the future for Ray, he imagines a noninvasive device that can measure the child’s sleep, and detect markers for a seizure. This device would then be able to wake the child or warn the caregivers before the seizure would occur. There is still work to be done in the development of a device like this, but Ray is looking forward for his work to be useful for therapeutic devices in the future.
Ray has presented this work at the Computation Neuroscience Conference in 2019 and has had his manuscript, “Circadian Regulation of Sleep in a Pre-Clinical Model of Dravet Syndrome: Dynamics of Sleep Stage and Siesta Re-entrainment” accepted into Sleep.