Sudden unexpected death in epilepsy (SUDEP) is defined as the sudden, unexpected, nontraumatic, and nondrowning death in people with epilepsy. SUDEP is currently acknowledged as the most important epilepsy-related mode of death and affects up to 5000 patients a year in the United States [Moghimi and Lhatoo, 2013]. Ictal or postictal cardiac arrhythmias, central hypoventilation or apnea, and neurogenic pulmonary edema have been postulated as the mechanisms of SUDEP. Among these categories, autonomic dysregulation appears to be a common element [Cheshire, 2013]. Animal studies show that there is either imbalance or overactivity of the autonomic nervous system preceding SUDEP ...view middle of the document...
Abnormalities of serotoninergic nuclei have been described in DBA/2J mice model of SUDEP [Paterson et al., 2006]. Studies showed that selective serotonin reuptake inhibitors could reduce seizure-related respiratory arrest in rodents and humans [Kanner, 2009]. But the underlying regulatory mechanism is not clear. Understanding the mechanisms of how abnormal brain activities, cardiac arrhythmias and respiration are regulated via 5-HT and vagus nerve may lead to effective prevention and treatment of SUDEP. I plan to test my central hypothesis by pursuing the following two specific aims:
1. Testing the hypothesis that vagus nerve mediates the transduction of brain and cardiac signals in SUDEP.
In this aim, we will take advantage of the DBA/2J mice, which is the most well-established model of SUDEP [Venit et al., 2004]. When exposed to pure tone sound at an intensity of 122dB, DBA/2J mice exhibit audiogenic seizure, followed by respiratory arrest and sudden death. The expected result is that vagus nerve mediates a well-organized coupling between electrical activities of the brain and the heart during SUDEP, and blocking the activity of vagus nerve could prevent SUDEP. We will test the hypothesis in three subaims:
(1) Test if there is sequential coupling between brain oscillations, vagus nerve activity and heart rhythm during SUDEP using advanced signal processing algorithms in Matlab.
(2) Test if specifically blocking or overactivating vagus nerve could lead to the changes in...