Research efforts in the Buchanan laboratory are focused on understanding basic mechanisms of epilepsy and sleep-wake regulation. We are particularly interested in the effects of seizures and vigilance state on cardio-respiratory control and how these may interact to lead to death following a seizure, or sudden unexpected death in epilepsy (SUDEP). We employ behavioral, surgical, electrophysiological, molecular, and histological techniques in conjunction with a variety of seizure induction methods to address our research questions. Our goal is to understand factors that render a given seizure fatal in an effort to help prevent SUDEP.
Mechanisms of hypercapnia-induced arousal from sleep:
Carbon dioxide potently induces arousal from sleep. Such arousal is a key component of diseases such as obstructive sleep apnea and the sudden infant death syndrome (SIDS), and is likely important in SUDEP. Serotonin (5-HT) neurons comprise part of the ascending arousal system (AAS) and as such are involved in sleep wake regulation. 5-HT neurons, including those that may contribute to the AAS, are chemosensitive, increasing their firing rate in response to acidosis. Dysfunction of the 5-HT system has been implicated in all of the above mentioned diseases. With his mentor, Dr. George Richerson, Dr. Buchanan has shown that 5-HT neurons are important for CO2-induced arousal from sleep. Work in our lab continues to probe mechanisms of CO2-induced arousal from sleep. Ongoing studies are aimed at determining which serotonergic neuron populations are responsible for CO2-induced arousal, identifying downstream effector sites after stimulation of 5-HT neurons with CO2, and understanding larger network mechanisms underlying CO2 induced arousal.
Mechanisms of seizure-related death with relevance to sudden unexpected death in epilepsy (SUDEP)
SUDEP is the leading cause of death in patients with refractory epilepsy. Among neurological diseases, SUDEP is second only to stroke in years of potential life lost to disease. Respiratory, cardiac, autonomic and primary electrocerebral etiologies have been proposed for SUDEP. An on-going line of research in the lab is geared toward understanding how a seizure can result in death. We have first been attempting to establish models of increased seizure susceptibility and mortality. We are beginning to employ these models to understand serotonergic mechanisms in cardio-respiratory control during and after a seizure, post-ictal arousal mechanisms, and seizure-related death.
State-dependence of seizures, epilepsy and SUDEP
SUDEP occurs commonly during the night and during sleep. There is evidence that at least a subset of these cases may be attributed to reduced supervision and delayed resuscitation efforts, or to the patients being in the prone position during sleep. However, the influences of sleep state on epilepsy and on cardiac and respiratory physiology suggest that sleep state may be an independent risk factor for SUDEP. We have established experimental paradigms to assess the cardio-respiratory consequences of seizures that occur during different sleep states. We are now working to probe possible mechanisms for the sleep state dependence of SUDEP.